bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–05–24
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.
  2. Aortic Segments-Depending Hypertensive Remodeling Is Driven by Mitochondrial Fusion Dysfunction.
  3. Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.
  4. Formoterol Induced Mitochondrial Biogenesis and PINK1-Parkin Mitophagy via activation of β2-Adrenergic Receptor Signaling and Downregulation of miR-421/miR-103a in Acute Kidney Injury.
  5. Mitophagy in cardiovascular diseases: a literature review.
  6. Deficiency of FUNDC1-mediated mitophagy impairs macrophages immunometabolism to drive Sepsis-induced immunosuppression.
  7. Jintiange ameliorates age-related sarcopenia by inhibiting the cGAS-STING signaling pathway via maintaining mitochondrial homeostasis.
  8. Qilin Pills Protect Against Diminished Ovarian Reserve by Suppressing Pathological Overactivation of PINK1/Parkin-Mediated Mitophagy in Granulosa Cells.
  9. Targeted degradation of aberrant Tau for the discovery of Pulsatilla chinensis in Alzheimer's disease.
  10. Investigation of the modulatory effects of fabomotizole and/or sertraline on cisplatin nephrotoxicity via in vivo and in vitro approaches: insights into the role of Sig-1R/ERK1/2 signaling in regulating mitochondrial dynamics and apoptotic cellular death.
  11. Targeting mitochondrial fission-autophagy axis in rheumatoid arthritis: leflunomide promote apoptosis of fibroblast-like synoviocytes.
  12. Nestin promotes imatinib resistance in gastrointestinal stromal tumors by enhancing PINK1-dependent mitophagy.
  13. CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats.
  14. Advances in mitophagy research in hepatocellular carcinoma: mechanisms and therapeutic implications.
  15. FAM72A Knockdown Drives Cell Mitophagy and Pyroptosis in Ovarian Cancer Via the PINK1/Parkin Pathway.
  16. Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
  17. Supervised machine learning identifies impaired mitochondrial quality control in β-cells with development of type 2 diabetes.
  18. Fusobacterium nucleatum-induced mitophagy in macrophages supports intracellular bacterial persistence and promotes esophageal squamous cell carcinoma metastasis.
  19. Exercise-Induced Lactate Is Associated with the Modulation of Mitophagy and Ferroptosis and Reduced Amyloid-Beta and Tau in Type 2 Diabetes.
  20. Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
  21. Antioxidant Proline Carbon Dot-Composited Poly(L-methionine) Hydrogel Restores Mitophagy to Alleviate Cellular Senescence in Intervertebral Disc Degeneration.
  22. Transmembrane protein 106C promotes lung adenocarcinoma progression through GSPT1-mediated compensatory mitophagy.
  23. Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.
  24. Dapagliflozin attenuates cisplatin-induced nephrotoxicity in rats through modulation of ROS/NF-κB, BCL2/Bax and PINK1/Parkin signaling pathways.
  25. Mitochondrial micro-nano reactors via enhancing mitochondrial transfer and mitophagy for alleviating metabolic crisis.
  26. A sono-piezoelectric scaffold prompts disc regeneration by activating Ca2+/CaMKII/Parkin-mediated mitophagy.
  27. Deficiency of LAMP2A in macrophages accelerates hypoxia-induced atherosclerosis by inhibiting BNIP3-mediated mitophagy.
  28. Naringin and hesperidin protect ovarian granulosa cells from cisplatin-induced mitochondrial dysfunction by enhancing bioenergetics and mitophagy.
  29. Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
  30. Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
  31. Herba Lysimachiae Polysaccharide-Modified Selenium Nanoparticles Alleviate Oxidative Injury in Kidney Stones via TOMM22-Regulated Mitophagy Activation.
  32. Mitophagy-Oxidative Stress Molecular Subtypes Define an Immunosuppressive Ecosystem and Vulnerabilities in Glioblastoma.
  33. Mitoredox Shifts in Mitochondrial Dysfunction.
  34. Inhibition of the oncogenic GTPase dynamin-related protein 1 (DRP1) by the FDA-approved drug fosaprepitant: In silico, biophysical, and in vitro characterization of its anti-myeloma activity.
  35. The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
  36. Effect of mitochondrial dysfunction on scar formation after spinal cord injury.
  37. Sevoflurane ameliorates cerebral ischemia-reperfusion injury by modulating mitochondrial dynamics and attenuating apoptosis via Shh-YAP1 signaling pathway.
  38. Corrigendum to "Mechanistic study on nonylphenol-induced depressive-like behavior: PINK1/parkin-mediated mitophagy regulates synaptic remodeling in neurons" [Ecotoxicol. Environ. Saf. 316 (2026) 120149].
  39. A defined multi-metabolite formulation derived from Salvia miltiorrhiza alleviates obesity-associated cardiac lipotoxicity via modulating mitochondrial dynamics.
  40. Mitochondrial Metabolism and Dynamics in Cancer Cells.
  41. Convergent targeting of FUNDC1-dependent mitophagy sensitises and overcomes resistance to EGFR inhibition.
  42. Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
  43. Upregulation of the Mitophagy-Related Gene EXOSC4 Is Associated with Immune Dysregulation in Spinal Cord Injury.
  44. UCHL1-mediated deubiquitination of GLOD4 regulates mitochondrial homeostasis and PTC malignant progression via GLO1.
  45. Multi-omics profiling of the diabetic human heart reveals coupled dysregulation in lipid metabolism, mitophagy, and extracellular matrix remodeling.
  46. Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
  47. Nanoencapsulated chrysin protects against cadmium-induced renal tissue injury through modulation of oxidative stress, inflammatory responses, mitochondrial dysfunction, and apoptotic pathways.
  48. Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.
  49. Blue Light Induces Retinal Ganglion Cell Damage by Stimulating Drp1-Dependent Mitochondrial Fission and Activating NF-κB/NOX4 Axis.
  50. The progress of mitochondrial function and transfer in stem cell regulation and therapy.
  51. From lamellar and storage bodies to mitophagy: a comprehensive view of mitochondrial ultrastructure in differentiated SH-SY5Y cells.
  52. FGF10 mitigated sepsis-induced pulmonary coagulopathy via Nrf2/PINK1/Parkin-modulated mitophagy.
  53. CerS6 orchestrates mitochondrial-immune crosstalk via BNIP3-dependent mitophagy suppression and mtDNA-STING/NLRP3 activation in acute lung injury.
  54. OPA1 in MC4R Neurons Regulates Dietary Fat Intake and Body Weight in Mice.
  55. Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.
  56. Silencing IL2RB attenuates abdominal aortic aneurysm-related pathology in experimental models by partially restoring mitochondrial homeostasis.
  57. Transgenerational persistence of neurodevelopmental disorder-like phenotypes in Drosophila melanogaster.
  58. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  59. Exogenous klotho as an adjunct to dapagliflozin ameliorates diabetic kidney disease by restoring mitophagy and mitigating apoptosis and fibrosis.
  60. Talin1 loss activates DRG neurons to accelerate bone remodeling and fracture healing in mice.
  61. Nanoparticle-based serine replenishment rescues SP1-BNIP3 mitophagy and ameliorates preeclampsia in preclinical models.
  62. AHR Activation Mediates Sodium Pentachlorophenol-Induced Mitochondrial Dysfunction and Cardiomyocyte Apoptosis through Oxidative Stress.
  63. Hybrid dextran/fibronectin nanogels for brain-targeted mitophagy inducer delivery to alleviate neuroinflammation and neuronal loss of Parkinson's disease.
  64. PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage.
  65. Environmental cadmium drives placental senescence and fetal growth restriction via activating CLPP-dependent mitochondrial stress.
  66. A mitochondrial-stress adipocyte-macrophage circuit sustaining metaflammation in human type 2 diabetic adipose tissue.
  67. Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.
  1. Acta Diabetol. 2026 May 22.
    Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.
    Wenkai Fu, Junqi Wang, Zhijiang Guo, Sang-Bing Ong, Yong Gao, Hang Zhu, Junyan Wang, Zhiyong Du, Miao Meng, Xing Chang.
      Diabetic cardiomyopathy (DCM) is a major contributor to the cardiovascular complications associated with diabetes. This condition is characterized by structural and functional abnormalities of the myocardium that occur independently of factors such as hypertension or other established cardiac diseases. In this review, we focus on the mitochondrial quality control (MQC) system, a critical determinant in the pathogenesis of DCM. In the diabetic milieu, chronic hyperglycemia and lipid overload disrupt mitochondrial homeostasis, leading to oxidative stress, impaired energy metabolism, and dysregulated mitochondrial dynamics. These disturbances serve as precursors to severe pathological outcomes, including cardiomyocyte death, myocardial fibrosis, and the progression of heart failure. This paper systematically examines the four pillars of MQC regulation-mitochondrial dynamics, selective autophagy (mitophagy), mitochondrial biogenesis, and the mitochondrial unfolded protein response (UPRmt)-and discusses how dysregulation of these regulatory networks contributes to the development of DCM. We further explore the molecular mechanisms involving key regulators such as Drp1 and Parkin, emphasizing their potential as therapeutic targets. Although current research has identified promising strategies, including hypoglycemic agents, melatonin, and various natural compounds that modulate MQC in preclinical models, translating these findings into clinical practice remains challenging due to species differences and the inherent complexity of MQC regulation. Future research should prioritize multi-target combination therapies and personalized treatment strategies aimed at preserving mitochondrial homeostasis and delaying the progression of DCM.
    Keywords:  Diabetic cardiomyopathy; Mitochondrial homeostasis; Mitochondrial quality control; Oxidative stress
    DOI:  https://doi.org/10.1007/s00592-026-02706-4
  2. FASEB J. 2026 May 31. 40(10): e71937
    Aortic Segments-Depending Hypertensive Remodeling Is Driven by Mitochondrial Fusion Dysfunction.
    Alexis Richard, Alicia Baptista Vicente, Clara Gourhand, Antoine Ducroix, Pauline Robert, Bertrand Toutain, Linda Grimaud, Emilie Vessières, Agnès Toutain-Barbelivien, Guy Lenaers, Juan-Manuel Chao de la Barca, Olivier Fouquet, Daniel Henrion, Céline Fassot, Laurent Loufrani.
      OPA1 haploinsufficiency exacerbates severe hypertension-induced aortic remodeling in a segment-specific manner, revealing differential vulnerability between the suprarenal abdominal aorta (SRAA) and the descending thoracic aorta (DTA). In the SRAA, hypertension activates mitochondrial fission pathways (DRP1, FIS1) and mitophagy markers (PINK1, PARKIN), without triggering full autophagic flux (LC3B, p62). Respiratory chain complexes I and IV are upregulated in hypertensive Opa1+/- mice across both segments, reflecting a compensatory mitochondrial stress response. Apoptotic analysis shows increased TUNEL staining in both regions, while caspase-3 and 9 activation is restricted to the SRAA. Inflammatory profiling reveals a predominance of M1 macrophages, specifically in the SRAA. Morphometric assessment highlights major impacts in SRAA, such as luminal dilation and adventitial thickening, confirmed by in vivo representative ultrasound images. These findings underscore the pivotal role of OPA1 in mitochondrial homeostasis and reveal, for the first time, a region-specific protective function of OPA1 within the aortic wall under severe hypertensive stress. This differential impact, according to aortic segment anatomy and physiology, opens new avenues for hypertension and pathological aorta remodeling therapies.
    Keywords:  Opa1 haploinsufficiency; aortic remodeling; hypertension; mitochondrial dysfunction; segmental vascular vulnerability
    DOI:  https://doi.org/10.1096/fj.202503667R
  3. Brain Dev. 2026 May 17. pii: S0387-7604(26)00048-3. [Epub ahead of print]48(3): 104547
    Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.
    Junxia Li, Qing Zhao, Hongyan He, Xueqin Song.
       OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe hereditary disorder characterized by dystrophin deficiency, leading to progressive muscle weakness. Mitochondrial dysfunction and impaired quality control, particularly via the PTEN-induced putative kinase 1 (PINK1)-E3 ubiquitin ligase PARK2 (PARKIN) mitophagy pathway, are implicated in DMD pathogenesis, but the impact of exercise remains unclear. This study investigated the effects of short-term high-intensity exercise on skeletal muscle pathology and mitophagy in mdx mice.
    METHODS: Skeletal muscle from DMD patients and non-dystrophic controls (CTR) was analyzed for mitochondrial content and PINK1-PARKIN expression. Eight-week-old male mdx and C57 control mice underwent a 5-day rotarod exercise protocol. Muscle pathology was assessed using hematoxylin and eosin (HE), acid phosphatase (ACP), and succinate dehydrogenase (SDH) staining. Mitophagy was evaluated via immunofluorescence for microtubule-associated protein 1 light chain 3 (LC3), cytochrome c oxidase subunit IV (COXIV), and voltage-dependent anion channel (VDAC), as well as western blotting for PINK1 and PARKIN. Transmission electron microscopy (TEM) was used to visualize mitochondrial ultrastructure.
    RESULTS: In DMD patients, skeletal muscle showed reduced mitochondrial content and dysregulated PINK1-PARKIN expression. In mdx mice, basal mitophagy markers were elevated. Short-term high-intensity exercise exacerbated muscle necrosis and inflammation in mdx mice while impairing the activation of PINK1-PARKIN-mediated mitophagy, contrasting with the adaptive response in wild-type mice.
    CONCLUSION: Short-term high-intensity exercise exacerbates skeletal muscle pathology in mdx mice, which is associated with impaired activation of PINK1-PARKIN-mediated mitophagy, underscoring the critical role of mitochondrial quality control in DMD and the need for tailored exercise regimens.
    Keywords:  Duchenne muscular dystrophy; Exercise; Mitophagy; Muscle injury; PINK1-PARKIN pathway
    DOI:  https://doi.org/10.1016/j.braindev.2026.104547
  4. Chem Biol Interact. 2026 May 21. pii: S0009-2797(26)00260-7. [Epub ahead of print] 112152
    Formoterol Induced Mitochondrial Biogenesis and PINK1-Parkin Mitophagy via activation of β2-Adrenergic Receptor Signaling and Downregulation of miR-421/miR-103a in Acute Kidney Injury.
    Gamal A Abourayya, Hend M Selim, Naglaa F Khedr.
       BACKGROUND: Gentamicin (GM) is widely used as antibiotic but limited by its nephrotoxic effects. The kidney's proximal tubules, rich in mitochondria, rely on mitophagy to maintain mitochondrial integrity. However, impaired mitophagy contributes to mitochondrial dysfunction and accelerates acute kidney injury (AKI).
    AIM: This study examined how FT, a long-acting β2-adrenergic receptor (β2-AR) agonist, can reduce GM-induced AKI and restore mitochondrial function by modulating the β2-AR-cAMP-CREB-PGC-1α-NRF1 axis and PINK1-Parkin-dependent mitophagy, as well as the related miR-421 and miR-103a.
    METHODS: Forty male Swiss albino mice were divided into four groups: control, FT (0.1 mg/kg), GM (80 mg/kg, injected i.p. from days 8-14), and FT+GM (0.1 mg/kg FT injected for 14 days and 80 mg/kg GM injected from day 8 to 14). Renal function, histopathology, oxidative stress markers (malondialdehyde (MDA) levels, catalase (CAT) activity), ATP levels, cAMP, CREB, PGC-1α, NRF1 as β2-AR-downstream mediators, and mitophagy/autophagy-associated proteins and miR-421 and miR-103a were assessed.
    RESULTS: FT markedly preserved renal histoarchitecture and ultrastructure observed by electron microscopy, improved renal function, and reduced tubular injury. It significantly decreased serum creatinine, blood urea nitrogen, albumin-to-creatinine ratio, and kidney injury molecule-1, while increasing urinary creatinine (p < 0.001) compared to GM group. FT enhanced CAT activity (p <0.01), reduced MDA (p < 0.001), and elevated ATP levels (p <0.01). Additionally, FT suppressed miR-421 and miR-103a (p < 0.01) gene expression and increased cAMP (p <0.01) concentration, CREB, PGC-1α, NRF1 (p <0.0001), PINK1, Parkin (p <0.05), LC3B (p <0.0001), and Beclin-1 (p <0.01) expressions, while downregulating p62 (p <0.0001) expression compared to GM group.
    CONCLUSION: FT exhibited potent reno-protective effects against GM-induced AKI by restoring mitochondrial homeostasis via β2-AR-cAMP-CREB-PGC-1α-NRF1 axis and PINK1-Parkin-dependent mitophagy and related miR-421 and miR-103a.
    Keywords:  Acute Kidney Injury; Gentamicin; PGC-1α; PINK1; Parkin; cAMP; miR-421/miR-103a; β2-adrenergic receptor
    DOI:  https://doi.org/10.1016/j.cbi.2026.112152
  5. Cardiovasc Diagn Ther. 2026 Apr 24. 16(2): 35
    Mitophagy in cardiovascular diseases: a literature review.
    Ran Zhang, Junyan Zhang, Shuangliang Ma, Li Rao, Zhongxiu Chen.
       Background and Objective: Mitochondria generate nearly 90% of cellular adenosine triphosphate (ATP) and are essential for maintaining cardiac energetic homeostasis. Mitophagy, a selective autophagic process that removes damaged mitochondria, is critical for preserving mitochondrial quality and ensuring cardiomyocyte survival under stress. Given that cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are profoundly influenced by mitochondrial dysfunction, understanding mitophagy has become increasingly important. This review aims to summarize the current mechanistic findings related to mitophagy, examine its roles across major CVDs, and evaluate emerging mitophagy-targeted interventions with potential clinical application.
    Methods: A comprehensive literature search of PubMed was conducted using keywords, including "mitophagy", "cardiovascular disease", "myocardial ischemia-reperfusion", to retrieve relevant studies published in English between January 2020 and March 2025. Original studies, reviews, and clinically relevant reports were included in the literature review to ensure broad coverage of mechanistic and translational findings.
    Key Content and Findings: The review synthesizes current knowledge on canonical and noncanonical mitophagy pathways, as well as their roles in myocardial ischemia-reperfusion injury, heart failure, cardiomyopathies, and metabolic cardiomyopathy. Recent evidence highlights the dual nature of mitophagy, where both insufficient and excessive activation impair cardiac function. The review further discusses innovative therapeutic strategies, including mitochondrial-targeted nanoparticles, small-molecule mitophagy activators, and exercise-induced mitochondrial remodeling, along with their potential benefits and limitations. Key knowledge gaps have been identified, including the tissue-specific regulation of mitophagy and uncertainties surrounding dose-dependent therapeutic activation.
    Conclusions: Mitophagy is a pivotal determinant of mitochondrial homeostasis and cardiac health. While emerging interventions show promise, precise modulation remains challenging. Advancing quantitative assessment tools, defining safe activation thresholds, and developing cell-type-specific targeting strategies will be essential for clinical translation. This review provides a comprehensive framework that may guide future research and inform the development of mitophagy-based therapies for CVDs.
    Keywords:  Mitochondria quality control; cardiovascular diseases (CVDs); mitophagy; mitophagy-targeted therapy
    DOI:  https://doi.org/10.21037/cdt-2025-438
  6. Int Immunopharmacol. 2026 Aug 01. pii: S1567-5769(26)00699-5. [Epub ahead of print]182 116853
    Deficiency of FUNDC1-mediated mitophagy impairs macrophages immunometabolism to drive Sepsis-induced immunosuppression.
    Mingjing Cai, Yawei Wang, Yujie Zhong, Huanyu Wang, Qiuli Li, Wenjing Dai, Yujiao Xie, Mingxin Tang, Lin Shen, Wenying Chen, Ling Yang, Yu Wang, Chunmeng Shi, Lijie Ma.
      Sepsis is a dysregulated host immune response to pathogen infection, characterized by an initial acute hyperinflammatory response followed by persistent immunosuppression. The immunosuppressive phase of sepsis is characterized by a marked impairment in the capacity of monocytes/macrophages to produce pro-inflammatory cytokines, a dysfunction linked to severe mitochondrial metabolic defects. Mitophagy is a crucial cellular process that regulates macrophage inflammation by maintaining mitochondrial homeostasis. FUN14domain- containing 1 (FUNDC1) is a known mitophagy receptor, but its role in macrophages during sepsis-induced immunosuppression remains unclear. In this study, we found that FUNDC1-mediated mitophagy is suppressed in immunosuppressive macrophages. Furthermore, both FUNDC1 knockdown and a cell-penetrating FUNDC1-inhibitory peptide P (CPP-P) further suppressed pro-inflammatory cytokines production in immunosuppressive macrophages. Mechanistic studies demonstrated that suppressing FUNDC1-dependent mitophagy exacerbates metabolic dysfunction of immunosuppressive macrophages. Additionally, CPP-P-treated mice exhibit reduced pro-inflammatory cytokines release and impaired bacterial clearance, resulting in exacerbated lung tissue damage and elevated mortality during the immunosuppressive phase of sepsis. Collectively, our study demonstrates that suppression of FUNDC1-mediated mitophagy in macrophages contributes to the immunocompromised state in sepsis and reveals potential therapeutic targets.
    Keywords:  FUNDC1-mediated mitophagy; Immunometabolism; Macrophages; Sepsis-induced immunosuppression
    DOI:  https://doi.org/10.1016/j.intimp.2026.116853
  7. J Ethnopharmacol. 2026 May 15. pii: S0378-8741(26)00725-7. [Epub ahead of print]368 121873
    Jintiange ameliorates age-related sarcopenia by inhibiting the cGAS-STING signaling pathway via maintaining mitochondrial homeostasis.
    Yuan Xu, Xiao-Li Li, Yi-Xun Guo, Ruo-Bing Wu, Ming-Chao He, Yan Zhang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Jintiange (JTG), a substitute for natural tiger bone, has been approved in China for the treatment of osteoporosis, osteoarthritis and rheumatoid arthritis. Clinical observations indicate that JTG can improve skeletal muscle atrophy and enhance skeletal muscle strength. However, the role and mechanism of action of JTG in sarcopenia remain unclear.
    AIM OF THE STUDY: This study aimed to investigate the therapeutic effects and the underlying mechanisms of JTG on age-related sarcopenia.
    MATERIALS AND METHODS: The 12-month-old male mice were orally treated with three doses of JTG for 3 months. The grip strength, weight-loaded swimming time, muscle mass (quadriceps femoris, gastrocnemius, tibialis anterior and soleus muscles), and the cross-sectional area (CSA) of myofibers were measured. The transcriptomic sequencing, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry were employed. Additionally, the other mice, after oral administration with JTG for 3 months, experienced a 3-month withdrawal period to observe the long-term effects of JTG on skeletal muscle.
    RESULTS: The treatment with JTG significantly enhanced grip strength and muscle mass, extended weight-loaded swimming time, elevated CSA, and up-regulated the expressions of muscular regulatory factors, as well as down-regulated the expressions of MuRF-1 and Atrogin-1 in the ubiquitin-proteasome system. The administration of 12-month-old mice with JTG for 3 months profoundly reduced the expression levels of senescence-associated secretory phenotypes and of age-related markers (β-gal, P53 & P16). JTG improved mitochondrial quality by promoting mitochondrial biogenesis through increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM), restoring mitochondrial dynamics via regulation of mitofusin-1 (MFN-1) and fission 1 (FIS-1), and activating PINK1/Parkin-mediated mitochondrial autophagy. The benefit of JTG on maintaining mitochondrial homeostasis led to the reduction in the leakage of mitochondrial DNA (mtDNA) into cytoplasm, thereby attenuating the activation of cGAS-STING signaling pathway and lowering NF-κB-evoked chronic low-grade inflammation in skeletal muscle, ultimately ameliorating age-related sarcopenia. After drug withdrawal for 3 months, the mice in JTG-treated groups still displayed better muscular performance than those vehicle-treated mice with the same age (18-month-old).
    CONCLUSIONS: JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway.
    Keywords:  Aging; JinTianGe capsule; Mitochondrial; Sarcopenia; Skeletal muscle; cGAS-STING
    DOI:  https://doi.org/10.1016/j.jep.2026.121873
  8. J Ethnopharmacol. 2026 May 20. pii: S0378-8741(26)00714-2. [Epub ahead of print] 121862
    Qilin Pills Protect Against Diminished Ovarian Reserve by Suppressing Pathological Overactivation of PINK1/Parkin-Mediated Mitophagy in Granulosa Cells.
    Fangfang Zhu, Congqi Hu, Shulin Huang, Xiaojing Cao, Xing Li, Yang Song, Mingli Chen, Jing Xiao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Qilin Pills (QLP) is a classic proprietary Chinese medicine derived from Wuziyanzong Pills, a traditional formula originating from the Tang Dynasty. It serves to tonify the kidneys and replenish essence, and is used to enhance fertility. QLP is widely used to treat diminished ovarian reserve (DOR), a condition characterised by ovulatory dysfunction and reduced fertility. However, its mechanism of action remains unclear.
    AIM OF THE STUDY: To investigate the protective effects of QLP against DOR and elucidated the underlying mechanisms.
    MATERIALS AND METHODS: We established a DOR mouse model by cyclophosphamide (CTX) and concurrently administered oral QLP at low, medium, and high doses, with oestradiol valerate (E2V) as the positive control. We evaluated the ovarian function by measuring ovarian index, follicular count, and serum anti-Müllerian hormone (AMH). UHPLC-QTOF-MS and network pharmacology techniques were used to identify therapeutic targets. KGN cells were treated with 4-hydroperoxy cyclophosphamide (4-HC) to mimic in vitro chemotherapy toxicity. Mitochondrial function was assessed by Seahorse XF analysis, JC-1 and MitoSOX Red staining, DHE fluorescence, mtDNA quantification, and transmission electron microscopy. Key gene in PINK1/Parkin related mitophagy were detected by western blotting and immunofluorescence in both ovarian tissue and KGN cells. PINK1 overexpression validated this mechanism.
    RESULTS: In vivo, QLP increased the ovarian reserve of DOR mice by enhancing growing follicles and AMH levels while reducing atrophic follicles and GC apoptosis, with the medium dose showing superior effects to E2V. Network pharmacology analysis of compounds identified by UHPLC-QTOF-MS revealed 166 targets enriched in mitochondrial bioenergetic metabolism and mitophagy pathways. QLP mitigated mitochondrial dysfunction, oxidative stress, and excessive mitophagy in GC. In vitro, QLP medicated serum restored mitochondrial respiratory function and membrane potential while reducing ROS. Mechanistically, CTX/4-HC upregulated PINK1/Parkin and induced excessive mitophagy. Notably, QLP exhibited a non-monotonic dose-response: the medium dose optimally rebalanced this overactivation to protect GC, whereas the high dose appeared to induce mild cellular stress, triggering a compensatory rebound in mitophagy. PINK1 overexpression abrogated QLP's protection, confirming PINK1/Parkin inhibition as essential for its therapeutic action.
    CONCLUSION: QLP prevents DOR by rebalancing the pathological overactivation of PINK1/Parkin-mediated mitophagy, thereby restoring mitochondrial homeostasis. These findings provide evidence for QLP in protecting ovarian function.
    Keywords:  Diminished ovarian reserve; Mitochondrial dysfunction; Mitophagy; PINK1/Parkin pathway; Qilin Pills; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jep.2026.121862
  9. Chin Med. 2026 May 20. pii: 137. [Epub ahead of print]21(1):
    Targeted degradation of aberrant Tau for the discovery of Pulsatilla chinensis in Alzheimer's disease.
    Lan Deng, Can Yin, Xiaogang Zhou, Chi Feng, Jianming Wu, Xiaobing An, Jianing Mi, Lufen Huang, Dalian Qin, Lu Yu, Ting Chen, Anguo Wu.
       BACKGROUND: Alzheimer's disease (AD) is characterized by Tau aggregation, mitochondrial dysfunction, and oxidative stress, yet effective interventions targeting these pathological cascades remain limited. Therapeutic strategies that enhance autophagic and mitophagic clearance, attenuate Tau toxicity, and restore mitochondrial homeostasis are crucial for AD management.
    METHODS: This study investigated the neuroprotective effects of Pulsatilla chinensis extract (PCE) in SH-SY5Y neuronal cells and Caenorhabditis elegans (C. elegans) models of Tauopathy. Autophagic flux was evaluated by GFP-LC3 puncta formation, LC3-II conversion, and p62 degradation. Mitochondrial function was assessed through reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ultrastructural analysis. The roles of autophagy and mitophagy were examined using 3-methyladenine (3-MA) and the Parkin inhibitor AC220. In C. elegans, locomotion, Tau aggregation, oxidative stress, and mitophagosome formation were assessed, and pink-1 knockdown was used to confirm mitophagy dependence.
    RESULTS: PCE significantly enhanced autophagic flux, decreased total and phosphorylated Tau (p-Tau Ser404) levels, and improved neuronal viability. It significantly reduced ROS accumulation, maintained MMP, and preserved mitochondrial morphology under both Tau overexpression and H2O2-induced oxidative stress. Inhibition of autophagy or Parkin-mediated mitophagy negated these protective effects. In C. elegans, PCE ameliorated neuromuscular dysfunction, suppressed Tau inclusions, and reduced oxidative injury, while the loss of pink-1 abolished its benefits, underscoring the critical role of mitophagy.
    CONCLUSION: PCE exerts potent neuroprotective effects by promoting mitophagy, reducing Tau phosphorylation and aggregation, and restoring mitochondrial integrity. These findings reveal a novel mechanism linking mitochondrial quality control with Tau proteostasis and highlight PCE as a promising natural therapeutic candidate for AD.
    Keywords:   Caenorhabditis elegans ; Pulsatilla chinensis extract; Alzheimer’s disease; Mitophagy; SH-SY5Y; Tau
    DOI:  https://doi.org/10.1186/s13020-025-01276-x
  10. Naunyn Schmiedebergs Arch Pharmacol. 2026 May 19.
    Investigation of the modulatory effects of fabomotizole and/or sertraline on cisplatin nephrotoxicity via in vivo and in vitro approaches: insights into the role of Sig-1R/ERK1/2 signaling in regulating mitochondrial dynamics and apoptotic cellular death.
    Aya M Zaki, Mohamed A Khattab, Dalia M El-Tanbouly, Rania M Abdelsalam, Hala F Zaki, Tarek M Abdelghany.
      Mitochondrial dynamics disruption and the proapoptotic proteins activation are reported to be the major protagonists of the pathological alterations in cisplatin-induced nephrotoxicity. This study assessed the impact of modulating Sig-1R activity by fabomotizole and/or sertraline on cisplatin nephrotoxicity focusing on the regulation of renal mitochondrial homeostasis and apoptotic cellular death. Four groups of rats received a single cisplatin injection, and were assigned to: cisplatin control, sertraline-treated, fabomotizole-treated, sertraline + fabomotizole-treated groups, along with a fifth normal control group. In parallel, HEK293 cells were used to evaluate the effects of the tested agents on renal cell viability. Elevated concentrations of sertraline reduced HEK293 cell viability. Additionally, sertraline maintained the noxious effect of cisplatin on mitochondrial homeostasis and renal apoptosis in rats. In contrast, fabomotizole improved cell viability in HEK293 cells exposed to cisplatin. It preserved the structural integrity of the renal tubular cells and suppressed plasma levels of NGAL, BUN and creatinine in cisplatin-intoxicated rats. Electron microscopy revealed that fabomotizole restored mitochondrial homeostasis, as shown by increased mitochondrial density. Mechanistically, fabomotizole downregulated the mitochondrial fission mediator Drp1 while upregulating the mitochondrial fusion mediator Mfn1; this was reflected on the mitochondrial function by reinstating renal ATP content. Furthermore, fabomotizole hindered ERK1/2 activation and reduced the proapoptotic proteins, Bax and Bak along with caspase 3 activity. As demonstrated by the Sig-1R antagonistic effect of sertraline, which notably negated fabomotizole's renoprotective potential, fabomotizole's capacity to preserve stable mitochondrial dynamics and hamper apoptosis following cisplatin nephrotoxicity may be ascribed to its Sig-1R activation-mediated ERK 1/2 inhibition.
    Keywords:  Apoptosis; Cisplatin; ERK1/2; Fabomotizole; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1007/s00210-026-05434-2
  11. Arthritis Res Ther. 2026 May 16.
    Targeting mitochondrial fission-autophagy axis in rheumatoid arthritis: leflunomide promote apoptosis of fibroblast-like synoviocytes.
    Xiaoxue Wang, Jianling Su, Shiqi Feng, Jiaqi Qu, Wei Jiang, Jiping Chen, Xuemei Fan, Yongmei Yu, Jiayi Luo, Yang Li.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint destruction, driven by aberrantly activated fibroblast-like synoviocytes (RA-FLS). Mitochondrial dysfunction, particularly excessive mitochondrial fission, contributes to RA-FLS activation and apoptosis resistance, yet the impact of disease-modifying antirheumatic drugs (DMARDs) on mitochondrial dynamics remains unclear. Here, we examined the correlation between mitochondrial dynamics proteins and RA disease activity and investigated the effects of leflunomide and methotrexate (MTX) on mitochondrial dynamics, autophagy, and apoptosis in RA-FLS and collagen-induced arthritis (CIA) mice. Mitochondrial dynamics proteins in synovial fluid correlated more strongly with disease activity than those in peripheral blood, and were partially normalized in RA patients receiving leflunomide or MTX. Both leflunomide and MTX attenuated TNF-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in RA-FLS. Notably, leflunomide, but not MTX inhibited DRP1 phosphorylation at Ser616, increased reactive oxygen species, and induced apoptosis via the BCL-2/BAX/caspase-3 pathway. Additionally, leflunomide influenced autophagy by promoting LC3B II/I and enhancing p62 expression. In CIA mice, leflunomide reduced the expression and phosphorylation of DRP1 on synovium, increased the expression of OPA1, and alleviated joint inflammation and destruction. These findings identify mitochondrial dynamics as a therapeutic target in RA and suggest that leflunomide promotes apoptosis of RA-FLS by modulating the mitochondrial fission-autophagy axis.
    Keywords:  Fibroblast-like synoviocytes; Leflunomide; Methotrexate; Mitochondrial fission; Rheumatoid arthritis
    DOI:  https://doi.org/10.1186/s13075-026-03828-4
  12. Mol Med. 2026 May 19.
    Nestin promotes imatinib resistance in gastrointestinal stromal tumors by enhancing PINK1-dependent mitophagy.
    Yuehan Yin, Juzheng Peng, Zhijian Huang, Dongsheng Li, Xiangyu Li, Zhengchao Hong, Yuqing Lin, Yulong He, Jiancheng Wang.
       BACKGROUND: Gastrointestinal stromal tumors (GIST) frequently develop secondary resistance to imatinib, which represents a major obstacle to achieving durable clinical benefit. However, the molecular mechanisms underlying acquired resistance remain poorly understood. Nestin, a cytoskeletal protein, has been implicated in tumor progression and cellular stress responses, but its role in imatinib-resistant GIST has not been fully elucidated.
    METHODS: Patient tumor specimens, imatinib-resistant GIST cell lines, and xenograft mouse models were analyzed to evaluate Nestin expression. Functional studies were performed using RNA interference-mediated silencing of Nestin. Mitophagy flux assays were conducted to evaluate mitochondrial quality control. The effects of Nestin modulation on PINK1 stability, mitophagy activity, mitochondrial integrity, and imatinib sensitivity were evaluated both in vitro and in vivo. Clinical correlations between Nestin expression, therapeutic response, and prognosis were also analyzed.
    RESULTS: Nestin expression was significantly upregulated in imatinib-resistant GIST across patient samples, resistant cell lines, and xenograft models. Mechanistically, Nestin stabilized PINK1, thereby enhancing PINK1-dependent mitophagy and preserving mitochondrial integrity under imatinib-induced stress. RNA interference suppression of Nestin reduced PINK1 accumulation, impaired mitophagy, increased mitochondrial damage, and restored imatinib sensitivity in vitro and in vivo. Clinically, elevated Nestin expression was associated with poor therapeutic response and unfavorable prognosis.
    CONCLUSIONS: The Nestin-PINK1 axis is a critical driver of imatinib resistance in GIST. Targeting Nestin-mediated mitophagy may represent a promising therapeutic strategy to overcome imatinib resistance and improve clinical outcomes in patients with GIST.
    Keywords:  Cytoskeleton; Gastrointestinal stromal tumor; Imatinib resistance; Mitophagy
    DOI:  https://doi.org/10.1186/s10020-026-01509-1
  13. Int J Mol Med. 2026 Jul;pii: 197. [Epub ahead of print]58(1):
    CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats.
    Tianzhu Liu, Longqing Zhang, Wei Mei.
      Neuropathic pain arises from an intricate network of interconnected pathophysiological mechanisms, yet the arsenal of effective therapeutic strategies remains frustratingly limited. Accumulating evidence has linked mitochondrial dysfunction to the progression of neuropathic pain. C1q‑tumor necrosis factor‑related protein‑3 (CTRP3), a newly identified adipokine with diverse cytoprotective capacities, has not been previously explored for its role in nociceptive processing. To explore the role of CTRP3 in pain hypersensitivity, pain‑related behavioral assessments were conducted using von Frey filaments and acetone drop method in male rats subjected to spared nerve injury (SNI). To unravel the underlying mechanisms, spinal cord tissues were subjected to western blotting, reverse transcription‑quantitative PCR, immunofluorescence staining, dihydroethidium staining, small interfering RNA (siRNA) technologies and biochemical assays for quantifying oxidative markers. The findings showed that SNI markedly reduced endogenous CTRP3 expression in spinal neurons. Intrathecal administration of recombinant CTRP3 (rCTRP3) alleviated mechanical allodynia and cold hyperalgesia in SNI‑induced rats. Additionally, rCTRP3 treatment enhanced PGC‑1α‑mediated mitochondrial biogenesis, ATF5‑triggered mitochondrial unfolded protein response (UPRmt), and mitigated spinal oxidative stress. Mechanistically, pharmacological inhibition of SIRT1 with EX‑527, or siRNA‑mediated silencing of PGC‑1α or ATF5, reversed the effects of CTRP3 on pain hypersensitivity, mitochondrial biogenesis, UPRmt and oxidative stress. The present study demonstrates that CTRP3 mitigates mechanical allodynia and cold hyperalgesia in male SNI rats by activating spinal SIRT1, thereby enhancing PGC‑1α‑mediated mitochondrial biogenesis and ATF5‑induced UPRmt. CTRP3 may therefore represent a novel therapeutic target for the management of neuropathic pain.
    Keywords:  C1q‑tumor necrosis factor‑related protein‑3; mitochondrial biogenesis; mitochondrial unfolded protein response; neuropathic pain
    DOI:  https://doi.org/10.3892/ijmm.2026.5868
  14. J Gastrointest Oncol. 2026 Apr 30. 17(2): 98
    Advances in mitophagy research in hepatocellular carcinoma: mechanisms and therapeutic implications.
    Qinyu Guo, Hang Wang, Lei Zhu, Hongsong Deng, Zhongyong Jiang.
      Mitophagy, a selective autophagic process crucial for mitochondrial quality control, plays a context-dependent dual role in hepatocellular carcinoma (HCC), functioning as both a tumor suppressor and a promoter of malignancy. This review provides a comprehensive analysis of the mechanistic landscape and therapeutic implications of mitophagy in HCC. We detail how mitophagy influences hepatocarcinogenesis, tumor progression, metabolic reprogramming, and the maintenance of liver cancer stem cells (LCSCs). Central to its function are two primary pathways: the ubiquitin-dependent PINK1/Parkin axis and receptor-mediated pathways such as FUNDC1 and BNIP3/NIX, each demonstrating scenario-specific outcomes that contribute to the complexity of HCC biology. A major focus is placed on mitophagy's significant role in fostering resistance to various therapies, including tyrosine kinase inhibitors (TKIs), chemotherapy, and radiotherapy, thereby presenting a formidable clinical challenge. In response, we critically evaluate emerging therapeutic strategies that target mitophagy. These approaches are strategically bifurcated: one aimed at inhibiting pro-survival mitophagy to sensitize tumors to cell death, and another designed to induce excessive, lethal mitophagy for direct cancer cell eradication. We further explore innovative frontiers that integrate mitophagy modulation with immunotherapy, metabolic intervention, and tumor microenvironment (TME) remodeling. This review underscores mitophagy as a pivotal yet complex therapeutic node in HCC. It concludes that a nuanced, context-dependent understanding of mitophagy's dual functions is essential for developing precise and effective treatment strategies to combat this aggressive cancer.
    Keywords:  Mitophagy; autophagy; hepatocellular carcinoma (HCC); resistance; therapy
    DOI:  https://doi.org/10.21037/jgo-2025-709
  15. Appl Biochem Biotechnol. 2026 May 20.
    FAM72A Knockdown Drives Cell Mitophagy and Pyroptosis in Ovarian Cancer Via the PINK1/Parkin Pathway.
    Songhong Tan, Li Wang, Zhengmei Xu, Rong Tang, Weimin Xie.
      This study explored the role of Family with Sequence Similarity 72 Member A (FAM72A) in regulating mitophagy and pyroptosis via the PINK1/Parkin pathway in ovarian cancer (OC). Bioinformatics analysis and clinical tissue and cell assays revealed that FAM72A was significantly overexpressed in OC. Silencing FAM72A in OC cells suppressed proliferation, invasion, and migration, while promoting apoptosis. Additionally, FAM72A knockdown increased mitochondrial ROS levels, autophagosome-mitochondria colocalization, and the LC3II/I ratio and reduced p62 expression, mitochondrial membrane potential, and ATP levels in OC cells. Downregulation of FAM72A upregulated PINK1 and Parkin expression and increased the expression of pyroptosis-related markers including NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18 in OC cells. Furthermore, the inhibitory effect of FAM72A knockdown was reversed by treating cells with mitochondrial inhibitors or by specifically knocking down PINK1. In vivo experiments confirmed that FAM72A promoted tumor growth by inhibiting the PINK1/Parkin pathway. Conclusively, FAM72A knockdown drives mitophagy and pyroptosis in OC by activating the PINK1/Parkin pathway, highlighting its potential as a therapeutic target for OC.
    Keywords:  FAM72A; Mitophagy; Ovarian cancer; PINK1/Parkin pathway; Pyroptosis
    DOI:  https://doi.org/10.1007/s12010-026-05718-6
  16. J Cell Commun Signal. 2026 Jun;20 e70080
    Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
    Luyang Jiang, Gongsang Cuomu, Sang Jijia, Yumei Yang, Jufen Liu, Yumin Tao.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria-endoplasmic reticulum contact sites, also known as mitochondria-associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER-mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER-mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age-related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER-mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context-dependent strategies. By reframing ophthalmic disorders as diseases of inter-organelle stress integration, this review positions the ER-mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage-specific precision therapies.
    Keywords:  calcium signaling; endoplasmic reticulum–mitochondria crosstalk; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; ophthalmic diseases; unfolded protein response
    DOI:  https://doi.org/10.1002/ccs3.70080
  17. NPJ Syst Biol Appl. 2026 May 18.
    Supervised machine learning identifies impaired mitochondrial quality control in β-cells with development of type 2 diabetes.
    Mirza Muhammad Fahd Qadir, Charles Dana, Madeleine Pittigher, Paul Mauvais-Jarvis, Nazmul Haque, Theodore Dos Santos, Patrick E MacDonald, Kyle J Gaulton, Franck Mauvais-Jarvis.
      Defining molecular pathways driving β-cell failure in type 2 diabetes (T2D) is challenging given donor heterogeneity. We developed an interpretable machine learning framework coupling sparse rule-based classification, pathway constrained modeling, and mitochondrial fitness stratification, applied to single-cell RNAseq from 52 human islet donors. A 50-gene classifier predicted T2D at single-cell resolution, outperforming ensemble models, with donor-level scores correlating with HbA1c. We identified a resilient non-diabetic (ND) β-cell subtype with preserved β-cell identity, while T2D β-cell subtypes showed cellular stress and suppressed oxidative phosphorylation. Mitophagy emerged as the dominant cellular pathway, with PINK1, BNIP3, and FUNDC1 as predictors. At the donor level, PINK1 expression decreased with T2D score and correlated with sex‑specific mitophagy patterns. We developed a mitochondrial fitness index (MFI, R² = 0.934) integrating mitophagy, proteostasis, biogenesis, and respiration, identifying PINK1, SQSTM1, PRKN, and BNIP3 as top T2D contributors. Interpretable machine learning revealed mitophagy as central to β-cell metabolic fitness.
    DOI:  https://doi.org/10.1038/s41540-026-00742-y
  18. Cell Mol Immunol. 2026 May 22.
    Fusobacterium nucleatum-induced mitophagy in macrophages supports intracellular bacterial persistence and promotes esophageal squamous cell carcinoma metastasis.
    Fangfang Chen, Yulin Liu, Han Xiao, Xiaoyun Pan, Shuyi Luo, Yiqiu Li, Shengxin Chen, Songhe Guo, Ge Zhang.
      The facultative intracellular bacterium Fusobacterium nucleatum (Fn) promotes tumorigenesis and progression in esophageal squamous cell carcinoma (ESCC). The intracellular survival strategy of Fn and whether Fn can spread through cell‒cell contact in intratumoral tissues and, if so, the underlying mechanisms and implications are currently unknown. Here, we report that Fn accumulates in macrophages from ESCC tumors and paracancerous normal tissues. We further revealed that Fn-induced macrophage mitophagy through the PINK1-Parkin-independent pathway decreases excessive mitochondrial ROS production to promote survival. Furthermore, Fn drives a biphasic metabolic switch between glycolysis and oxidative phosphorylation in macrophages to support the bioenergetic demands of survival. Notably, Fn can be carried by macrophages to tumor sites, where it promotes tumor metastasis via the CCL2-CCR2 axis in ESCC. Treatment with a mitochondrial division inhibitor (mdivi-1) reduced the intracellular Fn concentration and inhibited Fn-positive tumor metastasis in mice. This study highlights the crucial interactions between Fn and host macrophages that influence tumor progression. These findings indicate that mitophagy inhibitors or mitophagy machinery targeting may serve as efficient therapeutic strategies to treat Fn-positive tumors.
    Keywords:   Fusobacterium nucleatum ; Energy metabolism; Esophageal cancer; Intracellular survival; Metastasis; Mitophagy
    DOI:  https://doi.org/10.1038/s41423-026-01426-7
  19. Iran Biomed J. 2026 01 01. 30(1): 67-80
    Exercise-Induced Lactate Is Associated with the Modulation of Mitophagy and Ferroptosis and Reduced Amyloid-Beta and Tau in Type 2 Diabetes.
    Pouria Khosravi, Fereshteh Shahidi, Arezoo Eskandari, Kayvan Khoramipour.
       Background: Type 2 diabetes (T2D) is associated with increased oxidative stress, impaired mitophagy, enhanced ferroptosis, and the accumulation of amyloid beta (Aβ) and hyperphosphorylated tau in the hippocampus. Exercise-induced lactate exerts neuroprotective effects via mitochondrial quality control and redox-regulating pathways. This study investigated whether high-intensity interval training (HIIT)-induced lactate accumulation can attenuate Aβ and tau pathology in diabetic rats by modulating mitophagy and ferroptosis-related protein signaling, as it remains unclear how HIIT-induced lactate impacts these pathways in T2D.
    Methods: Thirty-two male Wistar rats were assigned to control (CO), exercise (EX), diabetes (DB), and diabetes + exercise (DB+EX) groups. T2D was induced using a high-fat diet and streptozotocin (35 mg/kg). The EX and DB+EX groups performed treadmill-based HIIT (4-10 intervals at 80-100% maximum running velocity). We measured serum lactate levels and the hippocampal protein levels of MCT2, SIRT1, BDNF, p62, Keap1, NRF2, MDA, GPX4, PINK1, parkin, Aβ, and Tau using standard laboratory methods.
    Results: The DB group exhibited a significant increase in hippocampal oxidative stress markers and accumulation of Aβ and Tau compared to the control groups. In contrast, the DB + EX group showed elevated serum lactate levels and higher hippocampal protein levels of MCT2, SIRT1, BDNF, p62, NRF2, GPX4, PINK1, and Parkin. This group also demonstrated reduced levels of Keap1, MDA, Aβ, and Tau relative to the DB group.
    Conclusion: HIIT enhanced mitophagy and reduced ferroptosis in the hippocampus of T2D rats, coinciding with the activation of lactate-SIRT1-BDNF and p62-Keap1-NRF2 pathways and reduced Aβ and Tau accumulation.
    Keywords:  Ferroptosis; High-intensity interval training; Lactate; Mitophagy; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.61882/ibj.5311
  20. Mitochondrion. 2026 May 19. pii: S1567-7249(26)00061-9. [Epub ahead of print] 102171
    Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
    Yu-Ting Wu, Hui-Yi Tay, Hsiao-Hui Liao, Jung-Tse Yang, Yau-Huei Wei.
      Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A > G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A > G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.
    Keywords:  MERRF syndrome; Mitophagy; N-acetylcysteine; PINK1; iPSC-derived neural stem cells (iNSCs); iPSC-derived neurons; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.mito.2026.102171
  21. Adv Mater. 2026 May 21. e72951
    Antioxidant Proline Carbon Dot-Composited Poly(L-methionine) Hydrogel Restores Mitophagy to Alleviate Cellular Senescence in Intervertebral Disc Degeneration.
    Zongtai Liu, Qingzheng Zhang, Haochen Yao, Changfeng Fu, Yirong Sun, Jianxun Ding.
      The senescence of nucleus pulposus cells (NPCs) is a hallmark pathological feature of intervertebral disc degeneration. Senescent NPCs exhibit mitochondrial dysfunction and impaired mitophagy, thus compromising mitochondrial turnover and quality control. Current therapeutic strategies predominantly target external risk factors but do not restore mitophagy. In this study, a proline carbon dot-composited poly(L-methionine) (EG45M25/Pro-CD) hydrogel is developed and employed to re-establish the impaired mitophagy pathway. Expression levels of Parkin and phosphorylated Parkin increase, indicating successful activation of the mitophagy pathway. Restoration of mitochondrial function markedly reduces oxidative stress and the senescence-associated secretory phenotype in NPCs. The levels of type II collagen and aggrecan recover to 84.63% and 77.31% of their normal ones, respectively. In an animal model, the administration of Pro-CD in a thermo-sensitive and injectable hydrogel effectively preserves the water content and height of intervertebral discs while maintaining the structural integrity and functional activity of NPCs. The mean Pfirrmann grade improves from 5.00 in the Control group to 3.33 after treatment, whereas the disc height index recovers to 82.06% of the physiological value. Collectively, our findings demonstrate that the EG45M25/Pro-CD composite hydrogel has therapeutic potential to promote endogenous disc regeneration by enhancing mitophagy, re-establishing redox homeostasis, and alleviating NPC senescence.
    Keywords:  alleviation of intervertebral disc degeneration; attenuation of cell senescence; attenuation of oxidative stress; carbon dot‐composited hydrogel; promotion of mitophagy
    DOI:  https://doi.org/10.1002/adma.72951
  22. Int J Biol Macromol. 2026 May 20. pii: S0141-8130(26)02566-3. [Epub ahead of print] 152639
    Transmembrane protein 106C promotes lung adenocarcinoma progression through GSPT1-mediated compensatory mitophagy.
    Xueting Wang, Motong Xu, Lingxin Feng, Lu Wang, Qi Qi, Yanan Liang, Xue Yang, Zhuang Yu, Jing Wang.
      Despite advances in lung adenocarcinoma (LUAD) therapy, 5-year survival remains low, necessitating new targets. In this study, TMEM106C and GSPT1 expressions were evaluated using qRT-PCR and Western blot. The targeting relationship between TMEM106C and GSPT1 was validated by RNA-sequencing, RNA immunoprecipitation, and cycloheximide tracing assays. Functional effects of cells were assessed through CCK-8, colony formation, flow cytometry, wound healing, and Transwell. Western blot was used to study the expression of autophagy-related markers. The changes in mitophagy after transfection or treatment were observed by GFP-mRFP-LC3 fluorescence, transmission electron microscopy, and mitochondria-specific markers. In vivo effects were verified in nude mouse models. The results showed that TMEM106C was significantly upregulated in TCGA-LUAD dataset, clinical samples, and LUAD cells, correlating with poor prognosis. Silencing TMEM106C suppressed the growth and metastatic potential of A549 and H1299 cells while increasing apoptotic cell death. Similarly, TMEM106C knockdown suppressed xenograft tumor growth and tumor weight, whereas overexpression had the opposite effect. GSPT1 is a downstream gene of TMEM106C, and its overexpression reversed the inhibitory function of TMEM106C silencing on lung cancer growth, migration, and invasion-associated phenotypes. Moreover, GSPT1 promoted Parkin ubiquitination and was associated with altered Parkin turnover under mitochondrial stress, accompanied by enhanced compensatory mitophagy. In H1299 cells, TMEM106C silencing impaired compensatory mitophagy and increased apoptosis, whereas restoration of GSPT1 partially rescued the tumor-suppressive effects of TMEM106C silencing. In summary, TMEM106C promotes LUAD progression by maintaining GSPT1 expression and enhancing compensatory mitophagy, accompanied by altered Parkin ubiquitination and reduced apoptosis.
    Keywords:  Apoptosis; GSPT1; Lung adenocarcinoma; Mitophagy; TMEM106C
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152639
  23. Food Funct. 2026 May 15.
    Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.
    Xiaocong Li, Yi Xiao, Fang Liu.
      Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPRmt) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPRmt pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.
    DOI:  https://doi.org/10.1039/d6fo00251j
  24. Sci Rep. 2026 May 17. pii: 15227. [Epub ahead of print]16(1):
    Dapagliflozin attenuates cisplatin-induced nephrotoxicity in rats through modulation of ROS/NF-κB, BCL2/Bax and PINK1/Parkin signaling pathways.
    Esraa K Khallaf, Eman A Ramadan, Mohey M Elmazar, Marwa M Safar.
      Dapagliflozin (DPG), an anti-diabetic drug, has gained attention for its renal protective effects through multiple molecular pathways, yet its impact on mitophagy in cisplatin (CIS) nephrotoxicity remains unclear. This study aimed to examine the impact of DPG against CIS-induced nephrotoxicity in rats, targeting mainly PINK1/Parkin-mediated mitophagy and inflammatory/apoptotic pathways. Male Sprague Dawley rats received DPG (10 mg/kg; p.o) daily for 14 consecutive days and AKI was induced by a single injection of CIS (7 mg/kg; i.p) on day 10. Blood glucose, serum levels of creatinine and urea nitrogen, oxidative stress, inflammatory, apoptotic, mitophagy markers, and histological changes were assessed. DPG reduced glomerular and tubular damage by alleviating NGAL and KIM-1 protein expression as well as MDA and NO accompanied by enhanced GSH expression. It mitigated gene expression of NF-κB, TNF-α and IL-6 along with downregulation of Bax and upregulation of BCL2 mRNA expression. DPG prevented apoptotic activity through reduction in cleaved caspase-3 immunoreactivity. Moreover, DPG restored CIS-mediated mitophagy inhibition evidenced by elevation of PINK1, Parkin and LC3II/LC3I ratio and reduction of TIMM23, TOMM20 and p62. In conclusion, DPG prevents CIS nephrotoxicity probably, via activating PINK1/Parkin, meanwhile attenuating oxidative stress and apoptotic activity.
    Keywords:  Acute kidney injury (AKI); Apoptosis; Cisplatin; Dapagliflozin; Mitophagy; Sodium-glucose cotransporter-2 (SGLT-2) inhibitors
    DOI:  https://doi.org/10.1038/s41598-026-50755-0
  25. Bioact Mater. 2026 Sep;63 975-997
    Mitochondrial micro-nano reactors via enhancing mitochondrial transfer and mitophagy for alleviating metabolic crisis.
    Jiayi Mao, Wenzheng Xia, Minxiong Li, Xin Huang, Yun Zhao, Zheyuan Hu, Yinghong Su, Juan Wang, Wenguo Cui, Tao Zan.
      Energy metabolic dysfunction is a major cause of impaired chronic wounds healing, in which disrupted mitochondrial transfer and autophagy imbalance further aggravate the cellular energy crisis. In this study, single-cell RNA sequencing (scRNA-seq) of clinical diabetic wound samples first identified a pivotal role for macrophage-to-fibroblast mitochondrial transfer in wound healing. This finding was further validated using diabetic wound models and histological analyses, highlighting these processes as potential therapeutic targets for alleviating energy metabolic stress. Based on these findings, we innovatively developed a mitochondrial micro-nano reactor (MtNR) that alleviates the energy metabolic crisis by concurrently enhancing mitochondrial transfer and autophagy. First, hypoxic-preconditioning combined with gene-edited techniques was used to generate M2 macrophage-derived mitochondria-trained apoptotic bodies (mABs). Subsequently, mABs were conjugated with piezoelectric short fibers (PSFS) via copper-free strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry to self-assemble into MtNR. This system promotes intercellular mitochondrial transport through the Miro1-mitochondria-dynein-microtubule complex. It also generates bionic electrical signals via mechano-electrical conversion, thereby restoring Pink1-Parkin-P62/SQSTM1-LC3-mediated mitophagy and mitochondrial homeostasis. In a diabetic mouse wound model, MtNR restored mitochondrial morphology, enhanced cellular energy biogenesis, reduced p62 accumulation, increased LC3 expression, and significantly promoted tissue repair, providing a promising therapeutic strategy for addressing the energy deficit in diabetic wounds.
    Keywords:  Apoptotic bodies; Energy metabolism; Mitochondrial transfer; Mitophagy; Piezoelectricity
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.03.048
  26. Biomaterials. 2026 May 15. pii: S0142-9612(26)00340-6. [Epub ahead of print]334 124316
    A sono-piezoelectric scaffold prompts disc regeneration by activating Ca2+/CaMKII/Parkin-mediated mitophagy.
    Haiyang Gao, Wenbo Wu, Xianglong Chen, Pengzhi Shi, Anran Zhang, Wang Wu, Zimu Yu, Cao Yang, Zhangrong Cheng, Yukun Zhang.
      Mitochondrial dysfunction in nucleus pulposus (NP) cells is a key driver of intervertebral disc degeneration (IDD), leading to metabolic imbalance and cellular senescence. To address this, we developed an injectable "sono-electrical coupling" hydrogel (GBC@PNA) based on a thermosensitive P(NIPAM-AAM) network loaded with gallic acid, barium titanate and carbon nanotubes. Upon ultrasound exposure, the scaffold generates a localized micro-electric field and controllably releases gallic acid. This combined stimulation significantly enhanced the viability of degenerated NP cells, promoted extracellular matrix synthesis, and reduced inflammation and senescence in vitro. Mechanistically, the sono-electrical effect activated intracellular calcium signaling, leading to CaMKII-dependent mitochondrial translocation and phosphorylation of Parkin, thereby restarting PINK1/Parkin-mediated mitophagy to clear damaged mitochondria and restore energy metabolism. This pathway was systematically validated through transcriptomics, protein interaction and functional inhibition studies. In a rat IDD model, the intervention effectively maintained disc height, improved histology and delayed degeneration, demonstrating good biosafety. This work pioneers a strategy that couples external physical energy with intracellular mitochondrial quality control, offering a novel "sono-electro-chemical" therapy for IDD and a new paradigm for "energy-biology"-based tissue engineering.
    Keywords:  GBC@PNA hydrogel; Intervertebral disc degeneration; Mitophagy; Sono-electrical coupling; Tissue engineering
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124316
  27. Int Immunopharmacol. 2026 May 20. pii: S1567-5769(26)00701-0. [Epub ahead of print]183 116855
    Deficiency of LAMP2A in macrophages accelerates hypoxia-induced atherosclerosis by inhibiting BNIP3-mediated mitophagy.
    Ning Wang, Zhiyuan Wang, Pinpeng Xie, Weichun Zhu, Zehao Chen, Jieqiong Peng, Longjin Xu, Dan Xu, Kang Fu, Wentao Chen, Chungang Zhai, Wenqiang Chen, Lei Qiao.
      Chaperone-mediated autophagy (CMA) is a critical biological process responsible for degrading proteins in lysosomes. Our previous studies demonstrated that impaired CMA in macrophages accelerated atherosclerosis under normoxic conditions. Hypoxia is an independent risk factor for atherosclerosis, and the role of CMA in atherosclerosis under hypoxic conditions is not clear. In this study, we generated myeloid-specific LAMP2A-knockout mice and LAMP2A-deficient THP-1 macrophage cells to investigate the role of CMA in hypoxia-induced atherosclerosis. We found that the expression of LAMP2A, the rate-limiting component of CMA, was increased in peripheral blood mononuclear cells (PBMCs) from patients with obstructive sleep apnoea syndrome (OSAS) and in atherosclerotic plaques of ApoE-/- mice exposed to hypoxic conditions. Furthermore, knockout of LAMP2A in macrophages promoted the development of atherosclerosis in vivo under hypoxic conditions, along with an obvious impairment of mitophagy in atherosclerotic plaques and in LAMP2A-deficient THP-1 macrophages. Mechanistically, LAMP2A deficiency impaired mitophagy by inhibiting the expression of NIX/BCL2-interacting protein 3 (BNIP3) via miR-134-5p, while upregulation of BNIP3 restored mitophagy function in LAMP2A-deficient macrophages. In conclusion, our study demonstrated that deficiency of LAMP2A in macrophages accelerated hypoxia-induced atherosclerosis, partially through the inhibition of BNIP3-mediated mitophagy via miR-134-5p.
    Keywords:  Atherosclerosis; BNIP3; Chaperone-mediated autophagy; Hypoxia; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2026.116855
  28. Biol Direct. 2026 May 22.
    Naringin and hesperidin protect ovarian granulosa cells from cisplatin-induced mitochondrial dysfunction by enhancing bioenergetics and mitophagy.
    Jiying Liu, Ekramy M Elmorsy, Ahmed Abdeen, Nuha Anajirih, Farouk S Elgendy, Heba M Abdelkareem, Hend E Nasr, Sania K Elwia, Mai A Sherif, Noha O El-Shaer, Hend S El-Wakeel, Mustafa Shukry, Samah F Ibrahim, Shaymaa Ali, Mohammed A Gebba, Amal S Abu-Almakarem, Qingda Ge.
       BACKGROUND: Cisplatin (CDDP) is a widely deployed chemotherapeutic medication used to treat various solid tumors, but its clinical utility is limited by dose-dependent ovarian toxicity. Naringin (NG) and hesperidin (HD) are two naturally occurring flavonoids found in citrus fruits and have protective effects on mitochondrial function.
    RESULTS: The current study examined the protective effects of NG and HD on CDDP-induced mitochondrial dysfunction and cytotoxicity in granulosa cells. The cells are treated with CDDP alone or with NG or HD. CDDP reduced cell viability, ATP synthesis, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), and mitochondrial complex functions in a dose-dependent pattern. It also altered mitochondrial dynamics and enhanced glycolytic activity, as exhibited by lactate levels. MMF increased, and fatty acid composition changed, resulting in a higher unsaturated/saturated ratio. PINK1 and PARKIN levels were reduced upon CDDP treatment, suggesting mitophagy disruption. Co-treatment of NG and HD enhanced complex activity, MMP, OCR, ATP generation, and cell viability. MMF was protected by NG and HD, which also stabilized fatty acids and enhanced ion permeability and mitochondrial swelling. Compared to NG, HD preserved numerous attributes more effectively and restored them almost completely.
    CONCLUSIONS: NG and HD effectively preserve mitochondrial bioenergetics, structure, and dynamics in granulosa cells, mitigating CDDP-induced dysfunction. These findings highlight their potential as natural adjuvants to reduce ovarian toxicity and support fertility preservation in female cancer patients.
    Keywords:  Bioenergetics; Chemotherapy; Mitochondrial complexes; Mitochondrial membrane potential; Mitophagy; Molecular docking; PINK1/PARKIN pathway
    DOI:  https://doi.org/10.1186/s13062-026-00830-3
  29. Pharmacol Res. 2026 May 18. pii: S1043-6618(26)00142-8. [Epub ahead of print] 108227
    Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
    Julia Brechtel, Christine Lietz, Selin Akpinar Adscheid, Kristina Friedland.
      Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.
    Keywords:  Alzheimer’s Disease; Mitochondria-Targeted Therapies; Mitochondrial Dynamics; Mitochondrial Dysfunction; Parkinson’s Disease; Phytochemicals; Small Molecule
    DOI:  https://doi.org/10.1016/j.phrs.2026.108227
  30. Free Radic Biol Med. 2026 May 20. pii: S0891-5849(26)00771-9. [Epub ahead of print]
    Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
    XueXia Liu, XiaoXin Wang, FuJun Liu.
      Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.
    Keywords:  Extracellular vesicles; Mesenchymal stromal cells; Mitochondrial transfer; Redox homeostasis; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.291
  31. Adv Sci (Weinh). 2026 May 19. e75784
    Herba Lysimachiae Polysaccharide-Modified Selenium Nanoparticles Alleviate Oxidative Injury in Kidney Stones via TOMM22-Regulated Mitophagy Activation.
    Junyi Yang, Guoruiyu Lyu, Wenlong Wan, Dongfeng Yuan, Jiabo Li, Yongqi Wang, Baokang Wang, Zhilong Ma, Yuanyuan Yang, Yang Xun, Xiao Yu.
      Pharmacological treatments for kidney stones remain limited, with oxidative stress and injury to renal tubular epithelial cells (RTECs) as key pathological drivers. We prepared a novel Herba Lysimachiae polysaccharide-modified selenium nanoparticle (HLP-SeNPs) formulation that enhances the stability and antioxidant activity of selenium nanoparticles (SeNPs) to alleviate oxalate-induced renal injury. In vivo and in vitro studies showed that HLP-SeNPs possess pronounced anti-oxidative stress capacity, restore mitochondrial membrane potential, alleviate mitochondrial damage, reduce RTEC death, and inhibit renal calcium oxalate (CaOx) crystal deposition. Mechanistically, HLP-SeNPs downregulate TOMM22 (translocase of the outer mitochondrial membrane 22, a core TOM complex subunit) to activate PINK1-Parkin-mediated mitophagy, thereby effectively limiting oxidative stress-induced injury at its source. These findings indicate that HLP-SeNPs exert substantial renoprotective effects and prevent CaOx stone formation, providing an experimental foundation for mitochondria-targeted nanotherapeutics in kidney stone disease and highlighting the potential of integrating traditional Chinese medicine with nanomaterials.
    Keywords:  Herba Lysimachiae polysaccharide; TOMM22; kidney stones; mitophagy; selenium nanoparticles
    DOI:  https://doi.org/10.1002/advs.75784
  32. J Cell Mol Med. 2026 May;30(10): e71154
    Mitophagy-Oxidative Stress Molecular Subtypes Define an Immunosuppressive Ecosystem and Vulnerabilities in Glioblastoma.
    Changjiang He, Yang Wang, Hongliang Zhong.
      Glioblastoma (GBM) is an aggressive brain tumour with an immunosuppressive environment and poor prognosis; however, the roles of mitophagy and oxidative stress in its prognosis remain underexplored. This study analysed multi-omics data from TCGA-GBM (n = 168) and two GEO cohorts (GSE43378, n = 50; GSE147352, n = 85), compiling 603 mitophagy and oxidative stress-related genes. Unsupervised consensus clustering identified molecular subtypes, and prognostic genes were found via univariate Cox regression, leading to a refined gene signature using LASSO. The tumour immune microenvironment was characterized with ESTIMATE, CIBERSORT, and ssGSEA, while immunotherapy response was predicted using TIDE and IPS. Drug sensitivity was evaluated with GDSC and CTRP data, and a clinical nomogram integrating the gene signature and clinical variables was constructed and validated. Two molecular subtypes, C1 and C2, showed different prognoses (HR = 0.64, p = 0.011) and immune profiles. A 7-gene signature indicated high-risk patients had worse survival (p < 0.001) and an immunosuppressive environment. The risk score correlated with anti-PD-1 response (p < 0.05) and predicted therapy sensitivity. The signature was an independent prognostic factor (HR = 3.37, p < 0.001), and the nomogram accurately predicted survival at 1, 3, and 5 years. An innovative prognostic signature from mitophagy and oxidative stress genes stratifies GBM patients, characterizes the immunosuppressive microenvironment, and identifies therapeutic vulnerabilities for personalized treatment.
    Keywords:  glioblastoma; immunotherapy; mitophagy oxidative stress; prognostic signature; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.71154
  33. Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]
    Mitoredox Shifts in Mitochondrial Dysfunction.
    Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.
      Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.
    Keywords:  Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.307
  34. Int J Biol Macromol. 2026 May 20. pii: S0141-8130(26)02560-2. [Epub ahead of print] 152633
    Inhibition of the oncogenic GTPase dynamin-related protein 1 (DRP1) by the FDA-approved drug fosaprepitant: In silico, biophysical, and in vitro characterization of its anti-myeloma activity.
    Emanuela Marchese, Pierpaolo Murfone, Ilenia Valentino, Maria Eugenia Gallo Cantafio, Francesca Alessandra Ambrosio, Irene Gado, Noemi Puccio, Massimo Gentile, Antonino Neri, Giuseppe Viglietto, Stefano Alcaro, Francesca Vasile, Giosuè Costa, Nicola Amodio.
      Mitochondrial fission plays a crucial role in sustaining cellular homeostasis, and disturbances in this process have been linked to numerous pathological conditions, including cancer. The central regulator of mitochondrial division is the large GTPase dynamin-related protein 1 (DRP1), whose enzymatic activity drives the constriction and separation of mitochondria. Given its pivotal function, DRP1 has gained attention as a potential oncogenic target across several cancer types. However, the availability of small-molecule inhibitors targeting DRP1 remains limited. To discover novel inhibitors, we performed a virtual screening campaign of FDA-approved drugs obtained from the DrugBank database, leading to the identification of three compounds predicted to interact with the GTPase domain of DRP1. Among these, the antiemetic agent fosaprepitant emerged as a promising hit. Computational docking and GTPase activity assays supported its inhibitory potential, which was further confirmed through saturation transfer difference nuclear magnetic resonance (STD-NMR) spectroscopy, demonstrating direct binding between fosaprepitant and DRP1 and elucidating key contact sites. Consistent with inhibition of mitochondrial fission, fosaprepitant treatment in multiple myeloma (MM) cell lines induced mitochondrial hyperfusion, decreased cell viability and colony formation in a DRP1-dependent manner, and disrupted oxidative phosphorylation (OXPHOS), ultimately leading to mitochondrial dysfunction and apoptotic cell death. Overall, this study provides a robust platform for the identification of novel DRP1 inhibitors among FDA-approved compounds, highlighting fosaprepitant as a promising candidate for drug repurposing with anti-cancer potential.
    Keywords:  Drug repurposing; Dynamin-related protein 1; Fosaprepitant; Mitochondrial dynamics; STD-NMR; Virtual screening
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152633
  35. Cardiovasc Toxicol. 2026 May 20. pii: 53. [Epub ahead of print]26(6):
    The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
    Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh.
      Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPRmt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPRmt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPRmt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPRmt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPRmt signaling, and suggest that activation of the UPRmt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.
    Keywords:  ATF5; CHOP; Cardiomyocytes; Cardiotoxicity; Doxorubicin; Mitochondria; UPRmt ; eIF2α
    DOI:  https://doi.org/10.1007/s12012-026-10124-9
  36. Front Neurol. 2026 ;17 1782114
    Effect of mitochondrial dysfunction on scar formation after spinal cord injury.
    Yuchen Zhang, Zhengxin Jin, Bin Ning.
      Spinal cord injury (SCI) triggers a cascade of primary and secondary pathological events that culminate in the formation of glial and fibrotic scars, which constitute a major barrier to axonal regeneration and functional recovery. Emerging evidence highlights mitochondrial dysfunction as a central driver of this process. Mitochondria are essential for sustaining ATP production, maintaining redox balance, and regulating calcium homeostasis. Following SCI, direct mechanical disruption, oxidative stress, and calcium overload impair mitochondrial integrity, leading to energy metabolism collapse, excessive reactive oxygen species (ROS) accumulation, and disrupted mitochondrial dynamics. These alterations promote reactive gliosis, fibroblast activation, and maladaptive extracellular matrix deposition. Furthermore, defective mitophagy amplifies neuroinflammation and glial scar consolidation through the PINK1/Parkin and BNIP3/NIX pathways. Recent advances in mitochondrial-targeted therapies-including antioxidants (MitoQ, SS-31), metabolic modulators (AMPK agonists, NAD+ precursors), and strategies enhancing fusion or mitophagy-have demonstrated promising results in reducing scar formation and promoting neural repair. In addition, cutting-edge approaches such as mitochondrial transplantation, stem cell-derived mitochondrial transfer, and CRISPR-based mitochondrial gene editing provide new opportunities for restoring mitochondrial homeostasis. This review summarizes the multifaceted roles of mitochondrial dysfunction in SCI-induced scar formation and discusses novel therapeutic strategies targeting mitochondrial metabolism and dynamics to enhance neural regeneration.
    Keywords:  fibrotic scar; glial scar; mitochondrial dynamics; mitochondrial dysfunction; oxidative stress; spinal cord injury
    DOI:  https://doi.org/10.3389/fneur.2026.1782114
  37. Mol Brain. 2026 May 21.
    Sevoflurane ameliorates cerebral ischemia-reperfusion injury by modulating mitochondrial dynamics and attenuating apoptosis via Shh-YAP1 signaling pathway.
    Li Peng, Mengmeng Yang, Jiayuan Liu, Tianyue Yin, Jun Li, Shuaijie Sun, Hongrui Zhu, Sheng Wang.
      Ischemia-reperfusion injury (IRI) is a critical issue in the prevention and treatment of ischemic stroke. Inhalational anesthetics have been proven to have neuroprotective effects and sevoflurane is currently the most commonly used inhaled anesthetic in the clinic. However, the effects and underlying mechanism of sevoflurane on cerebral IRI have not been fully elucidated. In this study, oxygen-glucose deprivation model was established in primary mouse cortical neurons and HT22 cells, while the middle cerebral artery occlusion model was established in mice. Using laser speckle imaging, TTC staining, HE staining, Nissl staining, flow cytometry, calcium imaging and neurologic deficit scoring, we found that sevoflurane post-conditioning (SPC) significantly increased cerebral blood flow, reduced the infarct volume, alleviated neuronal pathological damage, promoted the survival of cortical neurons, reduced cell apoptosis, enhanced calcium responses and decreased the neurologic deficit scores after IRI. The results of RNA sequencing, Western blot, co-immunoprecipitation, TUNEL staining, immunofluorescence, transmission electron microscopy imaging, MPTP measurement, MMP detection, and ATP production measurement showed that the sonic hedgehog (Shh) signaling pathway crosstalk with Hippo-YAP signaling pathway, and the Shh-YAP1 pathway regulated mitochondrial dynamics and mitochondrial ultrastructure and function. In addition, SPC affected the phosphorylation and SUMOylation of dynamin-related protein 1 (Drp1), and there was an interaction between the phosphorylation and SUMOylation of Drp1. In conclusion, this study revealed that SPC might affect the phosphorylation and SUMOylation of Drp1 through the Shh-YAP1 signaling pathway, regulating mitochondrial dynamics, reducing cell apoptosis and ameliorating IRI. These findings offer new insights into the therapeutic strategies for ischemic stroke.
    Keywords:  Apoptosis; Ischemic stroke; Mitochondrial dynamics; SUMOylation; Sevoflurane; Sonic hedgehog
    DOI:  https://doi.org/10.1186/s13041-026-01312-3
  38. Ecotoxicol Environ Saf. 2026 May 18. pii: S0147-6513(26)00613-5. [Epub ahead of print] 120284
    Corrigendum to "Mechanistic study on nonylphenol-induced depressive-like behavior: PINK1/parkin-mediated mitophagy regulates synaptic remodeling in neurons" [Ecotoxicol. Environ. Saf. 316 (2026) 120149].
    Huawen Yu, Jie Yu, Xiao Yang, Feng Wang, Kai Pan, Feng Li, Ya Luo, Jianliang Zhang, Zhenghao He, Jie Xu.
      
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120284
  39. Front Pharmacol. 2026 ;17 1674821
    A defined multi-metabolite formulation derived from Salvia miltiorrhiza alleviates obesity-associated cardiac lipotoxicity via modulating mitochondrial dynamics.
    Hetong Xu, Jing Kong, Ruoyu Wu, Zefei Chu, Weiya Zhang, Xiaoyi Zhao, Zhongxia Zhang, Shengjun An.
       Background: Obesity is a major risk factor for lipotoxic cardiomyopathy, a process involving lipid metabolism disorders, inflammatory responses, and mitochondrial dysfunction. Salvia miltiorrhiza (Danshen), a traditional Chinese medicinal plant, contains water-soluble metabolites with multitarget regulatory potential. Although some monomers of S. miltiorrhiza have been proved to be effective in cardiovascular diseases, the combined effects of metabolites and the mechanism remains unclear. This study aimed to investigate the cardioprotective effects and potential mechanisms of SABP, a defined formulation of four metabolites derived from S. miltiorrhiza (danshensu, salvianolic acid A, salvianolic acid B, and protocatechuic aldehyde), against lipotoxic myocardial injury, with a focus on the regulation of mitochondrial dynamics.
    Methods: A palmitic acid (PA)-induced lipotoxicity model in H9c2 cardiomyocytes and a high-fat diet (HFD)-induced obesity model in ApoE -/- mice were established. In vitro, the effects of SABP on cell viability (CCK-8), mitochondrial membrane potential (JC-1), mitochondrial dynamics-related proteins (Drp1, Fis1, Mfn2, Opa1), and apoptosis-related proteins (cleaved caspase-3, caspase-3) were assessed. In vivo evaluations involved fat distribution (Micro-CT), cardiac function (echocardiography), cardiac structure (HE, Masson staining, and TEM), serum lipid levels, inflammatory factors, cardiac enzyme activity (ELISA), and protein expression analysis in cardiac tissue (Western blot).
    Results: In vitro results showed that SABP significantly improved PA-induced reductions in cell viability and mitochondrial membrane potential, downregulated Drp1 and Fis1, upregulated Opa1 and Mfn2, and decreased the cleaved caspase-3/caspase-3 ratio. In vivo, SABP intervention reduced heart weight index and heart-tibia ratio, improved left ventricular systolic function, decreased fat accumulation and serum lipid abnormalities, attenuated inflammatory cytokine and myocardial enzyme levels, alleviated myocardial structural damage and fibrosis, and restored mitochondrial morphology. Western blot findings in cardiac tissue were consistent with in vitro results.
    Conclusion: SABP may protect against cardiac lipotoxic injury by improving lipid metabolism, reducing inflammation, and restoring mitochondrial dynamics homeostasis, highlighting its potential as a multi-component herbal therapy for metabolic cardiomyopathy and providing experimental support for the development of such plant-derived therapeutics targeting this disease.
    Keywords:  SABP; Salvia miltiorrhiza; lipotoxic cardiomyopathy; mitochondrial dynamics; obesity
    DOI:  https://doi.org/10.3389/fphar.2026.1674821
  40. Cancer Treat Res. 2026 ;195 109-120
    Mitochondrial Metabolism and Dynamics in Cancer Cells.
    Pedram Fadavi, Farzad Taghizadeh-Hesary.
      Cancer metabolism has long been interpreted through Otto Warburg's original observation that malignant cells favor aerobic glycolysis due to defective mitochondria. Although foundational, this view is now recognized as incomplete. Contemporary evidence demonstrates that mitochondria in cancer cells remain highly functional and play indispensable roles far beyond adenosine triphosphate (ATP) production. Many tumors actively engage mitochondrial oxidative phosphorylation (OXPHOS) alongside glycolysis, enabling metabolic flexibility across the heterogeneous tumor microenvironment (TME). Mitochondria also generate reactive oxygen species (ROS) that stabilize hypoxia-inducible factor-1 (HIF-1), reinforcing pathways that promote angiogenesis, invasion, and survival under hypoxic stress. Beyond bioenergetics and redox regulation, mitochondria critically shape cancer progression through calcium homeostasis and dynamic remodeling. Meanwhile, mitochondrial fusion and fission govern organelle quality control and functional redistribution. Fusion sustains OXPHOS and cancer stem cell quiescence, whereas fission promotes proliferation, migration, immune evasion, and therapy resistance. Collectively, these findings establish mitochondria as central regulators of tumor evolution, influencing survival in the TME, immune escape, malignant upgrading, and resistance to chemotherapy, radiotherapy, and immunotherapy. Understanding mitochondrial biology, therefore, provides essential insight into cancer progression and reveals promising therapeutic opportunities.
    Keywords:  ATP; Calcium homeostasis; Cancer; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/978-3-032-21861-2_6
  41. Clin Transl Med. 2026 May;16(5): e70685
    Convergent targeting of FUNDC1-dependent mitophagy sensitises and overcomes resistance to EGFR inhibition.
    Fan Xu, Xiaoshan Wang, Min Li, Yi Li, Xiaojuan Li, Qingqing Yan, Fanming Kong, Qihong Huang, Xin Cao, Ying Xue.
      Combination therapies are critical for enhancing and prolonging the efficacy of EGFR inhibitors. Here, we uncover FUNDC1-dependent mitophagy as a key protective mechanism in EGFR-mutant non-small cell lung cancer (NSCLC). We discover that nitidine, a bioactive component of the traditional Xihuang Pill formulation, synergises with the EGFR inhibitor osimertinib. Mechanistically, nitidine and osimertinib synergistically disrupt FUNDC1-mediated mitophagy, leading to mitochondrial dysfunction and accumulation of reactive oxygen species in EGFR-mutant NSCLC. We further show that both osimertinib and nitidine decrease HIF-1α protein levels, thereby downregulating FUNDC1 expression. Nitidine-induced downregulation of HIF-1α and FUNDC1 depends on the mitochondrial transporter ABCB6. Notably, acquired resistance to osimertinib exhibits adaptive downregulation of FUNDC1, rendering resistant EGFR-mutant NSCLC cells more sensitive to nitidine. Collectively, these findings position nitidine as a promising therapeutic strategy to enhance the efficacy of EGFR inhibitors and overcome osimertinib resistance in EGFR-mutant NSCLC.
    Keywords:  ABCB6; EGFR‐mutant NSCLC; FUNDC1‐mediated mitophagy; mitochondrial dysfunction; nitidine; osimertinib resistance
    DOI:  https://doi.org/10.1002/ctm2.70685
  42. bioRxiv. 2026 May 05. pii: 2026.05.01.718031. [Epub ahead of print]
    Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
    Praveen Kumar Guttula, Ganesan Muthusamy, Chin-Chi Liu, Priscilla Devora, Emi Sasaki, Tyler Butsch, Hasand Gandhi, James Moran, Manas Ranjan Gartia, Andrea N Johnston.
      The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the complex transition from hepatic steatosis to hepatocellular carcinoma. PGAM5 is a serine/threonine/histidine phosphatase that plays a role in mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Increased expression of PGAM5 in hepatocellular carcinoma is correlated with reduced patient survival. In this study, we demonstrate that loss of PGAM5 alters the bioenergetic landscape of liver cancer by promoting mitochondrial oxidant injury and suppressing the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion downregulates fatty acid biosynthesis, resulting in reduced cellular diacylglycerol concentrations through two probable mechanisms: attenuated long chain fatty acid uptake and suppressed de novo synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 to disrupt lipid metabolism in hepatocellular carcinoma.
    DOI:  https://doi.org/10.64898/2026.05.01.718031
  43. Mol Neurobiol. 2026 May 21. pii: 642. [Epub ahead of print]63(1):
    Upregulation of the Mitophagy-Related Gene EXOSC4 Is Associated with Immune Dysregulation in Spinal Cord Injury.
    Xiaoqin Liu, MengFan Li, Jiating Hu, PanFeng Fang, Yuxin Ma, Ziyu Guo, Hongqiang Wang, Chao Xu.
      Spinal cord injury (SCI) profoundly impairs patients' quality of life and imposes a substantial economic burden on society, often resulting in irreversible neurological deficits. To investigate the involvement of mitophagy-related genes (MRGs) in SCI, the GSE151371 dataset, comprising 38 SCI samples and 10 healthy control samples from the Gene Expression Omnibus (GEO) database, was analyzed. Key genes linking mitophagy to SCI pathogenesis were identified through an integrative approach combining differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning. A total of 1138 differentially expressed genes (DEGs) were identified between SCI patients and healthy controls (HC), among which 31 overlapping signature genes were shared between MRGs and WGCNA-derived module genes. Functional enrichment analysis revealed that these genes were mainly involved in biological processes related to neurotransmission and membrane dynamics. Machine learning-based feature selection identified seven hub genes, of which EXOSC4 was the only candidate consistently validated in the independent GSE45006 dataset. Immune infiltration analysis further demonstrated a pro-inflammatory microenvironment in SCI, characterized by increased neutrophil and macrophage infiltration. Single-cell RNA sequencing analysis using the GSE162610 dataset showed that Exosc4 exhibited the highest mean expression in macrophage and endothelial cell populations. Moreover, quantitative PCR, Western blotting, and immunofluorescence analyses confirmed that EXOSC4 expression was significantly upregulated in SCI tissues. Collectively, these findings suggest that EXOSC4 may play an important role in SCI pathophysiology and has potential value as a diagnostic biomarker and therapeutic target. Despite limitations, including a relatively small sample size and the absence of clinical validation, this study highlights the significance of mitophagy-related gene regulation in SCI and provides a foundation for future studies aimed at validating EXOSC4 in larger cohorts and exploring its therapeutic relevance.
    Keywords:  Machine learning; Mitophagy; Spinal cord injury; WGCNA
    DOI:  https://doi.org/10.1007/s12035-026-05899-5
  44. Mol Cell Biochem. 2026 May 21.
    UCHL1-mediated deubiquitination of GLOD4 regulates mitochondrial homeostasis and PTC malignant progression via GLO1.
    Lei Cai, Li-Yuan Qian, Wei Wu, Bo-Ni Ding, Zi-Run Luo, Juan Du.
      Papillary thyroid carcinoma (PTC) is prone to metastasis, and patients with metastatic PTC have a poor prognosis. This study aimed to investigate the function of GLOD4 in PTC. Cancerous and paracancerous tissues were collected from patients with PTC. CO-IP was performed to detect the level of GLOD4 or ubiquitination modification, as well as to verify protein interactions of GLOD4 with UCHL1 or GLO1. Cell proliferation was detected by CCK-8 or EdU staining, cell migration and invasion by transwell assay, GLO1 enzyme activity by ELISA, total and mitochondrial methylglyoxal levels by commercial kits, mitochondrial ROS levels by flow cytometry, and oxygen consumption rate and ATP levels by seahorse energy metabolism analyzer. GLOD4 knockdown subcutaneous xenograft model was constructed in nude mice, HE staining was used to detect the histopathological condition of the tumor, and IHC was used to detect Ki67 and GLOD4 expression. GLOD4 levels were significantly upregulated in PTC tissues and cells, and overexpression of GLOD4 enhanced PTC cell proliferation, migration, and invasion. Mechanistically, UCHL1 could directly bind to GLOD4 and enhance its protein stability by promoting K48-linked deubiquitination, whereas the ability of GLOD4 to promote invasion and migration in PTC cells depends on this regulatory function of UCHL1. Furthermore, GLOD4 regulated GLO1 to detoxify methylglyoxal, a toxic by-product of glycolysis, to maintain mitochondrial homeostasis. GLOD4 knockdown inhibited PTC tumor growth in vivo. UCHL1 enhances the protein stability of GLOD4 through deubiquitination, promoting its interaction with GLO1 to cooperatively detoxify methylglyoxal, maintain mitochondrial homeostasis, and ultimately drive PTC progression.
    Keywords:  GLO1; GLOD4; Mitochondrial homeostasis; Papillary thyroid cancer; UCHL1
    DOI:  https://doi.org/10.1007/s11010-026-05574-2
  45. Genome Med. 2026 May 18.
    Multi-omics profiling of the diabetic human heart reveals coupled dysregulation in lipid metabolism, mitophagy, and extracellular matrix remodeling.
    Qiuhan Lu, Shulin Tang, Sijia Fang, Yuwen Wu, Liang Chen, Mintong Liang, Jiaqi Chen, Pengju Wen, Leigang Jin, Jianshe Yu, Feng Jiao, Yueheng Wu, Guozhi Jiang.
       BACKGROUND: Diabetic cardiomyopathy (DbCM) is a major complication of type 2 diabetes whose molecular basis in human hearts remains poorly understood. This study aimed to define the multi-omics landscape of DbCM in the human myocardium.
    METHODS: We performed integrated transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic analysis on left ventricular tissues from matched Chinese cohorts: DbCM (n = 11), non-diabetic cardiomyopathy (n = 11), and healthy donors (n = 4). Key findings were validated by histological assessment and western blotting of candidate proteins. External validation was conducted using public datasets, and phenotypic support was derived from mouse models.
    RESULTS: Multi-omics profiling revealed distinct, coordinated dysregulation in DbCM. Proteomics and transcriptomics profiling revealed a rewired fatty acid oxidation-mitophagy axis characterized by elevated acyl-CoA synthetase long-chain family member 1 (ACSL1) and suppressed fatty acid synthase (FASN), impaired mitochondrial quality control marked by a significant reduction in the mitophagy regulator BNIP3L, which showed a strong inverse correlation with ACSL1, and disrupted extracellular matrix homeostasis, with specific downregulation of key structural components (COL5A1, COL5A2, and fibrillin-1). Metabolomics confirmed enhanced but incomplete fatty acid oxidation, evidenced by triglyceride depletion and accumulation of acylcarnitines and lipotoxic lipids. Integrated multi-omics identified impaired BNIP3L-associated mitophagy as a potential molecular node associated with lipid metabolic dysregulation with mitochondrial dysfunction.
    CONCLUSIONS: This human multi-omics study defines DbCM by the concurrent dysregulation of cardiac fuel metabolism, mitochondrial quality control, and matrix remodeling, offering novel mechanistic insights and highlighting ACSL1 and BNIP3L as potential therapeutic targets for diabetes-associated cardiac dysfunction.
    Keywords:  Cardiomyopathy; Diabetes; Lipid metabolism; Matrix remodeling; Mitophagy; Multi-omics
    DOI:  https://doi.org/10.1186/s13073-026-01668-0
  46. Mol Neurodegener. 2026 May 16.
    Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
    Prabhavathi Maddineni, Balasankara Reddy Kaipa, Bindu Kodati, Karthikeyan Kesavan, Linya Li, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode.
       BACKGROUND: Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma. We further explore the therapeutic potential of enhancing autophagy to improve mitochondrial turnover, mitigate RGC loss, and preserve visual function.
    METHODS: Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers (TOM20/COX IV), oxidative DNA damage (8-OHdG), and mitophagy/autophagy-related proteins (p62, LC3, Phospho-ubiquitin (Ser65), and LAMP1) in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation in glaucomatous ON. Mitophagy flux was assessed at early and late stages of neurodegeneration using mitophagy reporter Mt-Keima mice. The effect of RGC-specific autophagy deficiency on mitochondrial accumulation and neurodegeneration was further investigated using Atg5flox/flox mice, in which Atg5 deletion was induced by AAV2-Cre delivery. Additionally, the therapeutic effect of enhancing autophagy with Torin 2 to restore mitochondrial turnover and prevent glaucomatous neurodegeneration was evaluated in both GC-induced and myocilin-associated glaucoma models, as well as in ex vivo human retinal explants.
    RESULTS: Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In Mt-Keima mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration. RGC-specific Atg5 deletion induced the accumulation of damaged mitochondria, leading to neurodegeneration in Atg5 flox/flox mice. Notably, pharmacological restoration of impaired autophagy with Torin 2 prevented mitochondrial accumulation and preserved the structural and functional integrity of RGCs and their axons in glaucoma mouse models and ex vivo human retinal explant cultures.
    CONCLUSION: Our study indicates impaired autophagy contributes to damaged mitochondrial accumulation and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing autophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.
    Keywords:  Autophagy; Glaucoma; Intraocular pressure; Mitochondrial dysfunction; Mitophagy; Mouse models of glaucoma; Neurodegeneration; Optic neuropathy; Oxidative DNA damage; Torin 2
    DOI:  https://doi.org/10.1186/s13024-026-00950-4
  47. Tissue Cell. 2026 May 18. pii: S0040-8166(26)00313-7. [Epub ahead of print]102 103620
    Nanoencapsulated chrysin protects against cadmium-induced renal tissue injury through modulation of oxidative stress, inflammatory responses, mitochondrial dysfunction, and apoptotic pathways.
    Ekramy M Elmorsy, Ayat B Al-Ghafari, Huda A Al Doghaither, Muhammad Jan, Syed Sajid Hussain Shah, Asmara Syed, Eman M Fawzy, Gehad E Elshopakey.
       BACKGROUND: Cadmium (Cd) is a major environmental nephrotoxicant that induces renal injury through oxidative stress, inflammatory activation, mitochondrial dysfunction, and apoptosis, resulting in marked tissue and ultrastructural damage. This study evaluated the protective effects of chrysin (Chry) and casein nanoparticle-encapsulated chrysin (Chry-Cas-NPs) against Cd-induced renal injury, with emphasis on mitochondrial homeostasis and cellular integrity.
    METHODS: Sixty male Wistar rats were allocated into six groups (control, Chry, Chry-Cas-NPs, Cd, Cd + Chry, Cd + Chry-Cas-NPs; n = 10). CdCl₂ (5 mg/kg/day, orally) was administered for eight weeks, while Chry and Chry-Cas-NPs were given one hour before Cd exposure. Renal function markers, oxidative stress indices, inflammatory mediators, mitochondrial bioenergetics, mitophagy-related parameters, apoptotic markers, histopathology, and ultrastructural alterations were assessed.
    RESULTS: Cd exposure caused significant renal dysfunction accompanied by elevated oxidative stress, depletion of GSH, SOD, and CAT, increased NO/iNOS production, and upregulation of TNF-α, IL-1β, and IL-6. Mitochondrial dysfunction was evident by reduced ATP generation, impaired respiratory chain complex activities, downregulation of mitochondrial regulatory genes, and suppression of mitophagy. These alterations were associated with enhanced apoptotic signaling, tubular degeneration, glomerular injury, mitochondrial swelling, and cristae disruption. Chry partially improved these changes, whereas Chry-Cas-NPs showed superior efficacy by restoring antioxidant defenses, preserving mitochondrial function, enhancing mitophagy, suppressing inflammation and apoptosis, and markedly improving renal histological and ultrastructural architecture.
    CONCLUSION: Casein nanoencapsulated chrysin confers marked renoprotection against Cd-induced renal tissue injury through coordinated modulation of oxidative stress, inflammation, mitochondrial dysfunction, mitophagy, and apoptosis.
    Keywords:  Chrysin Casein-nanoencapsulation Mitochondrial dysfunction; Mining-associated nephrotoxicity, Cadmium nephrotoxicity; Mitophagy; NF-κB–mediated inflammation; Oxidative stress; Renal ultrastructure
    DOI:  https://doi.org/10.1016/j.tice.2026.103620
  48. Front Physiol. 2026 ;17 1721230
    Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.
    Guanheng He, Qian Sun.
      Macrophage functional plasticity is intrinsically linked to metabolic reprogramming, including mitochondrial function, substrate utilization, and redox signaling. In response to hypoxia, infection, or tissue injury, macrophages rely on mitochondria not only for energy provision but, critically, for metabolic intermediates and reactive oxygen species (ROS) that serve as signaling molecules to guide gene expression reprogramming. While macrophage activation exists along a continuous spectrum, this review summarizes the distinct metabolic paradigms characterizing the classical M1-like (glycolysis-dominant) and M2-like (oxidative phosphorylation, OXPHOS-dominant) extremes, highlighting the molecular mechanisms where metabolic events-specifically tricarboxylic acid (TCA) cycle truncation and succinate accumulation-drive inflammatory polarization. Furthermore, we discuss the role of mitochondrial quality control, particularly dynamics and mitophagy, in maintaining macrophage homeostasis. Notably, recent evidence identifies "intercellular mitochondrial transfer" as a novel mode of immune microenvironment regulation, enabling damaged macrophages to restore function by acquiring exogenous mitochondria. A deeper understanding of these mechanisms offers new intervention targets for metabolic immunotherapy in sepsis, cancer, and chronic inflammatory diseases. Importantly, we emphasize that many of these metabolic and mitochondrial regulatory mechanisms are highly context-dependent, varying significantly across different tissues and disease microenvironments.
    Keywords:  intercellular mitochondrial transfer; macrophage polarization; metabolic reprogramming; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2026.1721230
  49. Invest Ophthalmol Vis Sci. 2026 May 01. 67(5): 62
    Blue Light Induces Retinal Ganglion Cell Damage by Stimulating Drp1-Dependent Mitochondrial Fission and Activating NF-κB/NOX4 Axis.
    Xin-Hao Han, Tao Wang, Gui-Feng Sun, Xin Xie, Kun Zhang, Xiao-Yu Wang, Zhen Zhang, Xing Wang, Xin-Hui Qu, Xiao-Jian Han.
       Purpose: This study aimed to investigate the mechanisms of blue light-induced neurotoxicity in retinal ganglion cells (RGCs), focusing on the roles of mitochondrial dynamics and oxidative stress.
    Methods: The impact of blue light exposure was assessed in vitro and in vivo. Key molecular changes were analyzed, and the effects of pharmacological inhibition of Drp1 and/or NOX4 were evaluated on mitochondrial function and RGC apoptosis.
    Results: Blue light triggered mitochondrial fission by upregulating Drp1 and downregulating MFN2. This disruption promoted the nuclear translocation and phosphorylation of p65, which subsequently enhanced NOX4 transcription and increased mitochondrial reactive oxygen species (ROS) production. Inhibiting either Drp1 or p65 suppressed NOX4 expression and ROS generation. Furthermore, combined inhibition of Drp1 and NOX4 effectively restored mitochondrial function and reduced RGC apoptosis.
    Conclusions: Both Drp1 and NOX4 contribute to blue light-induced RGC damage, and our findings highlight the importance of the Drp1/mitochondrial fission/p65/NOX4 signaling axis in this process, leading to oxidative stress. Targeting this signaling axis represents a promising therapeutic strategy for preventing blue light-induced retinal injury.
    DOI:  https://doi.org/10.1167/iovs.67.5.62
  50. J Physiol Biochem. 2026 May 21. pii: 53. [Epub ahead of print]82(1):
    The progress of mitochondrial function and transfer in stem cell regulation and therapy.
    Yubing Zhang, Zhuojian Qu, Zhiliang Guo, Lijuan Zhang, Hong Li, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Wenxu Wang, Min Cheng.
      Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.
    Keywords:  Mitochondrial function; Mitochondrial transfer; Mitophagy; Reactive oxygen species; Stem cell regulation
    DOI:  https://doi.org/10.1007/s13105-026-01192-0
  51. Ultrastruct Pathol. 2026 May 20. 1-41
    From lamellar and storage bodies to mitophagy: a comprehensive view of mitochondrial ultrastructure in differentiated SH-SY5Y cells.
    Jacques Gilloteaux, Valérie Suain, Corry Charlier, Charles Nicaise.
      Differentiated human SH-SY5Y neuroblastoma cells used to model neurodegenerative defects, cholinergic neuron differentiation, neurotropic virus infection, and neurotoxicity have not been comprehensively studied with fine structure. Our goal is thus to further disclose their cytology. Differentiated in vitro with retinoic acid (RA), SH-SY5Y cells were processed for fine structure analyses with transmission, scanning electron microscopy, and X-ray spectroscopy microanalysis. The neoplastic cells showed typical high nucleus: cytoplasm ratio with neuron-like profiles extending to one long neurite that can carry dense core vesicles and associated cytoskeletons. Among the organelles, one-fifth of mitochondria profiles were noted to bear prominent anomalies of both outer and internal membranes. These organelles formed bursts, long or folded lamellae, with the matrix either replaced by accumulated contrasted compound or striated content created through random sectioning sorts of appendages constituting views of so-called "lamellar bodies," and other dense bodies accompanied by mitophagy. Most lining membranes joined the endoplasmic reticulum network with lipid storage droplets. RA differentiation of neuroblastoma cells involved cell genome and mitochondria metabolism to favor an increased lipid and phospholipids precursors to store associated endoplasm and mitochondria membrane and matrix changes resulting in defective fine structures and content. Some of them bore analogy with those noted when one or more mitochondria regulatory proteins (e.g. OPA1 and mitofusin) occurred in other neurodegenerative pathologies, including Parkinson's disease. Our observations should incite further molecular investigations about this neuroblastoma cell proteome and lipidome organelles because of this cell line usage in numerous biomedical investigations.
    Keywords:  Dense body; Parkinson disease; SH-SY5Y cells; lamellar bodies; mitochondria; mitophagy; retinoic acid
    DOI:  https://doi.org/10.1080/01913123.2026.2668403
  52. Am J Respir Cell Mol Biol. 2026 May 18. pii: aanag082. [Epub ahead of print]
    FGF10 mitigated sepsis-induced pulmonary coagulopathy via Nrf2/PINK1/Parkin-modulated mitophagy.
    Minmin Wu, Hongwei Wang, Yueyue Huang, Lingling Wang, Yanyan Xu, Chunxue Li, Mina Yang, Bicheng Chen, Jingye Pan.
      Severe coagulation and endothelial dysfunction are characteristics of sepsis-induced acute pulmonary coagulopathy with high morbidity and mortality. The primary objective of this research is to investigate the role rFGF10 in ameliorating sepsis-induced coagulation and endothelial dysfunction. FGF10 expression levels in sepsis-induced mice lung tissues and lipopolysaccharide (LPS) stimulated Human umbilical vein endothelial cells (HUVECs) were detected and the results showed that they were both elevated. Supplementation with rFGF10 protected HUVECs against LPS stimulation and ameliorated sepsis-induced pulmonary coagulation evidenced by the suppressed coagulation factors and alleviated lung injury. Mechanistically, rFGF10 activated Nrf2-modulated mitophagy by PINK1/Parkin pathway in septic mice, which maintained mitochondrial quality, promoted activities of anti-oxidation and suppressed mitochondrial reactive oxygen species (mtROS), therefore, suppressed phosphorylation of NF-𝑘B, Erk1/2 and P38, which thus, is crucial for rFGF10 protection against sepsis induced pulmonary coagulation. Suppression of Nrf2 with its inhibitor ML385 abolished all beneficial effects of rFGF10 on sepsis-induced mice. These findings revealed the therapeutic effects of rFGF10 on sepsis-induced pulmonary coagulation and endothelial dysfunction, which could be a potential pharmacological strategy for clinic.
    Keywords:  coagulopathy; endothelial dysfunction; fibroblast growth factor 10 (FGF10); sepsis
    DOI:  https://doi.org/10.1093/ajrcmb/aanag082
  53. Cell Mol Life Sci. 2026 May 20.
    CerS6 orchestrates mitochondrial-immune crosstalk via BNIP3-dependent mitophagy suppression and mtDNA-STING/NLRP3 activation in acute lung injury.
    Guoqing Luo, Dinghui Li, Zhiwei Wang, Guorui Li, Yifan Zuo, Wanli Jiang, Yi Liu, Boyang Li, Xiaoping Xie, Ning Li, Bohao Liu.
      Acute lung injury (ALI) is characterized by impaired alveolar epithelial barrier function and mitochondrial dysfunction in type II alveolar epithelial cells (AT2 cells). Ceramide synthase 6 (CerS6), a key enzyme in sphingolipid metabolism responsible for generating C16:0 ceramide, has not previously been implicated in ALI. This study reveals that CerS6 expression is significantly upregulated in AT2 cells during lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced ALI. Specific knockout of CerS6 in AT2 cells attenuates apoptosis, inflammation, oxidative stress, and barrier disruption in an ALI mouse model while preserving mitochondrial function. Mechanistically, CerS6 directly interacts with the mitophagy receptor BNIP3, disrupting its binding to LC3 and thereby inhibiting mitophagy. The impaired mitochondrial clearance mechanism promotes cytoplasmic release of mtDNA and activates the STING/NLRP3 signaling cascade. RNA-Seq further confirmed that CerS6 knockdown suppressed the STING/NLRP3 pathway and upregulated BNIP3. Notably, CerS6 metabolite C16:0 ceramide also participated in these effects, reinforcing the pivotal role of sphingolipid metabolism in linking mitochondrial stress to innate immune activation. In summary, this study establishes CerS6 as a core driver of mitochondrial dysfunction and redox imbalance in acute lung injury, and indicates that both CerS6 and C16:0 ceramide may serve as potential therapeutic targets.
    Keywords:  Acute lung injury; C16:0 ceramide; CerS6
    DOI:  https://doi.org/10.1007/s00018-026-06227-9
  54. FASEB J. 2026 May 31. 40(10): e71941
    OPA1 in MC4R Neurons Regulates Dietary Fat Intake and Body Weight in Mice.
    Shigenobu Matsumura, Mizuki Fujiwara, Soyoka Horie, Miona Marutani, Eri Nousou, Nanase Iki, Yuka Yamato, Yui Otonashi, Tsutomu Sasaki, Mina Fujitani, Teppei Fujikawa.
      Melanocortin 4 receptor (MC4R) neurons in the hypothalamus regulate appetite and energy balance, and mitochondrial dynamics are important for neuronal function. However, how dietary fat intake affects mitochondrial regulation in the hypothalamus has not been fully clarified. Here we examined the effects of soybean oil intake on hypothalamic mitochondrial gene expression and generated MC4R neuron-specific mitochondrial fusion factor OPA1 (Optic atrophy-1) knockout mice. Voluntary ingestion of soybean oil increased hypothalamic OPA1 expression in wild-type male mice but not in female mice. In contrast, loss of OPA1 in MC4R neurons led to elevated soybean oil consumption and progressive obesity, with a more pronounced obesity phenotype in females. MC4R agonist administration suppressed food intake, but this effect was attenuated specifically in female knockout mice. Together, these results suggest that OPA1 in MC4R neurons is involved in the response to dietary fat intake and contributes to the control of feeding and body weight, with clear differences between males and females. This study provides new insight into how mitochondrial function in the hypothalamus is linked to energy metabolism under conditions of dietary fat intake.
    Keywords:  MC4R neurons; OPA1 deficiency; energy metabolism; mitochondrial dynamics
    DOI:  https://doi.org/10.1096/fj.202600452R
  55. Nat Commun. 2026 May 22.
    Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.
    Xin Guan, Bingsheng Yang, Bowen Bai, Naiqian Cui, Muqi Wang, Jianwen Su, Xiaohu Wu, Chenghua Zhang, Hui Dai, Peng Zhao, Bin Yu, Bowei Wang.
      Staphylococcus aureus (S. aureus)-induced osteomyelitis remains challenging in clinical practice, wherein macrophages with impaired bactericidal function serve as reservoirs for intracellular bacterial survival, contributing to persistent and relapsing infections. Here, we show that exogenous manganese (Mn2+) enhances the bactericidal capacity of S. aureus-infected macrophages. By repressing the mitochondrial protein Sirt3, Mn2+ inhibits S. aureus-induced mitophagy via the PTEN-induced kinase 1/parkin pathway, thereby boosting the production of mitochondrial reactive oxygen species to eradicate intracellular bacteria. Pharmacological activation or genetic overexpression of Sirt3 abolishes these effects, identifying this axis as a key molecular target of Mn2+. Based on this, we further develop a biomimetic nanotherapeutic system for targeted Mn2+ delivery. In a mouse model of osteomyelitis, this nanosystem precisely represses Sirt3 in macrophages within the infected medullary cavity, markedly reduces bacterial burden, and effectively alleviates bone destruction. Our findings implicate an immunomodulatory mechanism by which Mn2+ enhances macrophage bactericidal activity and develops a potent Mn2+-based metalloimmunotherapeutical strategy for S. aureus-induced osteomyelitis.
    DOI:  https://doi.org/10.1038/s41467-026-73529-8
  56. Gen Physiol Biophys. 2026 Jan;45(1): 1-18
    Silencing IL2RB attenuates abdominal aortic aneurysm-related pathology in experimental models by partially restoring mitochondrial homeostasis.
    Pang Li, Hao Zhang, Jinfu Huang, Yijing Gao.
      Abdominal aortic aneurysm (AAA) remains a life-threatening vascular disease with limited therapeutic options. The role of interleukin-2 receptor subunit beta (IL2RB) in AAA via mitochondrial dysfunction is unclear. In this study, integrated bioinformatics analyses identified IL2RB as a key gene. In a rat AAA model and angiotensin II-stimulated vascular smooth muscle cells (VSMCs), IL2RB was upregulated and associated with mitochondrial impairment. IL2RB knockdown attenuated aortic dilation, reduced elastic fiber degradation (decreased by 45%), restored adenosine triphosphate (ATP) production (increased by 126.9%), suppressed interleukin-6 (decreased by 49.3%) and tumor necrosis factor-alpha (decreased by 51.8%) release, and decreased malondialdehyde (reduced by 47.7%) and reactive oxygen species (reduced by 38.5%) production in the rat model. In VSMCs, silencing IL2RB rescued angiotensin II-induced ATP depletion, preserved mitochondrial membrane potential, and reduced apoptosis. Mechanistically, IL2RB knockdown downregulated dynamin-related protein 1, and upregulated mitofusin 1 and parkin RBR E3 ubiquitin protein ligase. IL2RB knockdown mitigates AAA progression by restoring mitochondrial homeostasis and suppressing inflammation, identifying IL2RB as a potential therapeutic target for AAA.
    DOI:  https://doi.org/10.4149/gpb_2025039
  57. Chem Biol Interact. 2026 May 15. pii: S0009-2797(26)00255-3. [Epub ahead of print]435 112147
    Transgenerational persistence of neurodevelopmental disorder-like phenotypes in Drosophila melanogaster.
    Dieniffer Espinosa Janner, Frâncelly Marquez de Figueiredo, Andriele de Moura Brinck, Luana Barreto Meichtry, Pamela Piardi de Almeida, Elize Aparecida Santos Musachio, Eliana Jardim Fernandes, Mustafa Munir Dahleh Mustafa, Marina Prigol, Gustavo Petri Guerra.
      Neurodevelopmental disorders (NDDs) arise from complex interactions between genetic and environmental factors, and increasing evidence suggests that environmentally induced molecular changes can persist across generations. This study aimed to investigate the transgenerational effects of parental exposure to imidacloprid (IMI) in Drosophila melanogaster, focusing on behavioral phenotypes analogous to NDDs and alterations in proteins related to synaptic organization, epigenetic regulation, and mitochondrial dynamics. Male and female flies (F0) were exposed to IMI 400 ρM for seven days, and behavioral and molecular analyses were conducted in the unexposed F2 and F3 generations. Behavioral assays included negative geotaxis, open field, social interaction, aggression, and grooming tests. The immunoreactivity of SHANK, HDAC3, and MFN2 proteins was evaluated by Western blot. Parental IMI exposure induced hyperactivity and increased repetitive grooming in both F2 and F3 generations, while alterations in social interaction and aggression were restricted to F2. Molecular analyses revealed a significant reduction of SHANK and an increase in HDAC3 in F2, both returning to control levels in F3, suggesting transient transcriptional and epigenetic dysregulation. In contrast, MFN2 remained consistently reduced in both generations, indicating long-lasting mitochondrial impairment. These findings support the existence of an integrated epigenetic-mitochondrial-synaptic axis through which parental IMI exposure reprograms neuronal and metabolic pathways. Overall, Drosophila melanogaster is highlighted as a powerful model for studying non-genetic inheritance mechanisms linking environmental exposures to neurodevelopmental disturbances.
    Keywords:  Drosophila melanogaster; Epigenetic regulation; Imidacloprid; Mitochondrial dynamics; Neurodevelopmental disorders; Transgenerational effects
    DOI:  https://doi.org/10.1016/j.cbi.2026.112147
  58. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  59. Biochem Biophys Res Commun. 2026 May 17. pii: S0006-291X(26)00729-1. [Epub ahead of print]825 153965
    Exogenous klotho as an adjunct to dapagliflozin ameliorates diabetic kidney disease by restoring mitophagy and mitigating apoptosis and fibrosis.
    Pratik Shankar Rakshe, Anil Bhanudas Gaikwad.
      Diabetic kidney disease (DKD) is a growing global health concern arising as a secondary microvascular complication of diabetes. Despite current therapeutic approaches, significant residual risk persists, highlighting need for an improved treatment strategy. Impaired mitophagy, apoptosis, and fibrosis are key pathomechanisms in DKD progression. The present study aims to investigate the therapeutic potential of novel recombinant human klotho (rh-KL)-dapagliflozin (DAPA) combination in both streptozotocin-induced Type 1 diabetes in Sprague-Dawley rats and high-glucose+recombinant human TGF-β1(HG+rh-TGF-β1)-stimulated NRK-52E cells DKD model. Following treatment, urine, plasma, and renal tissues were harvested and analyzed for biochemical, histological, immunohistochemical, and qRT-PCR analysis. Furthermore, siRNA-mediated klotho knockdown was performed to elucidate its specific role in regulating apoptosis and fibrotic progression in DKD. The combination therapy of rh-KL and DAPA significantly improved metabolic, renal function, and histological analysis demonstrated marked preservation of renal architecture. The co-treatment significantly increased SIRT1, PGC-1α, PINK1, Parkin, and Bcl-2 expression and reduced TGF-β and NF-κB levels in diabetic rats, as evidenced by immunohistochemistry and qRT-PCR. Moreover, combination therapy significantly reduced vimentin, collagen-I, and Bax expression in NRK-52E cells, as confirmed by immunocytochemistry and qRT-PCR analyses. Collectively, the combination therapy showed greater potential than monotherapies to restore mitophagy, inhibit apoptosis, and fibrosis. Further, klotho knockdown confirmed its protective role in DKD, as reduced klotho expression was associated with exacerbated apoptosis and fibrosis under diabetic conditions. This evidence indicates that the rh-KL and DAPA combination enhances renoprotective effects and allows a lower DAPA dose, potentially minimizing adverse effects while improving overall therapeutic outcomes in DKD.
    Keywords:  Apoptosis; Dapagliflozin; Diabetic kidney disease; Exogenous klotho; Fibrosis; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153965
  60. J Orthop Translat. 2026 May;58 101113
    Talin1 loss activates DRG neurons to accelerate bone remodeling and fracture healing in mice.
    Qinnan Yan, Donghao Gan, Kangtai Xu, Zecai Chen, Sixiong Lin, Bo Zhou, Zhen Xu, Qiyue Zhong, Chu Tao, Yiming Zhong, Shaochuan Huo, Weihong Yi, Zilong Wang, Xuejun Song, Lei Qin, Guozhi Xiao.
       Background: Bone tissue is densely innervated by sensory nerve fibers, whose roles in bone remodeling and regeneration are poorly defined. This study aims to investigate the physiological function of Talin1, a key focal adhesion protein, in dorsal root ganglion (DRG) neurons in pain processing and its specific impact on bone remodeling and fracture healing.
    Materials and methods: We utilized a transgenic mouse model (Advillin-Cre ERT2 ; Talin1 fl/fl ) to delete Talin1 expression in sensory neurons under tamoxifen induction. Pain sensitivity, bone mass, and fracture healing were evaluated in adult mice. Transcriptomic analysis, immunofluorescence, western blot, scanning and transmission electron microscopy, alongside a highly localized pharmacological inhibition model using BIBN-loaded hydrogels, were employed to delineate the underlying mechanisms.
    Results: Talin1 is predominantly expressed in C-fiber DRG neurons and its expression is significantly downregulated following bone fracture. Talin1 loss markedly activates DRG sensory neurons and increases mechanical, but not thermal, pain sensitivity in mice. Concurrently, Talin1 deficiency inhibits mitophagy and impairs mitochondrial function, as indicated by altered mitochondrial morphology, abnormal reactive oxygen species production and reduced mitochondrial membrane potential. Furthermore, beyond its role in nociception, Talin1 loss not only increases bone mass in both adult and aged mice but also accelerates fracture healing by modulating bone remodeling. This pro-healing phenotype coincides with increased expression of calcitonin gene-related peptide (CGRP) in DRG neurons. Critically, pharmacological inhibition of CGRP receptors at the fracture site by BIBN abolishes the fracture healing-promoting effect caused by Talin1 loss.
    Conclusions: Our studies demonstrate that Talin1 plays a pivotal role in modulating sensory neuron activation, pain perception, and bone remodeling. Specifically, Talin1 loss accelerates bone repair by upregulating CGRP, thereby establishing a Talin1-CGRP signaling axis that mediates sensory neuron control of fracture healing.
    The translational potential of this article: This research highlights the dual role of Talin1 in sensory neurons in modulating both pain perception and bone remodeling, and emphasizes the potential for targeting Talin1 signaling as a therapeutic strategy to alleviate pain or to accelerate fracture healing.
    Keywords:  Bone remodeling; Dorsal root ganglion (DRG) neuron; Fracture healing; Mitophagy; Pain perception; Talin1
    DOI:  https://doi.org/10.1016/j.jot.2026.101113
  61. Cell Rep Med. 2026 May 20. pii: S2666-3791(26)00243-0. [Epub ahead of print] 102826
    Nanoparticle-based serine replenishment rescues SP1-BNIP3 mitophagy and ameliorates preeclampsia in preclinical models.
    Yinan Wang, Qiongjie Zhou, Huanqiang Zhao, Zhilin Liu, Wei Li, Meng Xu, Jiangyuan Du, Yinfei Chen, Wei Cheng, Xinping Ng, Wenhan Zhou, Xinyan Zhang, Yan Lin, Wei Xu, Shimin Zhao, Yiyuan Yuan, Xiaotian Li.
      Preeclampsia (PE) is a devastating hypertensive disorder affecting pregnant women worldwide. Disrupted metabolic reprogramming is recognized as a key feature of placental dysfunction in PE, yet the abnormal metabolic adaption and underlying mechanisms remain largely unknown. In this study, we perform targeted metabolomic profiling and identify placental serine deficiency as a hallmark metabolic alteration in PE, which favors PE occurrence. Serine-deficient chow exacerbates PE-like symptoms, such as hypertension and proteinuria, in mice. Mechanistically, serine deficiency attenuates SAM-dependent methylation, decreasing SP1 levels and impairing SP1-BNIP3-mediated mitophagy, thereby exacerbating oxidative stress to cause placental dysfunction. Notably, targeting serine to the placenta using mPEG5k-poly(D/L-serine) effectively relieves PE-like symptoms in the mouse model. Our findings elucidate an unknown serine-deficiency-mediated metabolic reprogramming in PE and suggest manipulating serine supplementation as a promising translational strategy for PE treatment.
    Keywords:  mPEG5k-Poly(D/L-serine); mitophagy; preeclampsia; serine deficiency
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102826
  62. J Agric Food Chem. 2026 May 20.
    AHR Activation Mediates Sodium Pentachlorophenol-Induced Mitochondrial Dysfunction and Cardiomyocyte Apoptosis through Oxidative Stress.
    Lidong Chao, Ruoning Wu, Yudi Zhang, Jilong Luo, Xue-Jiao Gao.
      Sodium pentachlorophenol (PCP-Na) is a persistent halogenated aromatic compound with poorly understood cardiotoxicity. This study investigated the underlying mechanisms using mouse models and HL-1 cardiomyocytes, integrating network toxicology, molecular docking, and targeted interventions with the AHR inhibitor CH223191, the antioxidant N-acetylcysteine (NAC), and the CYP1A1 inhibitor α-naphthoflavone (ANF). Findings demonstrate that PCP-Na promotes AHR nuclear translocation and dose-dependently activates the downstream target gene CYP1A1. This AHR/CYP1A1/ROS signaling axis triggers excessive oxidative stress, subsequently leading to mitochondrial dynamic imbalance, impaired ATP production, and cardiomyocyte apoptosis. By systematically elucidating these molecular pathways, this study highlights AHR as a direct target of PCP-Na and provides a critical theoretical basis for the safety assessment of agricultural and environmental matrices contaminated with persistent organic pollutants. These results offer novel insights into the protective potential of AHR/CYP1A1 inhibitors against halogenated contaminant-induced cardiac injury.
    Keywords:  apoptosis; aryl hydrocarbon receptor; cardiotoxicity; mitochondrial dynamics; sodium pentachlorophenol
    DOI:  https://doi.org/10.1021/acs.jafc.6c01710
  63. Carbohydr Polym. 2026 Aug 01. pii: S0144-8617(26)00527-8. [Epub ahead of print]385 125410
    Hybrid dextran/fibronectin nanogels for brain-targeted mitophagy inducer delivery to alleviate neuroinflammation and neuronal loss of Parkinson's disease.
    Meng Qin, Huxiao Sun, You Ji, Zhuo Li, Cheng Ni, Zhiqiang Wang, Dina Maciel, João Rodrigues, Xiangyang Shi, Mingwu Shen.
      Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss, chronic neuroinflammation, and α-synuclein aggregation. Blood-brain barrier (BBB)-penetrable, dual-target nanomedicines for microglial inflammation and neuronal degeneration remain challenging. In this study, we fabricated a brain-targeted, pH- and reactive oxygen species (ROS)-responsive nanogel (NG) platform using dextran (Dex) as the main polysaccharide backbone, crosslinked with inflammation-targeting fibronectin (FN), and loaded with neuroprotective quercetin (Que). Dex-FN/Que NGs exhibited a uniform spherical morphology with an average diameter of 187 nm, favorable colloidal stability, and stimuli-triggered drug release behavior. Abundant hydroxyl groups on Dex enabled efficient BBB penetration, while FN mediated integrin-dependent internalization in microglia and neurons. These NGs suppressed the nuclear factor-kappa B (NF-κB) signaling pathway, scavenged ROS, promoted favorable microglial polarization, and balanced oxidative stress. Meanwhile, mitophagy flux activated by the NGs in neurons exerted strong neuroprotection effect. In a mouse model of PD, Dex-FN/Que NGs effectively crossed the BBB and accumulated in injured brain regions, significantly protecting dopaminergic neurons, improving motor function, and relieving depressive-like behaviors. Therapeutic benefits arose from normalized microglial polarization, reduced oxidative stress, and inhibited neuronal ferroptosis. This Dex-based stimuli-responsive nanoplatform provides a promising brain-targeted strategy for the treatment of PD and other neurological disorders.
    Keywords:  Blood-brain barrier; Fibronectin; Nanogels; Parkinson's disease; Responsive drug release
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125410
  64. Autophagy. 2026 May 17.
    PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage.
    Tingting Fu, Yanglin Wu, Bo Wang, Qin Zhang, Lujun Guo, Zezhang Han, Jia Cao, Jun Lin.
      Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical studies indicatethat specific hypoglycemic agents alleviate the symptoms of RA, while the potentialmolecular mechanism remains unknown. Herein, we initially assess the efficacyof various categories of anti-diabetic medications including biguanides, GLP1R(glucagon like peptide 1 receptor) agonists, SLC5A2/SGLT2 (solute carrierfamily 5 member 2) inhibitors, DPP4 (dipeptidyl peptidase 4) inhibitors,sulfonylureas, thiazolidinediones, and insulin analog in RA models ofcollagen-induced arthritis (CIA) and serum-transfer arthritis (STA). Resultsdemonstrate that solely thiazolidinediones (pioglitazone [PIOG]) confersuperior efficacy, whereas the other anti-diabetic agents provide minimal or notherapeutic benefits. Mechanistically, thiazolidinediones (PIOG) activatesPPARG/PPARγ (peroxisome proliferator activated receptor gamma) to promotemitophagic flux, thereby inhibiting aberrant NLRP3 inflammasome activation andreducing pro-inflammatory factors IL1B/IL1-BETA (interleukin 1 beta) and IL18 (interleukin18) release. Notably, loss of autophagy either genetically or pharmacologicallysubstantially diminishes the anti-inflammatory effects of PIOG both in vitroand in vivo. In summary, these results offer new mechanistic insight intodisease crosstalk and support the translational value of thiazolidinedionesPIOG as a candidate for precision therapy in RA or multimorbidity of RA and type2 diabetes mellitus (T2DM).
    Keywords:  Antidiabetic drug; NLRP3 inflammasome; PPARG; bone erosion; mitophagy; pioglitazone; rheumatoid arthritis; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1080/15548627.2026.2676071
  65. J Hazard Mater. 2026 May 15. pii: S0304-3894(26)01378-6. [Epub ahead of print]512 142400
    Environmental cadmium drives placental senescence and fetal growth restriction via activating CLPP-dependent mitochondrial stress.
    Rui Pan, Jin Zhang, Lan-Lan Wu, Cheng-Fang Sun, Xin-Xin Zhang, Yu-Xi Wu, Xu-Ai Yin, Ye-Xin Luo, Si-Ting Liu, Zi-Jian Bao, Wei Chang, Ling-Li Zhao, De-Xiang Xu, Ya-Ling Feng, Hua Wang, Hua-Long Zhu.
      The role of placental cellular senescence in environmental cadmium (Cd)-evoked fetal growth restriction (FGR) and its underlying mechanisms require further clarification. Here, we generated a murine FGR model by simulating internal exposure doses of Cd in humans. Human and mouse studies revealed that placental senescence linked environmental Cd exposure to FGR. Furthermore, environmental Cd degraded mitochondrial anti-aging protein SIRT3 to evoke placental cellular senescence and FGR, as demonstrated by SIRT3 overexpression and its activator resveratrol treatment. Interestingly, CLPP was identified as a mitochondrial protease targeting placental SIRT3 degradation under environmental Cd. In vitro CLPP knockdown and in vivo CLPP inhibitor tamarixetin treatment reversed environmental Cd-induced SIRT3 degradation and placental cellular senescence. Additionally, environmental Cd elevated the level of METTL3 protein to promote m6A modification of ClpP mRNA in placentae. In vitro METTL3 knockdown and in vivo its inhibitor S-Adenosylhomocysteine treatment blocked the activation of CLPP-dependent mitochondrial protease stress, attenuating placental cellular senescence and FGR upon environmental Cd. Based on a human case-control study, m6A-driven CLPP-dependent mitochondrial protease stress was positively correlated with placental cellular senescence and all-cause FGR. Taken together, environmental Cd enhances m6A modification to activate CLPP-dependent mitochondrial protease stress, thereby causing placental cellular senescence and FGR.
    Keywords:  CLPP; Environmental cadmium; M6A; Mitochondrial protease stress; Placental cellular senescence
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.142400
  66. Front Immunol. 2026 ;17 1768845
    A mitochondrial-stress adipocyte-macrophage circuit sustaining metaflammation in human type 2 diabetic adipose tissue.
    Haibin Ji, Tian Cao, Zixuan Tan, Rui Zheng, Jinhui Bian, Wenfeng Lin, Xiufan Xu, Chunze Yuan, Yongfeng Shao, Huanhuan Chen, Junjie Du.
      Type 2 diabetes mellitus (T2D) features chronic low-grade inflammation in white adipose tissue (WAT), where adipocytes and innate immune cells engage in immunometabolic crosstalk. Mitochondrial damage-associated molecular patterns (mtDAMPs) released from stressed adipocytes are thought to sustain metaflammation, but how they are handled by specific macrophage subsets in human T2D WAT is unclear. We hypothesized that in T2D subcutaneous white adipose tissue (scWAT), the mitochondrial stress-clearance circuit between adipocytes and macrophages becomes maladaptive. scWAT biopsies from 6 patients with T2D and 7 non-diabetic controls were profiled by single-nucleus RNA sequencing (snRNA-seq). We integrated transcriptomic data across donors, annotated adipocyte and immune cell states, and performed differential expression analysis along with pathway and immunometabolic module scoring. To map intercellular communication and mitochondrial waste handling, we applied metabolic flux inference (COMPASS), mitochondrial-derived vesicle (MDV) and phagocytosis gene signatures, ligand-receptor analysis (CellChat), and pseudotime trajectories of lipid-associated macrophages. Macrophages and adipocytes showed the strongest T2D-associated transcriptional and metabolic rewiring. We identified a stress-enriched adipocyte state (AD3) with upregulated mitophagy, vesicle and MDV trafficking, and inflammatory signaling, whose mitochondrial-stress module overlapped genes enriched in adipocyte-derived extracellular vesicles. Among lipid-associated macrophages, we resolved a LAM-ST1 subset with immunometabolic activation but downregulation of receptors and lysosomal programs for MDV uptake and degradation. Cell-cell communication and trajectory analyses indicated that AD3 engages LAM-ST1 through inflammatory and vesicular signaling and that LAM-ST1 occupies a terminal, clearance-incompetent branch along the LAM continuum, consistent with a maladaptive mitochondrial stress-clearance response. Our human snRNA-seq analysis delineates an adipocyte-macrophage immunometabolic circuit in which mitochondrial stress in AD3 adipocytes and defective MDV clearance by LAM-ST1 macrophages jointly sustain metaflammation in T2D scWAT. These findings highlight mitochondrial waste handling by tissue-resident macrophages as a potential checkpoint for restoring adipose immune homeostasis and reducing cardiometabolic risk.
    Keywords:  immunometabolism; lipid-associated macrophages; metaflammation; mitochondrial stress; mitochondrial-derived vesicles; single-nucleus RNA sequencing; subcutaneous white adipose tissue; type 2 diabetes
    DOI:  https://doi.org/10.3389/fimmu.2026.1768845
  67. Med Res Rev. 2026 May 20.
    Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.
    Lihua Liu, Minghui Yu, Xinnan Li, Jinyi Xu, Shaowen Xie, Shengtao Xu, Hong Yao.
      The caseinolytic protease P (ClpP) is a conserved serine protease that functions with ATPases associated with diverse cellular activities (AAA+) chaperones to ensure protein quality control in organisms ranging from bacteria to human mitochondria. Its tetradecameric structure and adjustable gating support selective substrate recognition, unfolding, and proteolysis, thereby contributing to proteostasis, metabolic balance, stress responses, and bacterial virulence. Growing insights into human ClpP and ClpX complex (hClpXP) have further underscored its relevance to human disease. This review summarizes current knowledge of ClpP architecture and regulatory mechanisms, with emphasis on its roles in cellular homeostasis and pathophysiology. We highlight advances in small-molecule ClpP modulators, including activators, inhibitors, and emerging heterobifunctional degraders such as bacterial proteolysis-targeting chimeras (BacPROTACs) and mitochondrial-targeted PROTACs (MtPTACs), which harness ClpP activity for targeted protein degradation in antibacterial and anticancer applications. Despite notable progress, challenges remain, particularly in achieving selectivity between bacterial and human ClpP (hClpP), minimizing off-target effects, and preventing resistance. Future opportunities include designing reversible covalent inhibitors, developing novel allosteric modulators, and optimizing degrader architectures to expand therapeutic potential. ClpP-directed therapeutic strategies therefore represent a promising avenue for next-generation antibacterial and anticancer drug discovery.
    Keywords:  ATPase chaperones; ClpP protease; agonists; future perspective; heterbifunctional molecules; inhibitors; small‐molecule modulators; targeted protein degradation; therapeutic applications
    DOI:  https://doi.org/10.1002/med.70056
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