bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–08–23
forty-six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial dynamics in Huntington's disease.
  2. PGAM5-mediated VDAC1 oligomerization Facilitates Ponatinib-Induced Cardiotoxicity via Disrupting the Mitophagy-Mitochondrial unfolded protein response Synergistic Defense Crosstalk.
  3. Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
  4. Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
  5. Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
  6. FIS1 dependent peripheral fission exacerbates mitochondrial fragmentation and dysfunction in prion diseases.
  7. Astragaloside IV attenuates oxidative stress-associated mitophagy-dependent ferroptosis in peritoneal mesothelial cells via suppression of STAT3 signaling.
  8. Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
  9. Mitochondrial-centric regulatory networks in MASLD: integrating quality control, organelle interactions, and gut-liver communication.
  10. Retinoic acid priming enhances myogenesis of bovine muscle stem cells for cultivated meat production by modulating mitochondrial function.
  11. Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.
  12. Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.
  13. Gut-derived metabolites and mitochondrial homeostasis in heart failure: mechanistic links and translational perspectives.
  14. Mitochondria-targeted natural products with potential for the treatment of mitochondria-related diseases.
  15. Nogo-B deletion mitigates mitochondrial dynamics imbalance in cerebral ischemia/reperfusion injury via the TLR4/ERK pathway.
  16. Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
  17. Targeting the 14-3-3θ protein with indole-3-propionic acid restores PINK1/Parkin mediated mitophagy and suppresses endothelial PANoptosis in atherosclerosis.
  18. Fzd7 Restrains Pink1-Dependent Mitophagy in Suture Stem Cells to Maintain Cranial Suture Patency.
  19. Retraction of The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
  20. Mo2Ti2C3/CeO2/Neurotrophin-3 MXene Hydrogel Combined with Electrical Stimulation Promotes Functional Recovery by Activating the Biogenesis and Fusion of Mitochondria in Spinal Cord Injury.
  21. NADH FLIM reveals cellular bioenergetics and mitochondrial morphology during Drosophila convergent extension.
  22. Pan-Cancer Oncolytic Virotherapy Through Disruption of Tumor Cell Mitochondrial Dynamics.
  23. Autophagy and mitophagy in pancreatic β-cell homeostasis and their involvement in diabetes pathophysiology.
  24. PDE5 Inhibitor LW1646 Improves Kidney Fibrosis by Alleviating ER Stress and Maintaining Mitochondrial Homeostasis.
  25. The protection of chitosan-coated triptolide-magnesium nanoparticles against intervertebral disc degeneration via MAPK signaling and mitophagy.
  26. Ginkgolide B Mitigates Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Mediated Mitochondrial Fission via P-Drp1/OPA1 and Apoptosis.
  27. GDD, a first-in-class APPL1 activator, restores mitochondrial homeostasis and insulin sensitivity with regulation of LKB1-AMPK axis.
  28. The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.
  29. [Research progress on acupuncture and moxibustion in regulating mitochondrial function for chronic fatigue syndrome].
  30. AKAP1 orchestrates mitochondrial dynamics and metabolic reprogramming to promote hypoxia tolerance in yak cardiac fibroblasts.
  31. USP22 Enhances Mitochondrial Biogenesis via Stabilizing MYBBP1A in Non-Small Cell Lung Cancer.
  32. Polygonatum sibiricum polysaccharide-based hydrogels regulate macrophage mitochondrial homeostasis for the treatment of radiodermatitis.
  33. TRF2 Recovers Ischemic Postconditioning Cardioprotection in Aged Myocardiocytes by Regulating CSNK2A2 Localization and FUNDC1 Dephosphorylation.
  34. Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
  35. Pituitary adenylate cyclase-activating polypeptide and mitochondrial homeostasis in neuronal injury: mechanisms and translational prospects.
  36. Mitochondrial-neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes.
  37. Allosteric rewiring of mitochondrial stress signaling through Miro1.
  38. Inhibition of RBM25 preserves cardiac mitochondrial homeostasis and attenuates ischemic heart failure.
  39. Long-chain chlorinated paraffins exposure induces premature ovarian failure by disrupting the balance of mitochondrial fission.
  40. CDK4/MERCs/PINK1 Axis Drives PFOA/HFPO-TA-Induced Cardiac Senescence via Mitophagy Defect and cGAS-STING Activation: In Vitro Amelioration by Cycloastragenol.
  41. Effects of moderate-intensity continuous training on cardiac mitochondrial bioenergetics, oxidative balance, and mitochondrial dynamic in juvenile overnourished rats.
  42. Melatonin in Peripheral Nerve Regeneration: Molecular Mechanisms, Schwann Cell Dynamics, and Translational Therapeutic Potential.
  43. Discovery of iodo-phenanthroimidazole derivatives as potential HDAC1 inhibitors inducing mitophagy to suppress glioblastoma progression.
  44. A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
  45. Involvement of SIRT3 downstream targets ANT1, VDAC, CYPD, and Drp1 in a rat model of hepatic encephalopathy: Therapeutic role of thymoquinone.
  46. Systemic redox switching of transcription factors: A context-sensitive framework for cell fate decisions.
  1. J Huntingtons Dis. 2026 Aug 17. 18796397261478163
    Mitochondrial dynamics in Huntington's disease.
    Beatriz Paiva, Ana Cristina Rego.
      Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.
    Keywords:  mitochondria; mitophagy; neurotoxicity; pathogenic mechanisms; preclinical models
    DOI:  https://doi.org/10.1177/18796397261478163
  2. Chem Biol Interact. 2026 Aug 21. pii: S0009-2797(26)00418-7. [Epub ahead of print] 112310
    PGAM5-mediated VDAC1 oligomerization Facilitates Ponatinib-Induced Cardiotoxicity via Disrupting the Mitophagy-Mitochondrial unfolded protein response Synergistic Defense Crosstalk.
    Yuyu Li, Dandan Yuan, Haitao Zhou, Mengxia Zhang, Maoxiang Zhao, Haowen Zhuang, Jing Cui, Junyan Wang, Yukun Li.
       OBJECTIVES: Ponatinib is an effective tyrosine kinase inhibitor for chronic myeloid leukemia with the T315I mutation, but its clinical use is often limited by serious cardiovascular toxicity. Although mitochondrial dysfunction has been implicated in this process, the upstream stress-sensing mechanism that converts ponatinib exposure into collapse of mitochondrial quality control (MQC) remains poorly defined. We therefore investigated whether the PGAM5/VDAC1 axis mediates ponatinib-induced cardiac injury by coordinately disrupting mitophagy and the mitochondrial unfolded protein response (UPRmt).
    METHODS: Cardiomyocyte-specific PGAM5 knockout mice (Pgam5_cko) and littermate controls (Pgam5_f/f) were fed a high-fat diet and then exposed to ponatinib. Cardiac function and adult cardiomyocyte contractility were assessed by echocardiography and IonOptix analysis. Single-cell RNA sequencing, in vivo genetic loss-of-function models, and HL-1 cells with stable Pgam5 knockdown were used to define the underlying mechanism. MQC status, including mitophagy and UPRmt, was evaluated by fluorescence imaging, RT-qPCR, western blotting, and biochemical assays.
    RESULTS: Ponatinib markedly increased PGAM5 expression in the heart and induced contractile dysfunction, inflammatory activation, and cardiomyocyte apoptosis. These changes were substantially attenuated in Pgam5_cko mice. Mechanistically, ponatinib promoted pathological oligomerization of the outer mitochondrial membrane protein VDAC1 in a PGAM5-dependent manner. This event was accompanied by simultaneous suppression of PINK1/Parkin-related mitophagy and the UPRmt program, resulting in mitochondrial fragmentation, oxidative stress, and impaired bioenergetic function. At the functional level, loss of PGAM5 restored MQC and preserved cardiac performance under ponatinib stress. Importantly, forced VDAC1 oligomerization with arsenic trioxide largely abolished the protective effects of PGAM5 deficiency, supporting VDAC1 oligomerization as a critical downstream event in this pathway.
    CONCLUSION: These findings identify the PGAM5/VDAC1 axis as a key mechanism linking ponatinib stress to coordinated failure of MQC in the heart. By simultaneously disabling mitophagy and UPRmt, this pathway drives mitochondrial dysfunction and cardiac injury. Targeting PGAM5-dependent VDAC1 oligomerization may therefore represent a potential strategy for limiting ponatinib-associated cardiotoxicity.
    Keywords:  Mitochondrial unfolded protein response; Mitophagy; PGAM5/VDAC1 axis; Ponatinib; cardiotoxicity
    DOI:  https://doi.org/10.1016/j.cbi.2026.112310
  3. Life Sci. 2026 Aug 20. pii: S0024-3205(26)00451-0. [Epub ahead of print]403 124642
    Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
    Ilitch A Marcondes-de-Castro, Thamyres Alves Sales, Thatiany Souza Marinho, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.
      Mitochondrial quality control (QC) preserves cellular homeostasis by coordinating mitochondrial structure, turnover, and bioenergetic function. Rather than operating through isolated pathways, QC is increasingly recognized as an integrated, redox-sensitive network in which reactive oxygen species (ROS), nicotinamide adenine dinucleotide (NAD+), and calcium (Ca2+) signaling regulate mitochondrial dynamics, mitophagy, biogenesis, and, ultimately, cell fate. In this narrative review, we propose a hierarchical framework in which these signaling systems function as interconnected sensors and transducers that determine whether mitochondria undergo repair, adaptive remodeling, or elimination. Under physiological conditions, controlled ROS production, adequate NAD+ availability, and tightly regulated Ca2+ flux promote a balanced mitochondrial fusion and fission, efficient mitophagic turnover, and mitochondrial biogenesis, thereby preserving bioenergetic competence and metabolic flexibility. Mitochondria-associated membranes (MAMs) emerge as key spatial platforms that integrate redox signaling, Ca2+ transfer, and lipid exchange, synchronizing communication between the endoplasmic reticulum and mitochondria. Conversely, persistent redox imbalance, characterized by excessive ROS, NAD+ depletion, and Ca2+ dysregulation, disrupts the coordination of QC pathways, resulting in mitochondrial fragmentation, defective turnover, impaired biogenesis, bioenergetic failure, and activation of apoptotic signaling. We critically discuss the mechanistic interplay among these pathways across metabolic disorders, cardiovascular disease, neurodegeneration, cancer, and aging, highlighting context-dependent adaptive and maladaptive responses. Finally, we identify unresolved questions regarding the spatiotemporal integration of redox signals, tissue-specific regulation of mitochondrial QC, and therapeutic targeting of network-level regulatory nodes. This framework provides a systems-level perspective for understanding how coordinated redox signaling governs mitochondrial adaptation and contributes to disease pathogenesis.
    Keywords:  Mitochondria-associated membranes; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Redox signaling
    DOI:  https://doi.org/10.1016/j.lfs.2026.124642
  4. IUBMB Life. 2026 Aug;78(8): e70127
    Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
    Peng Ran, Lifang Yang.
      Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.
    Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1002/iub.70127
  5. Autophagy. 2026 Aug 16.
    Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
    Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.
      How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in macroautophagy/autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals > 65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by promoting autophagosome generation through TFEB, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Partial organelle recovery occurred after inducing mitophagy or inhibiting mitochondrial fission. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in mitochondria-intrinsic mechanisms to avoid loss of energy production.
    Keywords:  Aging; TFEB; autolysosome; dynamics; live-cell; longitudinal; mitochondria; mitophagy; neuronal
    DOI:  https://doi.org/10.1080/15548627.2026.2719435
  6. Front Neurosci. 2026 ;20 1893232
    FIS1 dependent peripheral fission exacerbates mitochondrial fragmentation and dysfunction in prion diseases.
    Fengting Gou, Zhiping Li, Jie Li, Dongming Yang, Mengyang Zhao, Dongdong Wang, Pei Wen, Zhixin Sun, Jingjing Wang, Qing Fan, Yuexin Dai, Deming Zhao, Lifeng Yang.
       Introduction: Mitochondrial dysfunction is an early and critical feature of neuronal injury in prion diseases, a group of fatal transmissible neurodegenerative disorders. Mitochondrial dynamics, a core component of mitochondrial quality control, maintains neuronal homeostasis through balanced fission and fusion. Although mitochondrial fission can be further divided into distinct spatial subtypes, the specific subtype involved in prion-associated neurotoxicity and its regulatory mechanisms remain unclear. This study aimed to identify the mitochondrial fission subtype involved in prion toxicity and elucidate its underlying regulatory mechanisms.
    Methods: Using live-cell time-lapse imaging, we analyzed mitochondrial fission dynamics in mouse neuroblastoma (N2a) cells treated with the neurotoxic prion peptide PrP106-126. Molecular mechanisms regulating mitochondrial peripheral fission were investigated through protein interaction analysis, mitochondrial-lysosome contact assessment, DRP1 activity analysis, FIS1 knockdown, and pharmacological inhibition using P110.
    Results: PrP106-126 selectively enhanced mitochondrial peripheral fission, identifying this subtype as a key pathological event underlying early mitochondrial damage. FIS1 acted as a central adaptor regulating this aberrant process by recruiting TBC1D15 to promote RAB7 GTP hydrolysis, thereby destabilizing mitochondria-lysosome contacts. In parallel, FIS1 recruited activated DRP1 to mitochondria. PrP106-126 treatment increased DRP1 Ser616 phosphorylation, decreased DRP1 Ser637 phosphorylation, and enhanced DRP1 GTPase activity, which were required for mitochondrial peripheral fission. FIS1 knockdown and P110-mediated disruption of the DRP1-FIS1 interaction effectively suppressed PrP106-126-induced peripheral mitochondrial fission, restored mitochondrial integrity, and reduced neuronal apoptosis.
    Discussion: These findings define mitochondrial peripheral fission as a key early pathogenic event in prion toxicity and identify FIS1 as a potential therapeutic target for intervention in prion diseases.
    Keywords:  DRP1; FIS1; mitochondria–lysosome contacts; peripheral fission; prion diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1893232
  7. Front Pharmacol. 2026 ;17 1747615
    Astragaloside IV attenuates oxidative stress-associated mitophagy-dependent ferroptosis in peritoneal mesothelial cells via suppression of STAT3 signaling.
    Sijia Liu, Li Sheng, Xiaoqian Chen, Jinyi Sun, Xiaohui Meng, Yongqing You, Funing Wang, Manshu Yu, Yun Shan, Meixiao Sheng.
       Background: Peritoneal injury and subsequent fibrosis driven by oxidative stress are major contributors to peritoneal dialysis (PD) withdrawal. Ferroptosis and mitophagy are closely correlated with oxidative stress, but their roles and interplay in PD-related peritoneal injury remain incompletely defined. Astragaloside IV (AS-IV) has shown anti-fibrotic and antioxidant potential, yet its underlying mechanism in this context is not fully understood. This study aims to investigate the involvement of mitophagy and ferroptosis during PD and to evaluate whether AS-IV attenuates PD-related peritoneal injury by targeting mitophagy-dependent ferroptosis via STAT3 signaling.
    Methods: Mouse models of peritoneal fibrosis were established using either methylglyoxal or PD fluid (PDF). Peritoneal tissues were analyzed by histopathology and Western blotting, and serum malondialdehyde was measured. In vitro, human peritoneal mesothelial cells (PMCs; HMrSV5) were assigned to different groups and exposed separately to PDF, carbonyl cyanide m-chlorophenylhydrazone, erastin, or colivlin, followed by separate treatment with N-acetylcysteine, mitochondrial division inhibitor 1, S3I-201, or AS-IV. Ferroptosis and mitophagy were assessed by fluorescence staining and Western blotting, and mitochondrial ultrastructure was evaluated by transmission electron microscopy.
    Results: PDF exposure induced oxidative stress-associated mitophagy and ferroptosis in PMCs, with evidence supporting a close association between these processes. AS-IV treatment attenuated STAT3 activation, reduced mitophagy-related changes, and alleviated ferroptosis and peritoneal injury.
    Conclusion: Oxidative stress-associated, mitophagy-dependent ferroptosis contributes to PD-related peritoneal injury. AS-IV attenuates this process via suppression of STAT3 signaling in PMCs.
    Keywords:  astragaloside IV; ferroptosis; mitophagy; oxidative stress; peritoneal injury
    DOI:  https://doi.org/10.3389/fphar.2026.1747615
  8. WIREs Mech Dis. 2026 Jul-Aug;18(4):18(4): e70014
    Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
    Rosa Di Lorenzo, Rola S Zeidan, Riccardo Calvani, Vito Pesce, Emanuele Marzetti, Anna Picca.
      Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.
    DOI:  https://doi.org/10.1002/wsbm.70014
  9. Pharmacol Res. 2026 Aug 21. pii: S1043-6618(26)00325-7. [Epub ahead of print] 108410
    Mitochondrial-centric regulatory networks in MASLD: integrating quality control, organelle interactions, and gut-liver communication.
    Jingwen Liu, Kewei Li, Ying Deng, Xi Li, Ruhan Yang, Ping Huang, Chunyan Li, Yueshui Zhao, Fukuan Du, Yu Chen, Jing Shen, Zhangang Xiao, Kangxing Zhu, Tao Shui, Jianqiao Zhong, Mingxing Li, Xu Wu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to liver mitochondrial dysfunction, which is driven not as an isolated event but by a self-amplifying injury loop involving impaired intrinsic quality control, aberrant organelle crosstalk, and dysregulated gut-liver signaling. This review summarizes findings in three interconnected regulatory layers: (1) intrinsic mitochondrial quality control (MQC) (PINK1/Parkin- and BNIP3/NIX-mediated mitophagy, Drp1/Mfn-driven dynamics, and chaperone/protease-maintained proteostasis); (2) organelle interactions (ER-mitochondria contacts, lipid droplet tethering, and lysosome crosstalk); and (3) extrinsic modulation via the gut-derived metabolites. We highlight that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress. Furthermore, short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics. Preclinical evidence indicates that restoring MQC or targeting organelle interactions can improve MASLD symptoms. Given the multifactorial nature of MASLD, single-target interventions are insufficient; multi-target strategies and tissue-specific delivery are essential for clinical translation.
    Keywords:  MASLD; gut-liver axis; mitochondrial dynamics; mitochondrial quality control; mitophagy; organelle interactions
    DOI:  https://doi.org/10.1016/j.phrs.2026.108410
  10. Food Res Int. 2026 Oct 31. pii: S0963-9969(26)01491-2. [Epub ahead of print]242(Pt 1): 119807
    Retinoic acid priming enhances myogenesis of bovine muscle stem cells for cultivated meat production by modulating mitochondrial function.
    Yingying Mao, Eun Young Kim, Seon Woong Kim, Ryoung Eun Kim, Jin Woo Ham, Min Kyu Kim.
      Large-scale production of cultivated meat will require robust myogenic differentiation of muscle stem cells (MuSCs) into muscle tissue using food-compatible cues. Retinoic acid (RA), a bioactive metabolite of dietary vitamin A, is an attractive candidate for this purpose. Here, we demonstrate that RA priming transitions fetal bovine MuSCs from a PAX7+ proliferative state to an activated pre-differentiation program. The pro-myogenic effect observed in two-dimensional (2D) culture was recapitulated in three-dimensional (3D) scaffolds, where RA priming accelerated and enhanced myotube formation in a setting that is more relevant to tissue. This response required canonical retinoic acid receptor (RAR) signaling. RA-RAR signaling increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) and nuclear respiratory factor 1 (NRF1), which is consistent with enhanced mitochondrial biogenesis and improved mitochondrial function. These findings are supported by elevated mitochondrial membrane potential and higher levels of respiratory chain components, together with modest changes in mitochondrial dynamics. In parallel, RA reduced the expression of PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PRKN), and microtubule-associated protein 1 light chain 3 (LC3) and suppressed the transcriptional program associated with mitophagy. Taken together, these results suggest that the RA priming modulates mitochondrial function and quality-control pathways, reduces reliance on PINK1-PRKN-dependent mitophagy, and supports an activated, pro-myogenic primed state. This provides a food-compatible priming strategy with potential relevance for scalable cultivated beef production.
    Keywords:  Bovine muscle stem cells; Cultivated meat; Mitochondrial reprogramming; Mitophagy; Myogenic differentiation; Retinoic acid
    DOI:  https://doi.org/10.1016/j.foodres.2026.119807
  11. Mol Neurobiol. 2026 Aug 17. pii: 838. [Epub ahead of print]63(1):
    Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.
    Ya-Ning Wang, Xing Wang, Qin Huang, Yun Yang, Tao Wang, Xin-Hui Qu, Xiao-Jian Han.
      M itochondria act as the energetic hub of eukaryotic cells, orchestrating cellular energy metabolism via oxidative phosphorylation and the tricarboxylic acid (TCA) cycle, thereby subjecting them to continuous environmental stress. To address these challenges, mitochondria have developed a sophisticated array of quality-control mechanisms that provide adaptive resilience. These quality-control pathways encompassing mitochondrial biogenesis, dynamic remodeling, and mitophagy collectively safeguard cellular homeostasis. Among them, mitophagy plays a continuous role in surveying, identifying, and eliminating dysfunctional mitochondria, thereby preserving the integrity of the mitochondrial network and ensuring optimal bioenergetic function. When mitophagy is dysregulated, a cascade of protein homeostatic collapse and metabolic failure ensues, disrupting physiological cellular processes. Moreover, mitophagy plays a role in the development and progression of various pathologies, including neurodegenerative disorders, cardiovascular diseases, and cancer. In the context of neurodegeneration, aberrant mitophagy aggravates disease progression at the molecular, organellar, and cellular levels. Given that neuronal metabolism critically relies on oxidative phosphorylation, which primarily occurs within mitochondria, mitochondrial functional integrity directly determines neuronal energy supply and physiological capacity. Consequently, impaired mitophagy has been identified as a key determinant in the etiology of neurodegenerative diseases. This review systematically elucidates the key molecular mechanisms regulating mitophagy and how these mechanisms contribute to the onset and progression of neurodegenerative diseases. It also summarizes potential therapeutic agents targeting mitophagy to improve neurodegenerative disorders.
    Keywords:  Mitochondria; Mitophagy; Neurodegenerative diseases; SUMOylation; Ubiquitination
    DOI:  https://doi.org/10.1007/s12035-026-06104-3
  12. Biomed Mater. 2026 Aug 18. 21(4):
    Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.
    Jiaenli Bolati, Junjie Yang, Yueqi Yan, Donghua Yu, Chunmiao Yu.
      Mitophagy is a selective autophagic process responsible for the elimination of damaged or dysfunctional mitochondria, playing a critical role in maintaining mitochondrial quality control and cellular homeostasis. Dysregulated mitophagy has been implicated in the pathogenesis of numerous diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, inflammatory and immune diseases, and musculoskeletal diseases. In recent years, nanotechnology-based approaches for the targeted modulation of mitophagy have emerged as promising therapeutic strategies due to their ability to achieve precise regulation, enhanced subcellular targeting, and reduced off-target effects. Building upon advances in the understanding of mitophagy mechanisms, a variety of nano-delivery systems have been developed, incorporating strategies such as mitochondria-targeting, stimuli-responsive activation, ligand-mediated targeting, and combination therapies. However, a comprehensive review integrating the molecular mechanisms of mitophagy, disease-specific therapeutic applications, nanoplatform design strategies, and translational challenges remains lacking. The present review provides an integrated overview of the molecular regulatory mechanisms of mitophagy, summarizes recent advances in nanotechnology-based therapeutic interventions across multiple disease types, and critically discusses current nanoplatform design strategies. Furthermore, key challenges associated with mitophagy evaluation, biosafety, pharmacokinetics, clinical translation, and regulatory considerations are highlighted, together with emerging technologies that may accelerate the development of next-generation mitophagy-targeting nanomedicines.
    Keywords:  mitochrial dysfunction; mitophagy; nanotechnology; targeted delivery; therapeutic strategies
    DOI:  https://doi.org/10.1088/1748-605X/ae95c8
  13. Front Cardiovasc Med. 2026 ;13 1917012
    Gut-derived metabolites and mitochondrial homeostasis in heart failure: mechanistic links and translational perspectives.
    Daqiu Chen, Mingxuan Su, Zhanxiong Xie, Shanghua Xu, Shunxiang Luo.
      Heart failure is a chronic cardiovascular syndrome with high morbidity and mortality worldwide, and its progression is closely linked to myocardial metabolic remodeling and disruption of mitochondrial homeostasis. Increasing evidence suggests that the gut microbiota and its metabolites represent an important interface between diet, inflammation, metabolic stress, and cardiovascular remodeling. Gut-derived metabolites, including short-chain fatty acids, trimethylamine N-oxide, tryptophan-derived metabolites, bile acids, phenylacetylglutamine, indoxyl sulfate, and urolithins, may influence myocardial mitochondrial homeostasis by affecting substrate oxidation, oxidative phosphorylation, reactive oxygen species production, inflammatory signaling, mitochondrial dynamics, mitophagy, and cell-death pathways. However, these metabolites should not be interpreted as uniformly protective or detrimental, because their biological effects may depend on concentration, exposure duration, bioavailability, protein binding, renal clearance, cellular targets, host metabotype, experimental model, and heart failure phenotype. Short-chain fatty acids and indole-3-propionic acid (IPA) have been linked to mitochondrial oxidative metabolism, nicotinamide adenine dinucleotide (NAD+)/sirtuin 3 (SIRT3)-related mitochondrial signaling, and inflammatory regulation in selected experimental settings, whereas the choline/trimethylamine N-oxide axis, indoxyl sulfate, phenylacetylglutamine, and dysregulated bile acid metabolism are associated with myocardial fibrosis, oxidative stress, mitochondrial dysfunction, and adverse outcomes. Nevertheless, many clinical associations may be influenced by renal dysfunction, disease severity, and heart-to-gut reverse causality, and many mechanistic findings remain derived from animal models, ex vivo systems, or non-classical heart-failure models. This narrative review summarizes current evidence linking gut-derived metabolites to myocardial mitochondrial homeostasis in heart failure, with emphasis on energy metabolic remodeling, oxidative stress, inflammation, mitochondrial quality control, cell death, and fibrotic remodeling. Potential intervention strategies targeting the gut microbiota and its metabolic pathways are also discussed with attention to their translational limitations and to the need for direct mitochondrial readouts, cell-type-specific validation, and phenotype-specific clinical studies.
    Keywords:  context-dependent effects; gut microbiota; gut-derived metabolites; heart failure; mitochondrial quality control; myocardial mitochondrial homeostasis; short-chain fatty acids; trimethylamine N-oxide
    DOI:  https://doi.org/10.3389/fcvm.2026.1917012
  14. Chin J Nat Med. 2026 Sep;pii: S1875-5364(26)61204-6. [Epub ahead of print]24(9): 1068-1080
    Mitochondria-targeted natural products with potential for the treatment of mitochondria-related diseases.
    Xinyue Liu, Hu Li, Xuekai Wang, Jiandong Jiang, Zonggen Peng.
      Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.
    Keywords:  Apoptosis; Bioavailability; Mitochondrial dynamics; Mitochondrial quality control; Natural products; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/S1875-5364(26)61204-6
  15. Exp Neurol. 2026 Aug 21. pii: S0014-4886(26)00354-7. [Epub ahead of print] 115988
    Nogo-B deletion mitigates mitochondrial dynamics imbalance in cerebral ischemia/reperfusion injury via the TLR4/ERK pathway.
    Taotao Fan, Rong Xu, Zhangle Hu, Anran Guo, Qi Lou, Huiyu Jia, Min Si, Rui Li, Xiaoyu Zhu, Dongmei Yang, Shengyong Luo.
       BACKGROUND: Our previous studies have demonstrated that the downregulation of Nogo-B expression in microglia suppresses neuroinflammatory responses by modulating microglial polarization, thereby attenuating cerebral ischemia/reperfusion (I/R) injury. However, the direct role of Nogo-B in neuronal cells remains unclear.
    METHODS: Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation and reoxygenation (ODG/R) models were utilized to mimic ischemic stroke. Various methods, including Nogo-B shRNA transfection, balance beam and corner turn tests, immunofluorescence staining, electron microscopy, Western blot, and TUNEL, were used to investigate the effects of Nogo-B deletion on mitochondrial dynamics imbalance in neurons following cerebral I/R injury, as well as its underlying mechanisms.
    RESULTS: Neuron-specific conditional knockout (cko) of Nogo-B significantly reduced cerebral infarction volume and neurological deficit scores in mice subjected to cerebral I/R. Nogo-B deletion enhanced neuronal cell viability, suppressed apoptosis, improved mitochondrial respiratory chain activity, increased mitochondrial membrane potential and ATP production, and lowered ROS levels and oxidative stress markers. Additionally, it decreased the expression of fission-related proteins (p-Drp1, Fis1) and mitochondrial fragmentation while increasing the expression of fusion-related proteins (Opa1, Mfn1, and Mfn2). Mechanistic studies show that Nogo-B knockout can significantly reduce the expression of TLR4 and p-ERK1/2 proteins. Nogo-B downregulation also resulted in a significant reduction in TLR4 and p-ERK1/2, a marked decrease in mitochondrial fission proteins, a substantial increase in fusion proteins, and concomitant improvement in mitochondrial structure, function, and cell viability. Nogo-B downregulation produced effects comparable to TAK-242. However, these protective effects were substantially attenuated by the ERK activator TPA.
    CONCLUSION: Nogo-B deletion has a direct protective effect on neurons after cerebral ischemia-reperfusion injury. The mechanism may be related to Nogo-B reducing the expression of TLR4 on the cell membrane through some indirect action, thereby inhibiting the TLR4/ERK pathway and regulating mitochondrial dynamic imbalance.
    Keywords:  Ischemic stroke; Mitochondrial dynamics; Nogo-B; Oxidative stress; TLR4/ERK
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115988
  16. bioRxiv. 2026 Aug 01. pii: 2026.07.31.742112. [Epub ahead of print]
    Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
    Youmian Yan, Lianjie Wei, Thomas Schodl, Keri-Lyn Kozul, Maria Behrens, Stephen P Plassmeyer, Alex S Holehouse, Natalie M Niemi.
      The dual targeting of mitochondrial proteins regulates a host of cellular processes, including metabolism, cofactor biosynthesis, mitophagy, and stress responsiveness. Despite this importance, the mechanisms by which proteins dually localize are incompletely defined. Here, we identify multiple sequence elements that compromise the matrix localization of the phosphatase PPTC7 to facilitate its accumulation at the outer mitochondrial membrane (OMM), where it regulates mitophagy. We find that PPTC7 has a moderately 'weak' presequence, but this feature is insufficient to promote dual targeting of a generic cargo protein. Instead, our data suggest that a recently evolved glycine stretch decreases the helical potential of the PPTC7 presequence, weakening its import efficiency in vitro and in cells. Deletion of these glycine residues improves PPTC7 in vitro import and enrichment within the mitochondrial matrix, but only partially suppresses PPTC7-mediated regulation of mitophagy at the OMM. These data suggested additional elements may contribute to PPTC7 dual localization, including its mature phosphatase domain which has robust thermal stability and becomes further stabilized to an import-incompetent state upon binding to its requisite enzymatic co-factor manganese. Simultaneous increases in presequence strength and denaturation of the PPTC7 phosphatase domain are required to promote import in vitro, underscoring the multifactorial challenges associated with its matrix targeting. These data suggest that sequence-specific features can work combinatorially to impart dual-localization capacity to mitochondrial proteins, enabling functions across cellular compartments.
    DOI:  https://doi.org/10.64898/2026.07.31.742112
  17. Phytomedicine. 2026 Aug 12. pii: S0944-7113(26)00953-0. [Epub ahead of print]161 158722
    Targeting the 14-3-3θ protein with indole-3-propionic acid restores PINK1/Parkin mediated mitophagy and suppresses endothelial PANoptosis in atherosclerosis.
    Weishen Qiao, Dexin Han, Qi Liu, Gang Wang, Xingtao Huang, Xuedong Wang, Yufei Sun, Jingbo Hou.
       BACKGROUND: Indole-3-propionic acid (IPA) is a naturally occurring, microbiota-derived tryptophan metabolite; however, its vascular protective effects and the endothelial mechanisms involved in atherosclerosis remain unclear.
    PURPOSE: This study aimed to evaluate the anti-atherosclerotic efficacy of IPA and elucidate its endothelial targets and mechanisms underlying vascular protection.
    METHODS: In high-fat diet (HFD)-fed ApoE-/- mice, the anti-atherosclerotic effects of IPA were evaluated by en face aortic analysis, lipid deposition assessment, and collagen content quantification. In oxidized low-density lipoprotein (ox-LDL)-challenged human umbilical vein endothelial cells (HUVECs), PINK1/Parkin mediated mitophagy and PANoptosis-related signaling were examined by mitophagy flux assays and immunoblotting of pathway markers. Limited proteolysis-small molecule mapping/mass spectrometry (LiP-SMap/MS) and surface plasmon resonance (SPR) analysis were performed to profile IPA-interacting proteins, and adeno-associated virus (AAV)-mediated endothelial YWHAQ knockdown in ApoE-/- mice was used to validate target dependence.
    RESULTS: In HFD-fed ApoE-/- mice, oral IPA reduced en face aortic plaque burden, decreased lipid deposition and increased collagen content. In ox-LDL-challenged HUVECs, IPA enhanced PINK1/Parkin mediated mitophagy, improved mitochondrial function and mitigated PANoptosis. The 14-3-3θ protein (YWHAQ) was identified as a direct molecular target of IPA via LiP-SMap/MS and SPR analysis. Molecular docking predicted a Tyr48-centered binding pose on YWHAQ and substitution of Tyr48 with alanine markedly reduced IPA's cytoprotective effects. Mechanistically, ox-LDL weakened the YWHAQ-PINK1 association, which IPA restored in HUVECs. In vivo, AAV-mediated endothelial YWHAQ knockdown attenuated IPA's anti-atherosclerotic efficacy.
    CONCLUSION: These findings collectively indicate that IPA alleviates endothelial PANoptosis by engaging the 14-3-3θ protein to restore PINK1/Parkin mediated mitophagy and ultimately attenuates the progression of atherosclerosis.
    Keywords:  14-3-3θ protein; Atherosclerosis; Indole-3-propionic acid; Mitophagy; PANoptosis
    DOI:  https://doi.org/10.1016/j.phymed.2026.158722
  18. Adv Sci (Weinh). 2026 Aug 19. e77245
    Fzd7 Restrains Pink1-Dependent Mitophagy in Suture Stem Cells to Maintain Cranial Suture Patency.
    Xinyan Chen, Zong Chen, Chenzhi Lai, Yingying Yue, Tian He, Hao Gong, Jing Shi, Xiaoshuang Guo, Yu Wang, Guodong Song, Xiaolei Jin.
      Craniosynostosis results from premature fusion of the cranial sutures, yet the contribution of suture mesenchymal stem cell (SuSC) dysfunction to this process remains incompletely understood. Here, we combined single-cell RNA-seq with 2-µm Visium HD spatial transcriptomics to define stage-specific changes in Prrx1+ SuSCs in the Fgfr2C342Y/+ mouse model. We observed early downregulation of Frizzled-7 (Fzd7), increased mitophagy-associated signatures and readouts with elevated Pink1 expression, and premature osteogenic activation within the SuSC niche. In vitro, loss of Fzd7 increased mitophagy and osteogenic activity, whereas Fzd7 overexpression attenuated these changes. In vivo, conditional deletion of Fzd7 accelerated coronal suture fusion, while AAV-mediated Fzd7 overexpression reduced fusion. Conditional deletion of Pink1 suppressed the effects of Fzd7 loss, supporting Pink1-dependent mitophagy as a required component of the Fzd7-deficiency-associated osteogenic and fusion phenotypes. These findings support a model in which an Fzd7-Pink1 mitophagy axis contributes to the maintenance of suture patency in craniosynostosis and provide a mechanistic basis for future targeted studies.
    Keywords:  craniosynostosis; mesenchymal stem cell; mitophagy; pink1
    DOI:  https://doi.org/10.1002/advs.77245
  19. J Clin Invest. 2026 Aug 17. pii: e211052. [Epub ahead of print]136(16):
    Retraction of The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
    Hagir B Suliman, Martha Sue Carraway, Abdelwahid S Ali, Chrystal M Reynolds, Karen E Welty-Wolf, Claude A Piantadosi.
      
    DOI:  https://doi.org/10.1172/JCI211052
  20. ACS Appl Mater Interfaces. 2026 Aug 19. 18(32): 44644-44657
    Mo2Ti2C3/CeO2/Neurotrophin-3 MXene Hydrogel Combined with Electrical Stimulation Promotes Functional Recovery by Activating the Biogenesis and Fusion of Mitochondria in Spinal Cord Injury.
    Dengxing Lun, Ziming Zhao, Siying Li, Zhengbin Yuan, Ruyi Yang, Leming Mou, Wanping Zhu, Liang Liu, Tingjun Wang, Xihui Jia, Yifeng Dong, Shaoqiang Wang, Zhijian Wei, Hongyu Wang.
      Traumatic spinal cord injury (SCI) initiates a pathological cascade dominated by mitochondrial dysfunction and unregulated oxidative stress, collectively generating an inhibitory lesion microenvironment that abrogates endogenous neural regenerative capacity. Herein, we fabricate a multifunctional conductive hydrogel scaffold by incorporating Mo2Ti2C3 MXene nanosheets, hollow CeO2 nanoparticles, and neurotrophin-3 (NT-3) within a crosslinkable matrix. When paired with exogenous electrical stimulation (ES), this combinatorial therapeutic platform synergistically activates two core mitochondrial regulatory cascades in injured neurons: the PGC-1α/NRF1/TFAM axis governing mitochondrial biogenesis, and Mfn2/OPA1 signaling mediating mitochondrial fusion. Comprehensive in vitro characterizations validate the hydrogel's favorable long-term cytocompatibility, robust reactive oxygen species (ROS) scavenging activity, tunable biodegradation kinetics, and sustained NT-3 delivery; together, these properties effectively restrain intracellular ROS overproduction and stabilize mitochondrial structural and metabolic homeostasis. In a mouse contusion SCI model, local implantation of the Mo2Ti2C3/CeO2/NT-3 hydrogel combined with intermittent electrical stimulation substantially alleviates secondary tissue damage by shrinking lesion cyst volume and attenuating glial scarring, which in turn promotes pronounced axonal sprouting and restores hindlimb locomotor function. By merging conductive biomaterial bridging with targeted mitochondrial homeostatic modulation, this work establishes a dual-modal therapeutic strategy with great translational potential for neural tissue engineering and post-SCI regenerative repair.
    Keywords:  Mo2Ti2C3/CeO2/NT-3; electrical stimulation; mitochondrial biogenesis; mitochondrial fusion; spinal cord injury
    DOI:  https://doi.org/10.1021/acsami.6c10702
  21. Dev Biol. 2026 Aug 19. pii: S0012-1606(26)00184-3. [Epub ahead of print]
    NADH FLIM reveals cellular bioenergetics and mitochondrial morphology during Drosophila convergent extension.
    Maria Espana-Pena, Alan Woessner, Kyle P Quinn, Adam C Paré.
      Mitochondria are dynamic organelles that can fragment or fuse to support different bioenergetic demands and cellular processes, although the role of mitochondrial fission and fusion during embryonic development is not well understood. Fluorescence lifetime imaging (FLIM) of the mitochondrial cofactor NADH can be used to visualize mitochondrial networks and infer aspects of cellular bioenergetics in a label-free manner. We used NADH FLIM to test whether germband cells undergo changes in cellular metabolism during Drosophila convergent extension (CE)--a process in which hundreds of epithelial cells undergo coordinated intercalation to elongate the embryo. Contrary to our expectations, we did not observe significant changes in NADH lifetime or mitochondrial topology during CE, suggesting that germband cells do not need to alter their baseline metabolism to fuel intercalation. Inhibiting mitochondrial fission led to hyper-fused basal networks and robustly increased NADH lifetime, whereas inhibiting fusion led to hyperfragmented apical networks and decreased NADH lifetime. Inhibiting either mitochondrial fission or fusion increased cell intercalation errors during CE, suggesting that a precise network topology is required for proper tissue elongation. These defects could be rescued by knocking down ROS scavengers, suggesting that one of the roles of mitochondria during CE is to create a ROS-rich environment to support cell motility. This study demonstrates the utility of NADH FLIM for visualizing mitochondria and characterizing bioenergetics during development in live embryos, and this technique should be broadly applicable to many other systems.
    Keywords:  Drosophila; NADH FLIM; convergent extension; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.ydbio.2026.08.011
  22. Mol Ther. 2026 Aug 19. pii: S1525-0016(26)00708-2. [Epub ahead of print]
    Pan-Cancer Oncolytic Virotherapy Through Disruption of Tumor Cell Mitochondrial Dynamics.
    Shufeng Feng, Lu Cui, Yongxin Zhu, Yao Cheng, Dongmei Diao, Xuefeng Li, Huimin Duan, Haixia Zhang, Xiaoxiao Liu, Qing Pan, Fanpu Ji, Yu Zhang, Changbo Ou, Hai Li.
      Oxidative stress, a pervasive cancer vulnerability, remains a challenging therapeutic target attributed to tumor heterogeneity and adaptive resistance. Herein, we identify RhoA as a "redox rheostat" during oncolytic virotherapy through regulating mitochondrial dynamics, thereby addressing this bottleneck to enable pan-cancer therapy via oxidative-oncolytic synergy. Engineering oncolytic virus to express RhoA (rNDV-RHOA) elicits robust oxidative mitophagic cell death with inherent tumor selectivity and demonstrates superior oncolysis in a comprehensive panel of preclinical cancer models spanning in vitro, ex vivo, and in vivo settings, including models evaluated under intravenous administration. The construct exhibits favorable safety profiles without inducing seroconversion, facilitating repeated systemic dosing. Mechanistically, RhoA drives mitochondrial fission to impair mitochondrial Complex III, initiating oxidative stress while tempering it via mitophagy induction downstream of Akt/mTOR inhibition. Concurrently, viral infection serves as the decisive precipitating event that shifts the cellular response from adaptive mitophagy to mitochondrial catastrophe by enhancing Complex I and V activities to promote ATP biosynthesis, thereby culminating in acute cell death characterized by a precipitous decline in mitochondrial mass and ATP bioavailability. This establishes rNDV-RHOA as an oncolytic virotherapy platform that transcends conventional oncolysis to surmount tumor heterogeneity by exploiting inherent tumor redox dependency.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.08.027
  23. FEBS Lett. 2026 Aug 19.
    Autophagy and mitophagy in pancreatic β-cell homeostasis and their involvement in diabetes pathophysiology.
    Yunkyeong Lee, Mingming Tong, Anna L Gloyn.
      Autophagy is an evolutionarily conserved cellular quality control pathway that responds to the metabolic state of the cell, and its dysregulation has been broadly associated with metabolic disorders like diabetes mellitus. Among different types of autophagy, mitophagy or the selective autophagic clearance of dysfunctional mitochondria has emerged as particularly relevant in pancreatic β-cell biology and its pathophysiology. Recent advances in functional genomics and animal studies implicate the autophagy/mitophagy pathway components as effector transcripts at diabetes risk loci, providing a new rationale for investigation of genetic determinants of autophagy/mitophagy in β cells. In this review, we take a β-cell centric perspective to examine the evidence for autophagy/mitophagy across four clinically relevant diabetes categories (type 1, type 2, gestational, and monogenic diabetes) and discuss the functional significance and complexity of these pathways in β-cell failure.
    Keywords:  autophagy; diabetes; genetics; mitophagy; β‐cell
    DOI:  https://doi.org/10.1002/1873-3468.70436
  24. Free Radic Biol Med. 2026 Aug 19. pii: S0891-5849(26)01040-3. [Epub ahead of print]
    PDE5 Inhibitor LW1646 Improves Kidney Fibrosis by Alleviating ER Stress and Maintaining Mitochondrial Homeostasis.
    Minghui Wang, Meng Li, Xi Yuan, Xiaoduo Zhao, Long Xu, Junbing He, Qingxian Zhai, Luosha Long, Qiqi Zheng, Hailing Zhang, Chengbin Tang, Weidong Wang, Deyan Wu, Chunling Li, Haibin Luo, Qinghua Liu.
      Renal fibrosis is the terminal pathological manifestation of most chronic kidney diseases. The phosphodiesterase type 5 (PDE5) inhibitors have shown therapeutic potentials in a wide array of chronic conditions. LW1646 is a newly identified inhibitor with high specificity and potency against PDE5. The current study aims to investigate the therapeutic effects of LW1646 on renal fibrosis and its underlying mechanisms. mRNA and protein expression level of PDE5 was elevated in renal cortex of mice with unilateral ureter obstruction for seven days (7UUO). LW1646 effectively suppressed pro-fibrotic responses in TGF-β1-stimulated HK-2 cells as well as in mice with 7UUO-induced renal fibrosis. Genetic deletion or knockdown of Pde5a produced similar antifibrotic benefits. Mechanistically, both PDE5 inhibition with LW1646 and Pde5a knockout alleviated ER stress and mitigated mitochondrial dysfunction, as evidenced by restored mitochondrial biogenesis, suppression of excessive fragmentation, preservation of membrane potential, and reduction of oxidative stress. Further investigation revealed that ER stress-driven mitochondrial injury involved augmented mitochondria associated membrane (MAM) formation, characterized by increased expression of the hallmark IP3R1-GRP75-VDAC1 complex. This enhanced interaction facilitated excessive calcium transfer from the ER to mitochondria, culminating in mitochondrial calcium overload. PDE5 inhibition effectively suppressed MAM formation and reduced mitochondrial calcium accumulation, thereby maintaining mitochondrial homeostasis under fibrotic stress. Collectively, these findings identify activation of cGMP-PKG signaling by LW1646 as a promising therapeutic pathway for renal fibrosis through suppression of ER stress and stabilization of mitochondrial homeostasis.
    Keywords:  ER stress; Kidney fibrosis; LW1646; MAM; Mitochondria; PDE5
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.038
  25. Nanomedicine (Lond). 2026 Aug 20. 1-13
    The protection of chitosan-coated triptolide-magnesium nanoparticles against intervertebral disc degeneration via MAPK signaling and mitophagy.
    Yingchao Gao, Ning Zhang, Jun-Fei Zhang, Zhengqi Fei.
       OBJECTIVE: This study aimed to develop chitosan-based nanoparticles (ChNPs) for Triptolide (TPL) delivery to mitigate intervertebral disc degeneration (IDD).
    METHODS: TPL-magnesium (Mg) ChNPs were prepared by mixing TPL, magnesium sulfate, and chitosan under controlled stirring, followed by nanoparticle characterization. An in vitro IDD model was established by stimulating nucleus pulposus cells (NPCs) with IL-1β. The therapeutic effect and biosafety of TPL-Mg ChNPs was assessed using cell counting kit-8. In an in vivo IDD rat model, pathology of intervertebral discs was evaluated via micro-computed tomography and histological staining. Western blotting, immunofluorescence, and immunohistochemistry were used to assess MAPK signaling, mitophagy activity, and extracellular matrix (ECM) programs.
    RESULTS: TPL inhibited the proliferation of IL-1β-induced NPCs. TPL was complexed with Mg2+, and further coated with chitosan via electrostatic adsorption to obtain TPL-Mg ChNPs. TPL-Mg ChNPs exhibited physical stability and biosafety, and could control drug release. TPL-Mg ChNPs were internalized by damaged NPCs within 4 hours and inhibited reactive oxygen species release. In vitro, TPL-Mg ChNPs protected NPCs and maintained ECM metabolic balance. In vivo, TPL-Mg ChNPs significantly improved IDD pathology in rats by inhibiting MAPK signaling and activating mitophagy.
    CONCLUSION: TPL-Mg ChNPs ameliorate IDD progression by inhibiting the MAPK pathway and activating mitophagy.
    Keywords:  Intervertebral disc degeneration; MAPK signal; chitosan-based nanoparticles; mitophagy; triptolide
    DOI:  https://doi.org/10.1080/17435889.2026.2712545
  26. Arch Biochem Biophys. 2026 Aug 20. pii: S0003-9861(26)00251-1. [Epub ahead of print] 110979
    Ginkgolide B Mitigates Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Mediated Mitochondrial Fission via P-Drp1/OPA1 and Apoptosis.
    Zhuo Rong, Jing Shao.
       BACKGROUND: Doxorubicin (DOX) is an effective chemotherapeutic agent but is limited by its severe cardiotoxicity, causing mitochondrial dysfunction and apoptosis in cardiomyocytes. Ginkgolide B, derived from Ginkgo biloba, shows potential cardioprotective effects.
    OBJECTIVE: To investigate the protective effects of Ginkgolide B on DOX-induced cardiotoxicity, focusing on mitochondrial stability and apoptosis.
    METHODS: In vitro, H9C2 cardiomyoblasts were treated with DOX and Ginkgolide B to assess cell viability, apoptosis, ROS production, mitochondrial membrane potential, and related protein expression via CCK-8, flow cytometry, fluorescence staining, and Western blot. In vivo, male SD rats were assigned to five unique treatment groups; dose-response analyses compared control, DOX, DOX + Ginkgolide B 5 mg/kg, and DOX + Ginkgolide B 10 mg/kg groups, whereas AMPK-mechanism analyses additionally included the DOX + Ginkgolide B 10 mg/kg + O304 group. Cardiac function, histopathology, serum biomarkers, and mitochondrial/apoptotic signaling proteins were evaluated.
    RESULTS: Ginkgolide B improved the survival rate and cardiac function of DOX treated rats and reduced myocardial injury. It normalizes apoptosis and mitochondrial protein expression, increases mitochondrial membrane potential, reduces ROS levels and apoptosis in H9C2 cells, and also reduces DOX-associated AMPK phosphorylation. O304, an AMPK activator, partially reversed these protective effects, supporting the involvement of AMPK-associated signaling. The Ginkgolide B-associated changes in p-Drp1/OPA1 expression and cell viability were not observed after AMPK knockdown, further supporting AMPK involvement.
    CONCLUSIONS: Ginkgolide B alleviates DOX-induced cardiotoxicity by modulating AMPK-associated mitochondrial homeostasis and inhibiting apoptosis, supporting its potential as an adjunctive therapy in DOX-based treatments.
    Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin (DOX); Ginkgolide B; Mitochondrial Stability
    DOI:  https://doi.org/10.1016/j.abb.2026.110979
  27. Phytomedicine. 2026 Aug 11. pii: S0944-7113(26)00943-8. [Epub ahead of print]161 158712
    GDD, a first-in-class APPL1 activator, restores mitochondrial homeostasis and insulin sensitivity with regulation of LKB1-AMPK axis.
    Hao Zheng, Ya-Ru Zhao, Xian-Yan Deng, Dan-Yu Huang, Fang-Qiong Qiu, Chang Yan, Shu-Ying Li, Jing Chen, Wan-Bin Song, Hui-Qing Lv, Ri-Hui Wu, Ligen Lin, Li-She Gan.
       BACKGROUND: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder with increasing morbidity and mortality, and current pharmacotherapies are limited by adverse effects and an inability to reverse the underlying metabolic decline. Tussilago farfara L., a traditional Chinese medicine historically used for diabetes treatment, contains the highly abundant sesquiterpenoid GDD with favorable anti-diabetic properties.
    METHODS: Insulin sensitivity was assessed by 2-NBDG uptake in C2C12 myotubes and in high-fat diet (HFD)-induced mice, while mitochondrial content and function were evaluated via Mito-Tracker staining, ATP content, mitochondrial membrane potential, and mitochondrial ROS. Lip-MS, CETSA, DARTS, SPR, molecular docking, and molecular dynamics simulations were applied to identify and validate the direct target of GDD.
    RESULTS: GDD dose-dependently enhanced insulin-stimulated glucose uptake in C2C12 myotubes, an effect attributed to the clearance of lipotoxic intermediates through mitochondrial biogenesis and functional enhancement, with the LKB1-AMPK cascade participating in this process, as observed in Ampkα1 silencing assay. Critically, GDD bound the PTB domain of APPL1, inhibited its ubiquitination and degradation, and stabilized a conformation favoring APPL1-LKB1 interaction, thereby activating AMPK-related and AMPK-unrelated arms of insulin action. The insulin-sensitizing activity of GDD was abolished in Appl1-silenced cells. In HFD-fed mice, GDD improved insulin sensitivity, reduced fat mass gain, alleviated hyperlipidemia and hepatic steatosis, and restored mitochondrial function in skeletal muscle, with additional protective effects in liver, adipose tissue, pancreas, and kidney.
    CONCLUSION: These findings establish GDD as a first-in-class APPL1 activator that reprograms mitochondrial homeostasis and reinstates insulin signaling, providing proof of concept for pharmacological targeting of APPL1 as a novel anti-diabetic strategy.
    Keywords:  APPL1; GDD; Glucose uptake; Mitochondrial function; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.phymed.2026.158712
  28. Transl Neurodegener. 2026 Aug 17. pii: 38. [Epub ahead of print]15(1):
    The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.
    Wei Long, Mengqin Yuan, Sirui Wang, Xinyue Tan, Li-Chen Gao.
      Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.
    Keywords:  Inflammasome; Mitophagy; Targeted therapy; α-Synuclein; β-Amyloid
    DOI:  https://doi.org/10.1186/s40035-026-00578-w
  29. Zhen Ci Yan Jiu. 2026 Aug 25. pii: 1000-0607(2026)08-1087-10. [Epub ahead of print]51(8): 1087-1096
    [Research progress on acupuncture and moxibustion in regulating mitochondrial function for chronic fatigue syndrome].
    Yi An, Hui-Ying Li, Hui-Min Xu, Ting-Ting Luo, Jin Fan, Xi Wu.
      Chronic fatigue syndrome (CFS) is a neurological disorder primarily characterized by persistent fatigue, post-exertional malaise, and cognitive dysfunction. Mitochondrial dysfunction is considered as a core mechanism underlying its pathological changes. Acupuncture and moxibustion therapy has been shown to be a safe and effective treatment for CFS, with part of its therapeutic effects achieved through the regulation of mitochondrial function. This review summarized the research progress on acupuncture and moxibustion in regulating mitochondrial function for the treatment of CFS. The findings indicated that acupuncture and moxibustion can modulate mitochondrial quality control systems through multiple pathways, including repairing mitochondrial morphology and structure, promoting mitochondrial biogenesis, restoring mitochondrial dynamics balance, enhancing autophagy of damaged mitochondria, regulating calcium homeostasis, and modulating the activity of the electron transport chain (ETC) complexes, thereby improving mitochondrial function. In addition, acupuncture and moxibustion can further promote mitochondrial function recovery through reducing oxidative stress and inhibiting immune-inflammatory responses. Future research may further reveal the mechanisms of acupuncture and moxibustion in regulating ETC complex activity, explore the role of alleviating endoplasmic reticulum stress in acupuncture and moxibustion treatment of CFS, investigate potential synergistic effects among different mechanisms, and elucidate the differential effect mechanisms among various acupuncture and moxibustion treatment protocols, so as to optimize clinical treatment strategies and improve the clinical efficacy of acupuncture and moxibustion for CFS.
    Keywords:  Acupuncture and moxibustion; Chronic fatigue syndrome; Immune inflammatory response; Mitochondrial dysfunction; Mitochondrial quality control system; Oxidative stress
    DOI:  https://doi.org/10.13702/j.1000-0607.20251120
  30. Int J Biol Macromol. 2026 Aug 20. pii: S0141-8130(26)04019-5. [Epub ahead of print] 154073
    AKAP1 orchestrates mitochondrial dynamics and metabolic reprogramming to promote hypoxia tolerance in yak cardiac fibroblasts.
    Ci Huang, Hai Xiang, Yilie Liao, Maolin Zhang, Luping Yang, Haitao Shi, Hui Wang, Haibo Wang, Binglin Yue, Zhixin Chai, Xin Cai, Jincheng Zhong, Jikun Wang.
      High-altitude hypoxia poses a sustained energetic and oxidative challenge to the heart, often leading to mitochondrial dysfunction and metabolic inflexibility in nonadapted mammals. Yaks (Bos grunniens) exhibit remarkable cardiac tolerance to chronic hypoxia; however, the underlying intracellular mechanisms remain poorly defined. Herein, we identify A-kinase anchoring protein 1 (AKAP1) as an important regulator of hypoxia tolerance in yak cardiac fibroblasts. Through the genetic manipulation of AKAP1 combined with live-cell mitochondrial imaging, functional assays, and untargeted metabolomics, we demonstrate that AKAP1 confers a robust survival advantage under hypoxic stress. AKAP1 preserves mitochondrial membrane potential, maintains ATP production, limits reactive oxygen species accumulation, and sustains cell viability. Mechanistically, AKAP1 stabilizes mitochondrial network integrity by restoring the balance between fission and fusion, particularly by suppressing excessive fission. At the metabolic level, AKAP1 orchestrates cellular metabolic reprogramming, modulates lipid metabolism, maintains energetic flexibility, and regulates cAMP associated pathways. These findings provide new insights into the molecular mechanisms underlying hypoxic stress tolerance in yaks and highlight the potential role of AKAP1 in maintaining mitochondrial homeostasis and metabolic flexibility under oxygen-limited conditions.
    Keywords:  AKAP1; Bos grunniens; Hypoxia tolerance; Metabolomics; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154073
  31. Cancer Lett. 2026 Aug 21. pii: S0304-3835(26)00553-7. [Epub ahead of print] 218789
    USP22 Enhances Mitochondrial Biogenesis via Stabilizing MYBBP1A in Non-Small Cell Lung Cancer.
    Yue Sun, Fang Zhen, Hongyi Wang, Huiyuan Tian, Le Wang, Zhanpeng Liu, Jing Hu.
      Mitochondria, central hubs of cellular metabolism, play a pivotal role in tumorigenesis and the regulation of cellular metabolic processes. Cancer cells frequently undergo metabolic reprogramming, characterized by enhanced glycolysis, dysregulated oxidative phosphorylation (OXPHOS), and rewired mitochondrial biogenesis to meet the high bioenergetic and biosynthetic demands of proliferation. In non-small cell lung cancer (NSCLC), these metabolic alterations are hallmark features, yet the upstream regulatory mechanisms governing mitochondrial function remain poorly defined. In this study, we report the novel finding that ubiquitin-specific protease 22 (USP22), a key regulator of protein ubiquitination and transcriptional activity, regulates mitochondrial protein expression and oxidative phosphorylation. We further demonstrate that USP22 directly binds to MYB-binding protein 1A (MYBBP1A), thereby modulating the expression of nuclear- and mitochondrial-encoded OXPHOS-related proteins, ultimately promoting mitochondrial biogenesis in cancer cells. To our knowledge, this work provides the first evidence linking USP22 to mitochondrial biogenesis in NSCLC. These findings offer valuable insights into the regulatory network governing mitochondrial metabolism in NSCLC and suggest new avenues for targeting metabolic vulnerabilities in molecular diagnosis and targeted therapies.
    Keywords:  MYBBP1A; mitochondrial biogenesis; non-small cell lung cancer; ubiquitin-specific protease 22
    DOI:  https://doi.org/10.1016/j.canlet.2026.218789
  32. Mater Today Bio. 2026 Oct;40 103520
    Polygonatum sibiricum polysaccharide-based hydrogels regulate macrophage mitochondrial homeostasis for the treatment of radiodermatitis.
    Wenfeng Li, Yawei Wang, Yang Xu, Ziyan Zhou, Yang Wang, Quanying Liu, Chunmeng Shi.
      Radiation-induced skin injury (RISI) is the major complication of tumor radiotherapy, and the key to its refractory nature lies in the persistent oxidative stress caused by ionizing radiation. It is noteworthy that this process is closely associated with the disruption of mitochondrial homeostasis in macrophages. Injured mitochondria not only amplify reactive oxygen species (ROS) production but also drive the polarization of macrophages toward a pro-inflammatory phenotype, thereby impeding tissue repair. However, effective strategies to restore macrophage mitochondrial homeostasis for RISI treatment remain limited. This study designed an immunomodulatory dual-network hydrogel (PCA) composed of oxidized polygonatum sibiricum polysaccharide, quaternized chitosan and sodium alginate. The PCA hydrogel exhibited excellent radioprotective effects on keratinocytes against ionizing radiation injury in vitro, promoted wound healing, facilitated macrophage M2 polarization, and suppressed inflammation in a mouse radiodermatitis model. It was further demonstrated that the radioprotective mechanism of PCA hydrogel in macrophages involves scavenging mitochondrial ROS, maintaining the integrity of mitochondrial ultrastructure and membrane potential, restoring oxidative phosphorylation to remodel energy metabolic homeostasis, and ameliorating ionizing radiation-induced structural and functional abnormalities of mitochondria. Notably, PCA inhibited the cytoplasmic leakage of mitochondrial mtDNA, alleviated radiation-mediated excessive inflammation, and promoted the polarization of macrophages toward a reparative phenotype. Collectively, PCA hydrogel protects mitochondrial homeostasis and modulates inflammatory responses, providing a promising candidate strategy for the treatment of radiodermatitis.
    Keywords:  Hydrogel; Inflammation; Mitochondrial homeostasis; Polygonatum sibiricum polysaccharide; Radiation-induced skin injury
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103520
  33. Aging Cell. 2026 Aug;25(8): e70669
    TRF2 Recovers Ischemic Postconditioning Cardioprotection in Aged Myocardiocytes by Regulating CSNK2A2 Localization and FUNDC1 Dephosphorylation.
    Xuan Zhang, Ji Ma, Ruichen Shu, Yuan Li, Ying Zheng, Yiqing Yin.
      Ischemic postconditioning (I/Post), which is an effective intervention by activating endogenous cardioprotective pathways, recovers ischemia/reperfusion injury. However, this intervention is not as effective in older patients, and its mechanism needs to be further investigated. In this study, we found that myocardial telomeric repeat binding factor 2 (TRF2) protein expression in male aged mice (18 months of age) was lower than that in male adult mice (4 months of age). After ligation of the anterior descending branch of the heart to establish an in vivo model of ischemia/reperfusion injury, we found that TRF2 expression was further decreased after I/Post. To investigate the role of TRF2 in cardioprotection in I/Post in the senescent heart, we performed echocardiography, blood biochemical testing, and apoptosis-related detection after injecting adeno-associated virus type 9 overexpressing TRF2 into aged mice. We found that TRF2 improved myocardial I/Post protection in vivo. Knockdown of TRF2 in a cardiomyocyte cell line (HL-1) increased inflammatory factor release and aggravated mitochondrial and DNA damage in senescent myocardiocytes following hypoxic postconditioning (H/Post). TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes. Moreover, TRF2 interacted with casein kinase 2 alpha 2 polypeptide (CSNK2A2) to regulate the dephosphorylation of FUN14 domain-containing protein 1 (FUNDC1), which contributed to the protective effect of hypoxic postconditioning.
    Keywords:  TRF2; aged myocardiocytes; cGAS/STING pathway; ischemic postconditioning; mitophagy
    DOI:  https://doi.org/10.1111/acel.70669
  34. Autophagy. 2026 Aug 19. 1-22
    Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
    Oluwashanu Balogun, Pamela Cornuet, Elizabeth Lee, Garima Patel, Abdul-Shahid Raheem, Junjie Zhu, Amber Marie Vandevender, Anila P Ashokan, Raheleh Nasrollahi, Raymond E West, Octavia Peck Palmer, Jia-Jun Liu, Thomas D Nolin, Claudette St Croix, Xiaochao Ma, Grant Bullock, Silvia Liu, Satdarshan P Monga, Donna Beer Stolz, Michael Jurczak, M Bishr Omary, Kari Nejak-Bowen.
      Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
    Keywords:  Glutamine synthetase; heme biosynthesis; hepatic zonation; macroautophagy; mechanistic target of rapamycin (mTOR); mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2716960
  35. Front Immunol. 2026 ;17 1893747
    Pituitary adenylate cyclase-activating polypeptide and mitochondrial homeostasis in neuronal injury: mechanisms and translational prospects.
    Wuping Sun, Ruyue Mo, Mingzhu Zhai.
      Pituitary adenylate cyclase-activating peptide (PACAP) is a pleiotropic neuropeptide widely distributed in the nervous system, exhibiting potent cytoprotective effects across a spectrum of neurological disorders. Its neuroprotection is largely mediated through three G protein-coupled receptors (PAC1, VPAC1, VPAC2), activating downstream pathways that converge on preserving mitochondrial integrity. Mitochondrial dysfunction, characterized by bioenergetic failure, oxidative stress, perturbed dynamics (such as fusion and fission), and impaired quality control, is a hallmark of traumatic nerve injury, cerebral ischemia, and retinal neuropathy. This review systematically synthesizes recent evidence elucidating how PACAP counteracts these pathological processes. We detail its mechanisms in 1) mitigating neuropathic pain and promoting axonal regeneration after peripheral nerve trauma; 2) attenuating excitotoxicity, apoptosis, and neuroinflammation following cerebral ischemia by regulating mitochondrial permeability, fission/fusion balance, and NLRP3 inflammasome activation; and 3) protecting retinal ganglion cells against diabetic retinopathy and glaucomatous damage via modulating oxidative stress and apoptotic signaling. Furthermore, we discuss the translational potential of PACAP, including its biomarker value in cerebrospinal fluid and plasma for injury prognosis, and the promise of innovative delivery routes to enhance brain bioavailability. By focusing on mitochondrial-centric mechanisms, this review underscores PACAP as a neuroprotective regulator and highlights its candidacy for developing next-generation neurotherapeutics.
    Keywords:  PACAP; cerebral ischemia; mitochondrial dynamics; mitochondrial dysfunction; neuroprotection; oxidative stress; pituitary adenylate cyclase-activating polypeptide; retinal neuropathy
    DOI:  https://doi.org/10.3389/fimmu.2026.1893747
  36. Front Neurosci. 2026 ;20 1927695
    Mitochondrial-neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes.
    Zihang Huang.
      Post-stroke spasticity is a common and clinically consequential manifestation of the upper motor neuron syndrome, yet its mechanisms are incompletely explained by stretch reflex hyperexcitability alone. Established models emphasize corticospinal and corticoreticulospinal injury, altered brainstem descending drive, spinal reflex amplification, impaired inhibitory control, and secondary changes in skeletal muscle and connective tissue. In parallel, stroke induces profound mitochondrial stress and neuroimmune activation, including bioenergetic failure, mitochondrial reactive oxygen species production, mitochondrial quality-control disturbance, mitophagy dysregulation, mitochondrial danger signaling, glial activation, blood-brain barrier dysfunction, and peripheral immune responses. This Review examines how these mitochondrial-neuroimmune processes may interface with established neural and peripheral mechanisms to shape the onset, persistence, and heterogeneity of post-stroke spasticity. We distinguish strict reflex-mediated spasticity from broader spastic hypertonia, emphasizing that chronic clinical phenotypes often reflect mixed contributions from descending pathway imbalance, spinal disinhibition, spastic dystonia, passive muscle stiffness, pain, and contracture. We propose a brain-spinal cord-muscle framework in which mitochondrial and immune responses after stroke may modify motor-network plasticity, spinal inhibitory remodeling, skeletal muscle metabolism, autophagy-related tissue adaptation, and systemic inflammatory-metabolic vulnerability. Direct PSS-specific evidence remains limited. Accordingly, mitochondrial and neuroimmune pathways are framed here as candidate modifiers of phenotype trajectory rather than as established causes, validated biomarkers, or established therapeutic targets for PSS. The novelty of this Review lies in integrating established circuit and muscle mechanisms with broader stroke mitochondrial-immune biology to define testable interfaces and priorities for longitudinal phenotyping and mechanism-based trials.
    Keywords:  mitochondria; mitochondrial quality control; neuroimmune signaling; neuroinflammation; post-stroke spasticity; reticulospinal tract; skeletal muscle remodeling; spinal inhibition
    DOI:  https://doi.org/10.3389/fnins.2026.1927695
  37. Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073
    Allosteric rewiring of mitochondrial stress signaling through Miro1.
    Layla Drwesh, Julia C Fitzgerald.
      In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.011
  38. J Mol Histol. 2026 Aug 18. pii: 276. [Epub ahead of print]57(5):
    Inhibition of RBM25 preserves cardiac mitochondrial homeostasis and attenuates ischemic heart failure.
    Shu Liu, Hong Ding, Kejuan Li, Xiaowei Zhang.
      Heart failure (HF) after myocardial infarction (MI) is a serious complication that endangers the health of the patient. Mitochondrial dysfunction is an important mechanism in the development of ischemic HF. RNA-binding motif protein 25 (RBM25) is an RNA-binding protein that regulates a variety of biological processes and has been associated with HF. However, its role and underlying mechanism in mitochondrial dysfunction in ischemic HF remain unclear. Left anterior descending artery was ligated to establish an MI model in male C57BL/6 N mice, and cardiac function was evaluated by echocardiography and BNP levels at 4 weeks after ischemia. RBM25-overexpressing AC16 cell lines were constructed using a CRISPR-Cas9-mediated genome editing system. Adeno-associated virus 9-RBM25 shRNA was used to knock down RBM25 in mice. Mitochondrial morphology was observed by transmission electron microscopy, and protein expression was quantified by Western blotting. Cardiac pathology was evaluated by hematoxylin & eosin and Masson staining. Induction of post-ischemic HF in the MI model led to elevated RBM25 protein expression and impaired mitochondrial function in cardiomyocytes. Furthermore, overexpression of RBM25 in AC16 cells altered the expression of mitochondria-associated proteins. Notably, in vivo experiments showed that the knockdown of RBM25 could improve cardiac function after ischemia, along with maintaining mitochondrial morphology and the expression of mitochondrial-related proteins. These findings suggest that RBM25 could mediate HF progression post-infarction by impairing mitochondrial function. Thus, inhibition of RBM25 may have therapeutic potential in slowing down the progression of HF.
    Keywords:  Heart failure; Mitochondrial function; Myocardial infarction; RNA binding motif protein 25
    DOI:  https://doi.org/10.1007/s10735-026-10939-4
  39. Mol Cell Biochem. 2026 Aug 17.
    Long-chain chlorinated paraffins exposure induces premature ovarian failure by disrupting the balance of mitochondrial fission.
    Chenhui Xu, Haochu Deng, Xue Tian, Shuang Ma, Yuebing Kong, Ruoting Zhang, Shiyu Yao, Hainan Lan.
      Long-chain chlorinated paraffins (LCCPs) accumulate in reproductive organs due to their high persistence and bioaccumulation potential; however, the molecular mechanisms underlying their ovarian toxicity remain unclear. In this study, we used primary mouse granulosa cells, a human SVOG cell line, and an oral exposure model in female mice to systematically evaluate the ovarian damage effects of LCCPs and investigate the underlying signaling pathways. The results showed that concentrations of 0.02-2 µg/mL of LCCPs concentration-dependently reduced granulosa cell survival rates (by 12%-58%, P < 0.05), while significantly upregulating oxidative stress (MDA, ROS), inflammatory cytokines (IL-6, TNF-α), and aging markers (SA-β-gal activity). In vivo exposure led to morphological degeneration of ovarian tissue and a reduction in the number of primordial follicles, accompanied by decreased serum estradiol and elevated follicle-stimulating hormone (FSH) levels; these changes resemble the phenotype of clinical ovarian dysfunction. At the mechanistic level, LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence. These findings reveal a novel mechanism by which LCCPs mediate ovarian toxicity via the "excessive mitochondrial fragmentation- mtDNA leakage- cGAS- STING- cellular senescence" axis, providing direct experimental evidence for assessing the risks of persistent organic pollutants to female reproductive health.
    Keywords:  CGAS-STING pathway; Cellular senescence; LCCPs; Mitochondrial fission; Oxidative stress; Premature ovarian failure (POF)
    DOI:  https://doi.org/10.1007/s11010-026-05696-7
  40. Adv Sci (Weinh). 2026 Aug 18. e77280
    CDK4/MERCs/PINK1 Axis Drives PFOA/HFPO-TA-Induced Cardiac Senescence via Mitophagy Defect and cGAS-STING Activation: In Vitro Amelioration by Cycloastragenol.
    Nuo-Wa Li, Jun-Ze Jiang, Ying-Ying Liu, Tian-Tian Zhang, Kanwar Kumar Malhi, Xin Yao, Jin-Long Li.
      Per- and polyfluoroalkyl substances (PFAS) are ubiquitous persistent environmental pollutants with high bioaccumulation potential and widespread human exposure risks in contaminated water, soil, and biota. Although extensive studies have established the hepatotoxic potential of PFAS, much less is known regarding their cardiotoxicity and the underlying molecular mechanisms. Here, we investigated the cardiotoxic effects and molecular pathways of two representative PFAS, perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO-TA). Exposure to either PFOA or HFPO‑TA caused cardiac structural and functional damage, mitochondrial morphological abnormalities, and increased cardiac senescence, with HFPO-TA eliciting greater cardiotoxicity. Mechanistically, PFOA and HFPO-TA suppress CDK4 expression, destabilize mitochondria-endoplasmic reticulum contacts (MERCs), and impair PINK1/Parkin-mediated mitophagy. This defective mitophagy promotes mitochondrial DNA leakage and subsequent activation of the cGAS-STING pathway, ultimately driving cardiac senescence. Notably, cycloastragenol (CAG) effectively reverses CDK4 downregulation, restores MERCs stability, and attenuates PFOA/HFPO-TA-induced cardiac senescence in vitro. Collectively, this study uncovers a CDK4/MERCs/PINK1 axis mediating PFOA/HFPO-TA-induced myocardial toxicity and identifies CAG as a promising natural product for mitigating environmental pollutant-induced cardiac senescence, offering insights for PFAS health risk assessment and intervention strategies.
    Keywords:  CDK4; Cycloastragenol; HFPO‐TA; PFOA; cardiotoxicity; mitophagy
    DOI:  https://doi.org/10.1002/advs.77280
  41. Mol Cell Biochem. 2026 Aug 17.
    Effects of moderate-intensity continuous training on cardiac mitochondrial bioenergetics, oxidative balance, and mitochondrial dynamic in juvenile overnourished rats.
    Jefferson Thadeu Arruda Silva, Matheus Santos de Sousa Fernandes, Reginaldo Correia da Silva Filho, Elenilson Maximino Bernardo, Allifer Rosendo Pereira, Thyago de Oliveira Rodrigues, Mariana Pinheiro Fernandes, Burak Yagin, Fatma Hilal Yagin, Nouf H Alkhamees, Claudia Jacques Lagranha.
      Early life overnutrition can promote lasting metabolic and cardiovascular dysfunction. This study evaluated the effects of post-weaning exercise training on cardiac mitochondrial function, oxidative status, and mitochondrial-related gene expression in rats. After overnutrition period, male Wistar rats were assigned to sedentary or trained groups. The exercise protocol consisted of moderate-intensity treadmill running for 4 weeks. Exercise capacity was assessed before and after the intervention through a progressive running test to determine maximal running velocity (Vmax). Body weight was monitored and after euthanasia, fresh mitochondrial fractions were isolated from the left ventricle by differential centrifugation. Mitochondrial respiration was measured using a Clark-type oxygen electrode. Citrate synthase activity, swelling, reactive oxygen species (ROS) production, lipid peroxidation (MDA), protein carbonyls, redox status (NAD/NADH and GSH/GSSG), total thiol content, and the expression of PGC-1α, TFAM, FIS1, OPA1, and UCP2 were evaluated. Data were analyzed using Student's t-test and two-way ANOVA followed by Tukey's post hoc test. Exercise training increased Vmax (p = 0.014), indicating improved exercise capacity. In left ventricular mitochondria, training enhanced respiratory efficiency and citrate synthase activity (p = 0.028), reduced ROS production (p = 0.035), and attenuated oxidative damage, as shown by lower MDA (p = 0.011) and protein carbonyl levels (p = 0.022). However, mitochondrial swelling analyses did not differ between groups. Antioxidant defenses were strengthened, with an increased GSH/GSSG ratio (p = 0.009) and preserved thiol content (p = 0.041). Exercise also upregulated PGC-1α, TFAM, and FIS1 expression. Post-weaning exercise improves cardiac mitochondrial function, reduces oxidative stress, and modulates mitochondrial dynamics in rats exposed to early life overnutrition.
    Keywords:  Aerobic exercise; Cardiac metabolism; Mitochondria; Overnutrition; Oxidative stress
    DOI:  https://doi.org/10.1007/s11010-026-05697-6
  42. Mol Neurobiol. 2026 Aug 21. pii: 847. [Epub ahead of print]63(1):
    Melatonin in Peripheral Nerve Regeneration: Molecular Mechanisms, Schwann Cell Dynamics, and Translational Therapeutic Potential.
    Omar Alomari, Beyzanur Güney, Irem Uslu, Banu Şahin, Tasneem Alomari, Beyza Nur Ülker, Mehmet Yigit Sari, Duygu Sari-Ak, Russel J Reiter.
      Peripheral nerve injury (PNI) presents a significant clinical challenge often resulting in long-term functional disability. Following injury, successful regeneration heavily depends on the cellular plasticity of Schwann cells (SCs) to undergo dedifferentiation, proliferate, and guide axonal growth. Recently, the pineal hormone melatonin has emerged as a promising therapeutic candidate due to its potent antioxidant properties and ability to modulate SC biological behavior. However, its exact molecular mechanisms and direct impact on SC proliferation remain fragmented across literature. Following PRISMA 2020 guidelines and registered on PROSPERO (CRD420261373030), a systematic search was conducted across Medline via PubMed, Scopus, and Web of Science up to April 1, 2026. Original in vitro and in vivo studies evaluating melatonin's effects on SC proliferation and PNI models were included. Data extraction focused on signaling pathways, histological outcomes, and functional recovery. Risk of bias was assessed using QUIN for in vitro and SYRCLE for in vivo studies. Twenty-six studies (12 in vivo, 3 in vitro, 11 mixed) were analyzed. In vitro, melatonin administration was frequently associated with dose-dependent mitogenic responses in RSC96 and primary SCs, operating primarily via MT1 receptor interaction and downstream activation of the Ras/Raf/ERK-MAPK and Shh signaling pathways. It supported SC dedifferentiation alongside Sox2 upregulation and alternative FAK activation, while preserving cell viability under oxidative stress via Parkin-mediated mitophagy. In vivo, melatonin treatment was correlated with increased myelin sheath thickness, higher axon density, and elevated SC infiltration across sciatic, cranial, and brachial plexus models. These structural changes were accompanied by functional recovery trends, higher CMAP amplitudes, and reduced lipid peroxidation markers (lowered MDA/MPO). Advanced delivery platforms, including 3D-printed scaffolds and electrospun magnetic nanoparticles, achieved sustained local melatonin release in experimental models. Preclinical evidence indicates that melatonin modulates Schwann cell proliferation, migration, and cytoprotection through receptor-dependent and antioxidant mechanisms. These findings offer a foundational, evidence-based rationale for further investigation in large-animal models and prospective clinical trial designs.
    Keywords:  Axonal remyelination; Melatonin; Mitophagy; Nerve regeneration; PNI; SCs
    DOI:  https://doi.org/10.1007/s12035-026-06150-x
  43. Bioorg Chem. 2026 Aug 12. pii: S0045-2068(26)00906-5. [Epub ahead of print]181 110370
    Discovery of iodo-phenanthroimidazole derivatives as potential HDAC1 inhibitors inducing mitophagy to suppress glioblastoma progression.
    Xiaomei Shi, Jiangbo Liang, Zhuoyan Wu, Mengjiao She, Yan Liu, Chunguang Zhu, Ling Fang, Ranxi Dong, Qiong Wu, Wenjie Mei.
      Glioblastoma, the most prevalent and highly aggressive primary brain tumor, is characterized by high clinical recurrence rates and significant resistance to conventional therapies, highlighting the need for innovative targeted agents to address current treatment limitations. This study employed an integrated computational and experimental strategy to identify novel iodo-phenanthroimidazole derivatives (compounds 1-3). Compound 3 was identified as a lead candidate that inhibits HDAC1 and may trigger autophagy, thereby suppressing glioblastoma progression. Molecular docking and molecular dynamics simulations indicated stable interactions between compound 3 and the HDAC1 catalytic site (estimated binding energies of -7.75 and - 7.74 kcal/mol), with a notable halogen bond between the iodine atom and Asp104. The phenanthroimidazole scaffold was proposed as a potential zinc-binding group (ZBG) for HDAC1 inhibition. Biophysical validation using isothermal titration calorimetry (ITC) confirmed submicromolar binding affinity (Kd = 1.04 × 10-7 M, ΔH = -91.24 kJ·mol-1). In vitro evaluation demonstrated potent inhibition of U87-MG glioblastoma cell proliferation (IC50 = 0.23 μM), and flow cytometric analysis indicated concomitant cell cycle arrest at both G2/M and S phases. Transmission electron microscopy revealed autophagic vacuoles containing damaged mitochondria, and immunofluorescence showed an increased LC3-II/LC3-I ratio. Together with the observed loss of mitochondrial membrane potential and ATP depletion, these findings are consistent with the induction of a mitophagy-like process. Using an in vivo zebrafish orthotopic glioblastoma model, the lead compound demonstrated blood-brain barrier penetration and effectively suppressed tumor growth and U87-MG cell metastasis. This work highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma. The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression.
    Keywords:  Glioblastoma; HDAC1; Iodo-phenanthroimidazole derivatives; Mitophagy
    DOI:  https://doi.org/10.1016/j.bioorg.2026.110370
  44. Alzheimers Dement. 2026 Aug;22(8): e71680
    A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
    Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.
       INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
    METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
    RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
    DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.
    Keywords:  AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy
    DOI:  https://doi.org/10.1002/alz.71680
  45. Iran J Basic Med Sci. 2026 ;29(6): 952-960
    Involvement of SIRT3 downstream targets ANT1, VDAC, CYPD, and Drp1 in a rat model of hepatic encephalopathy: Therapeutic role of thymoquinone.
    Somayeh Hajipour, Mohammad Amin Dehghani, Alireza Sarkaki, Masoud Mahdavinia, Seyedeh Parisa Navabi.
       Objectives: Hepatic encephalopathy (HE) is a brain disorder linked to hyperammonemia from liver injury. Elevated ammonia levels are known to impair mitochondrial function, the primary energy source for cells. Therefore, this study aimed to evaluate energy-related signaling pathways enhancing mitochondrial biogenesis using thymoquinone (TQ) in an HE model.
    Materials and Methods: Wistar rats were randomly divided into three groups: sham, HE (200 mg/kg thioacetamide (TAA) in 2ml saline, administered intraperitoneally (IP) once every 48 hr for 14 consecutive days), and HE + TQ (20 mg/kg, IP, in 2 ml DMSO 5% administered once daily for seven consecutive days). Mitochondrial biomarkers (membrane potential [MMP], oxidative stress), gene expression (AMPK, PGC-1α), and protein expression (AMPK, P-AMPK, SIRT3, ANT1, CYPD, DRP1, VDAC, and P53) were measured in brain tissue. Additionally, electroencephalogram (EEG) recordings were obtained from the dentate gyrus (DG).
    Results: Our findings indicate that TQ was associated with a significant increase in MMP and a concomitant decrease in mitochondrial oxidative stress. Furthermore, TQ appeared to augment the AMPK/PGC-1α/SIRT3 signaling pathway, and was associated with the reversal of HE-induced down-regulation of ANT1 and VDAC, as well as up-regulation of CYPD, DRP1, and P53. Besides, TQ treatment was also linked to increased power recorded in the EEG from the DG region of the rat hippocampus.
    Conclusion: The AMPK/PGC-1α/SIRT3 signaling pathway appears to function as a key energy sensor that may help revitalize the metabolic machinery in mitochondria, potentially facilitating metabolic exchanges and energy production, particularly in response to neurodegenerative diseases such as HE.
    Keywords:  ANT1; CYPD; DRP1; Hepatic encephalopathy; Local EEG; VDAC
    DOI:  https://doi.org/10.22038/ijbms.2026.93478.20159
  46. Redox Biol. 2026 Aug 12. pii: S2213-2317(26)00347-2. [Epub ahead of print]96 104348
    Systemic redox switching of transcription factors: A context-sensitive framework for cell fate decisions.
    Elitsa Y Dimova, Thomas Kietzmann.
      Transcription factors often exhibit a striking paradox: they function as tumor suppressors in one context and promote oncogenesis in another. The underlying mechanisms of this context dependence have remained elusive. We propose a novel conceptual framework, systemic redox switching, to resolve this paradox. Based on our research on upstream stimulatory factor 2 (USF2) and convergent observations on other factors, our model suggests that redox regulation is network-embedded rather than driven by discrete cysteine switches. We propose that transcription factors occupy distinct regulatory regimes (homeostatic, adaptive, and survival states) which are connected by threshold-like, hysteretic transitions. Beyond classical graded input-output views, this framework explicitly posits discrete, hysteretic regime transitions at the transcriptional-network level and links them to a minimal dynamical model of the USF2-TFEB-NRF2-redox motif. These transitions convert continuous redox inputs into distinct changes in promoter occupancy and transcriptional programs. USF2 exemplifies a kinase-integrated, non-canonical switch that decodes mitochondrial and autophagy signals via phosphorylation (e.g., Ser155) and context-dependent cooperation with NRF2 and HIFs. Extending this logic to diverse archetypes (NRF2, HIFs, FOXOs, c-MYC, and AHR) demonstrates the framework's generalizability. The model is experimentally tractable; targeted perturbations of primary sensing modules (e.g., KEAP1 mutation, PHD inhibition, or USF2 phosphorylation disruption) should predictably alter regime transitions. By reframing paradoxical behaviors as controlled state transitions, this framework provides a unifying, network-level understanding with direct implications for targeting therapies in cancer, metabolic diseases, and age-related pathologies.
    Keywords:  Autophagy regulation; Cellular stress response; Context-dependent gene regulation; Mitophagy; Oxidative stress; Redox biology; Transcriptional switches; Tumor suppressor
    DOI:  https://doi.org/10.1016/j.redox.2026.104348
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