bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–04–27
forty-two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
  2. Krüppel-like factors in mitochondrial quality control.
  3. Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.
  4. SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
  5. TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
  6. Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
  7. Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
  8. Pathogenetic Involvement of Autophagy and Mitophagy in Primary Progressive Multiple Sclerosis.
  9. Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy.
  10. UPRmt alleviates bone cancer pain through the restoration of mitochondrial function.
  11. TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.
  12. TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
  13. Epicoccin A Ameliorates PD-like Symptoms in Zebrafish: Enhancement of PINK1/Parkin-Dependent Mitophagy and Inhibition of Excessive Oxidative Stress.
  14. Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer's disease.
  15. AMPK-YAP signaling pathway-mediated mitochondrial dynamics and mitophagy participate in the protective effect of silibinin on HaCaT cells under high glucose conditions.
  16. OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.
  17. Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
  18. Buyang Huanwu Decoction stabilizes atherosclerotic vulnerable plaques by regulating intestinal flora, TLR4-NF-κB-NLRP3 inflammatory pathway and mitophagy.
  19. Correction to "Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin RPB5 Interactor 1-Mediated Mitophagy".
  20. Deficiency of FUN14 domain-containing 1 enhances the migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis through mitochondrial dysregulation.
  21. S-9-PAHSA Attenuates Aβ Accumulation and Improves Cognitive Deficits by Promoting Mitochondrial Autophagy in 5xFAD Mice.
  22. Acupuncture alleviates hemorrhagic transformation after delayed rt-PA treatment for acute ischemic stroke by regulating the mitophagy-NLRP3 inflammasome pathway.
  23. Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.
  24. Mechanism of Nano-Microplastics Exposure-Induced Myocardial Fibrosis: DKK3-Mediated Mitophagy Dysfunction and Pyroptosis.
  25. SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
  26. Gestational Exposure to Black Phosphorus Nanoparticles Induces Placental Trophoblast Dysfunction by Triggering Reactive Oxygen Species-Regulated Mitophagy.
  27. MiR-718-mediated inhibition of prohibitin 1 influences mitochondrial dynamics, proliferation, and migration of keratinocytes.
  28. LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.
  29. YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
  30. MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy.
  31. TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy.
  32. Role of IP3R2-Mediated mitochondrial calcium homeostasis in early hypoxic stress injury of retinal pigment epithelial cells.
  33. Stibene glucoside prevents PM2.5 caused pulmonary fibrosis by Pseudo hypoxia, autophagy and NF-κB signal pathways.
  34. Mitochondrial Energy Homeostasis and Membrane Interaction Regulate the Rapid Growth of Moso Bamboo.
  35. rhCC16 Suppresses Cellular Senescence and Ameliorates COPD-Like Symptoms by Activating the AMPK/Sirt1-PGC-1-α-TFAM Pathway to Promote Mitochondrial Function.
  36. Correction: CircSPG21 ameliorates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells and mitigates intervertebral disc degeneration through the miR-217/SIRT1 axis and mitophagy.
  37. Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.
  38. Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
  39. Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
  40. Correction: Zhou et al. Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy. Cells 2019, 8, 213.
  41. Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
  42. Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.
  1. J Mol Biol. 2025 Apr 21. pii: S0022-2836(25)00227-X. [Epub ahead of print] 169161
    Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
    Bishal Basak, Erika L F Holzbaur.
      Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.
    Keywords:  PINK1; Parkin; autophagosomes; lysosomes; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.jmb.2025.169161
  2. Front Physiol. 2025 ;16 1554877
    Krüppel-like factors in mitochondrial quality control.
    M Y Zhang, H Zhang, Y M Yao, D W Yang.
      Krüppel-like factors (KLFs) are a group of transcription factors characterized by conserved zinc finger domains in the C-terminus, which are critically involved in basic cellular processes, including growth, differentiation, apoptosis, and angiogenesis, and play important roles in many pathophysiological responses. Mitochondrial homeostasis relies on a coordinated mitochondrial quality control system, which maintains the number and morphological stability and coordinates mitochondrial physiological functions through renewal and self-clearance. In this paper, we review the current advances of KLFs in mitochondrial quality control (MQC), including the potential roles and regulatory mechanisms in mitochondrial biogenesis, mitochondrial fusion/fission, mitophagy and mitochondrial unfolded protein response. We also introduce the specific pharmacological modulation of KLFs, expecting to transforming basic research achievements and providing the possibility of targeted therapy for KLFs.
    Keywords:  Krüppel-like factors; mitochondrial biogenesis; mitochondrial fusion/fission; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2025.1554877
  3. Plant Cell Physiol. 2025 Apr 23. pii: pcaf038. [Epub ahead of print]
    Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.
    Kacper Ludwig, Małgorzata Heidorn-Czarna.
      Mitochondria play a central role in cellular respiration and other essential metabolic and signaling pathways. To function properly, mitochondria require the maintenance of proteostasis-a balance between protein synthesis and degradation. This balance is achieved through the mitochondrial protein quality control (mtPQC) system, which includes mitochondrial proteases and mitophagy. Mitochondrial proteases ensure proper protein sorting within the mitochondria and maintain proteome homeostasis by degrading unassembled, damaged, or short-lived regulatory proteins. Numerous studies have demonstrated the critical role of mitochondrial proteases in regulating mitophagy-the selective degradation of damaged, aging, or excess mitochondria or their fragments via autophagy. Notably, the rhomboid PARL protease is involved in ubiquitin-dependent PINK1-Parkin mitophagy in mammals while the i-AAA protease Yme1 plays a role in mitophagy in budding yeast. Despite the conservation of core autophagy genes, knowledge about the molecular mechanisms and protein regulators of mitophagy in plants remains limited. In this review, we discuss recent advances in understanding the roles of mitochondrial proteases and mitophagy across plants, animals, and yeast. By comparing these mechanisms across kingdoms, we highlight the potential regulatory function of the plant i-AAA mitochondrial protease in controlling mitophagy, providing new insights into mitochondrial protein quality control networks in plants.
    Keywords:   Arabidopsis thaliana ; i-AAA protease; mitochondria; mitochondrial proteases; mitochondrial protein quality control system; mitophagy
    DOI:  https://doi.org/10.1093/pcp/pcaf038
  4. Autophagy. 2025 Apr 25. 1-3
    SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
    Mingzhu Tang, Guang Lu, Han-Ming Shen.
      Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of PINK1 transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.
    Keywords:  Mitophagy; PINK1; SMAD3; phosphorylation; transcription
    DOI:  https://doi.org/10.1080/15548627.2025.2496364
  5. J Cell Biol. 2025 May 05. pii: e202503004. [Epub ahead of print]224(5):
    TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
    Yu Sun, Terytty Yang Li.
      Mitochondrial function is critical for neuronal activity and systemic metabolic adaptation. In this issue, Li et al. (https://doi.org/10.1083/jcb.202408050) identify TMBIM-2 as a key regulator of calcium dynamics, coordinating the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt), pathogen-induced aversive learning, and aging.
    DOI:  https://doi.org/10.1083/jcb.202503004
  6. Mitochondrion. 2025 Apr 17. pii: S1567-7249(25)00037-6. [Epub ahead of print]84 102040
    Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
    Isabel Amador-Martínez, Ana Karina Aranda-Rivera, Mauricio Raziel Martínez-Castañeda, José Pedraza-Chaverri.
      Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.
    Keywords:  Cardio-renal disease; Integrated stress response; Mitochondrial dysfunction; Mitochondrial import; Mitochondrial quality control; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.mito.2025.102040
  7. PLoS Genet. 2025 Apr 25. 21(4): e1011678
    Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
    Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei.
      Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011678
  8. J Cell Mol Med. 2025 Apr;29(8): e70455
    Pathogenetic Involvement of Autophagy and Mitophagy in Primary Progressive Multiple Sclerosis.
    Simone Patergnani, Michele Laudisi, Massimo Bonora, Giulio Righes, Sofia Straudi, Mariusz R Wieckowski, Ilaria Casetta, Luana Semenzato, Konstantinos Koutsikos, Veronica Zanato, Carlotta Giorgi, Paolo Pinton.
      Primary progressive multiple sclerosis (PPMS) affects a subset of MS patients and is characterised by continuous progression from the onset. The molecular mechanisms underlying PPMS are poorly understood, and therapeutic options are limited, with no specific markers for early detection and monitoring. This study investigated the roles of autophagy and mitophagy in PPMS. We found that autophagy markers (ATG5 and ATG7) and mitophagy markers (Parkin and Optineurin) were significantly reduced in the serum of PPMS patients compared to control and relapsing-remitting MS (RRMS) individuals. This reduction was associated with an increase in markers indicative of neurodegeneration and mitochondrial dysfunction. Additionally, a positive correlation between autophagy and mitophagy proteins in the PPMS group suggests that these mechanisms are reciprocally associated and modulated in PPMS. Our investigation reveals that autophagy and mitophagy are actively involved in PPMS and exhibit distinct patterns across MS subtypes. Measurements of circulating components related to autophagy and mitophagy could serve as potential biomarkers for early PPMS detection.
    Keywords:  ATG5; ATG7; GFAP; Optineurin; Parkin; biomarker; lactate; serum
    DOI:  https://doi.org/10.1111/jcmm.70455
  9. Int Immunopharmacol. 2025 Apr 19. pii: S1567-5769(25)00661-7. [Epub ahead of print]156 114671
    Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy.
    Anqi Zhang, Shilan Luo, Peng Li, Lu Meng, Litang Huang, Hongxia Cheng, Chenhui Zhao, Hongbin Tu, Xiaomei Gong.
       BACKGROUND: Radiation pneumonitis (RP) is a common and severe complication of radiotherapy, whose pathogenesis involves complex inflammatory responses and cellular damage. Despite its clinical significance, effective treatments remain limited. This study investigates the role of radiation-induced PINK1/PRKN-mediated mitophagy and type I interferon responses in RP and evaluates the therapeutic potential of Urolithin A (UA) in regulating inflammation through mitophagy activation.
    METHODS: We established RP mouse models (20 Gy thoracic irradiation) and radiation-induced BEAS-2B cell models (6 Gy). We systematically investigated mitochondrial damage, mtRNA release, RIG-I/MDA5-MAVS pathway activation, and PINK1/PRKN-mediated mitophagy changes. Moreover, the effects of UA and the mitophagy inhibitor Mdivi-1 on inflammation and lung injury were analyzed.
    RESULTS: Radiation significantly caused mitochondrial damage in lung tissues, inducing mtRNA release and RIG-I/MDA5-MAVS-mediated type I interferon response. PINK1/PRKN-mediated mitophagy was significantly enhanced, clearing damaged mitochondria and reducing cytosolic mtRNA release, thereby suppressing inflammation. Pharmacological activation of mitophagy with UA markedly improved lung pathology, reduced inflammatory cytokine levels, and inhibited excessive activation of the RIG-I/MDA5-MAVS pathway. Conversely, the knockdown of PINK1 or PRKN weakened the protective effects of UA. Both in vitro and in vivo, UA reduced radiation-induced inflammation and improved lung tissue structure and function through mitophagy.
    CONCLUSIONS: Radiation-induced mtRNA release activates the RIG-I/MDA5-MAVS-mediated type I interferon response, driving inflammation in RP. PINK1/PRKN-mediated mitophagy significantly alleviates inflammation by reducing cytosolic mtRNA release. As a mitophagy inducer, UA demonstrates therapeutic potential for RP, providing a new direction for the development of anti-inflammatory strategies.
    Keywords:  Inflammation; Mitophagy; PINK1/PRKN; Radiation pneumonitis; Urolithin A
    DOI:  https://doi.org/10.1016/j.intimp.2025.114671
  10. Exp Cell Res. 2025 Apr 22. pii: S0014-4827(25)00164-8. [Epub ahead of print]448(2): 114568
    UPRmt alleviates bone cancer pain through the restoration of mitochondrial function.
    Dan Li, Mingming Xie, Haohao Zeng, Jiacheng Yu, Rui Xu, Zhen Wang, Yulin Huang, Yan Yang, Yu'e Sun.
      The mitochondrial unfolded protein response (UPRmt) is an intracellular retrograde signaling process that facilitates the restoration of mitochondrial homeostasis. Mitochondria are essential for neuronal signaling, and their dysfunction has been implicated as a significant mechanism in the development of chronic pain. Nevertheless, little is known about the exact function of UPRmt in bone cancer pain (BCP). This research intended to explore the connection between UPRmt and the progression of BCP. In BCP group, the ultrastructure of spinal cord mitochondria was disrupted, accompanied by a decline in ATP levels and a decrease in Mitochondrial membrane potential (MMP). Concurrently, mRNA and protein levels of UPRmt marker proteins (Atf5, Hsp60, LonP1, and ClpP) were upregulated, with the expression of Atf5, a key transcription factor of UPRmt, notably enhanced in spinal dorsal horn neurons. Nicotinamide riboside (NR)-mediated pharmacological augmentation of the UPRmt significantly alleviated BCP-induced nociceptive hypersensitivity, as demonstrated by elevated mechanical withdrawal thresholds and diminished spontaneous flinching behavior. Concomitant mitochondrial functional recovery was evidenced by restoration of MMP and normalization of ATP level. Notably, genetic knockdown of activating transcription factor 5 (Atf5) abolished both NR-induced UPRmt activation and the consequent protection against rotenone-mediated mitochondrial dysfunction. These findings establish UPRmt potentiation as an effective strategy for ameliorating mitochondrial dysfunction and attenuating BCP-associated nociception, proposing this pathway as a novel therapeutic target for clinical pain management.
    Keywords:  Bone cancer pain; Mitochondria; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114568
  11. Cell Death Differ. 2025 Apr 23.
    TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.
    Kang Chen, Jinyu Chen, Yukun Cong, Qingliu He, Chunyu Liu, Jiawei Chen, Haoran Li, Yunjie Ju, Liang Chen, Yarong Song, Yifei Xing.
      Bladder cancer (BC) remains a major global health challenge, with poor prognosis and limited therapeutic options in advanced stages. TTK protein kinase (TTK), a serine/threonine kinase, has been implicated in the progression of various cancers, but its role in BC has not been fully elucidated. In this study, we show that TTK is significantly upregulated in BC tissues and cell lines, correlating with poor patient prognosis. Functional assays revealed that TTK promotes proliferation and inhibits apoptosis of BC cells. Mechanistically, TTK enhances mitophagy by directly phosphorylating ULK1 at Ser477, thereby activating the ULK1/FUNDC1-mediated mitophagy pathway. TTK knockdown disrupts mitophagy, leading to impaired clearance of damaged mitochondria, excessive accumulation of mitochondrial reactive oxygen species (mtROS), and activation of mitochondrial apoptosis. Furthermore, TTK phosphorylates SRSF3 at Ser108, preventing ULK1 exon 5 skipping and maintaining ULK1 mRNA stability. These findings show that TTK plays a key role in maintaining mitophagy in BC cells. Targeting TTK could offer a promising new approach for BC treatment by disrupting mitophagy and inducing mitochondrial apoptosis.
    DOI:  https://doi.org/10.1038/s41418-025-01492-w
  12. Nat Chem Biol. 2025 Apr 22.
    TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
    Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren.
      Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41589-025-01894-4
  13. Mar Drugs. 2025 Apr 17. pii: 175. [Epub ahead of print]23(4):
    Epicoccin A Ameliorates PD-like Symptoms in Zebrafish: Enhancement of PINK1/Parkin-Dependent Mitophagy and Inhibition of Excessive Oxidative Stress.
    Haicheng Ye, Dan Li, Lei Zhang, Yufei Wang, Cong Wang, Meng Jin, Houwen Lin, Peihai Li, Chen Sun, Ning Li.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet effective agents for its prevention and therapy remain highly limited. Epicoccin A, a significant secondary metabolite from Exserohilum sp., demonstrates various biological activities; however, its neuroprotective effects have not been elucidated. Here, we investigated the therapeutic potential of epicoccin A for PD by evaluating its impact on neural phenotype, reactive oxygen species (ROS) generation, and locomotor activity in PD-like zebrafish. Transcriptomic analysis and molecular docking were conducted, with key gene expressions further verified using real-time qPCR. As a result, epicoccin A notably mitigated dopaminergic neuron loss, neural vasculature deficiency, nervous system injury, ROS accumulation, locomotor impairments, and abnormal expressions of hallmark genes associated with PD and oxidative stress. Underlying mechanism investigation indicated epicoccin A may alleviate PD-like symptoms by activating PINK1/Parkin-dependent mitophagy, as evidenced by the reversal of aberrant gene expressions related to the pink1/parkin pathway and its upstream mTOR/FoxO pathway following epicoccin A co-treatments. This finding was further confirmed by the robust interactions between epicoccin A and these mitophagy regulators. Our results suggest that epicoccin A relieves PD symptoms by activating pink1/parkin-dependent mitophagy and inhibiting excessive oxidative stress, highlighting its potential as a therapeutic approach for PD.
    Keywords:  MPTP; ROS; marine-derived fungus; molecular docking; neuroprotective effect; transcriptome analysis; underlying mechanism; α-synuclein
    DOI:  https://doi.org/10.3390/md23040175
  14. Organelle. 2024 ;pii: 2. [Epub ahead of print]1(1):
    Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer's disease.
    Yasin Asadi, Hongmin Wang.
      Transcriptional control is a pivotal mechanism governing various cellular processes. FOXO proteins, a subgroup of the forkhead family of transcription factors, play a key role in determining cell fate. The localization and function of FOXO proteins are regulated by post-translational modifications to control target gene expression, with a pronounced impact on various aspects of mitochondrial function, including mitochondrial dynamics, biogenesis, and quality control. Mitochondria stand out as the primary target of FOXO transcription factors, which recruit downstream signaling factors to govern mitochondrial processes. Essential signaling pathways are modulated by FOXOs, exemplified by their regulation of mitochondrial biogenesis through SIRT1-Pgc1α and NRF1-TFAM, as well as their influence on mitochondrial dynamics involving Mfn1, Mfn2, Drp1, and Fis1. Furthermore, FOXOs demonstrate the ability to upregulate and downregulate genes that serve as regulators in oxidative and apoptosis cascades. The functional role of FOXO proteins is highly context-dependent, varying with cell type, organ, and specific FOXO isoform. Notably, FOXOs emerge as prominent players in various pathological conditions, including ischemic conditions, neurodegenerative diseases, cancer, and metabolic disorders. Unraveling the intricate role of FOXOs in mammalian cell pathology positions them as promising therapeutic targets amenable to pharmacological intervention. This review aims to provide insights into the intricate roles of FOXOs in mitochondria, illuminating their potential as therapeutic targets amenable to pharmacological intervention in diverse pathological contexts, particularly in ischemic stroke and Alzheimer's disease.
    Keywords:  Alzheimer’s disease; FOXO; autophagy; ischemia; mitochondrial biogenesis; mitochondrial function; mitochondrial homeostasis; mitochondrial structure; stroke; transcription factor
    DOI:  https://doi.org/10.61747/0ifp.202403001
  15. Arch Biochem Biophys. 2025 Apr 21. pii: S0003-9861(25)00146-8. [Epub ahead of print] 110433
    AMPK-YAP signaling pathway-mediated mitochondrial dynamics and mitophagy participate in the protective effect of silibinin on HaCaT cells under high glucose conditions.
    Xianshi Wang, Xueying Sun, Xiaodi Zhang, Naiying Shen, Junlong Xia, Lu Wang, Shasha Ye.
      UVB irradiation and diabetes lead to skin injury. However, UVB irradiation has rarely been studied in the field of diabetes. Silibinin has a positive therapeutic effect on many diseases. Nevertheless, the inhibitory effects of silibinin on UVB-induced damage to epidermal cells under high glucose (HG) conditions have been infrequently investigated. Consequently, this study examined the protective efficacy and mechanisms of silibinin in mitigating UVB-induced apoptosis in epidermal cells cultured under HG conditions. The effects of combination of HG and UVB on mitochondrial apoptosis and pro-inflammatory factors production in human immortalized keratinocytes (HaCaT) were mitigated by silibinin. Meantime, silibinin reversed the UVB-induced imbalance of fission/fusion in HG-cultured HaCaT cells. Furthermore, UVB exposure increased ROS levels and reduced mitophagy in HaCaT cells under HG conditions; however, these effects were subsequently reversed by silibinin treatment. AMPK preserves energy balance by negatively regulating YAP. Silibinin increased the levels of p-AMPK and cytoplasmic YAP proteins in HaCaT cells subjected to HG and UVB treatment. Moreover, silibinin improved the dysfunction of mitochondrial dynamics, increased mitophagy levels, the viability and the expression of cytoplasmic YAP protein, and these effects were reversed via the application of an AMPK inhibitor (compound C). In summary, silibinin safeguarded epidermal cells from UVB-induced apoptosis under HG conditions by modulating mitochondrial dynamics and mitophagy through the AMPK-YAP signaling pathway.
    Keywords:  AMPK; UVB; YAP; apoptosis; mitochondrial dynamics; silibinin
    DOI:  https://doi.org/10.1016/j.abb.2025.110433
  16. J Transl Med. 2025 Apr 24. 23(1): 471
    OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.
    Kexuan Zhang, Wenqing Zhang, Lin Zhang, Xiaorong Hou, Runyi Tian, Zhengmao Hu, Lili Yin, Zhonghua Hu.
       BACKGROUND: Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear.
    METHODS: To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts.
    RESULTS: Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F.
    CONCLUSIONS: This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.
    Keywords:  Apoptosis; Autosomal dominant optic atrophy (ADOA); Bundle signaling element (BSE); GTPase activity; Mitochondrial dynamics; OPA1 mutations
    DOI:  https://doi.org/10.1186/s12967-025-06471-w
  17. Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290
    Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
    Mohamed A Eldeeb, Michael Shahid, Edward A Fon.
      Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.
    DOI:  https://doi.org/10.1016/j.cub.2025.03.011
  18. Phytomedicine. 2025 Apr 12. pii: S0944-7113(25)00390-3. [Epub ahead of print]142 156751
    Buyang Huanwu Decoction stabilizes atherosclerotic vulnerable plaques by regulating intestinal flora, TLR4-NF-κB-NLRP3 inflammatory pathway and mitophagy.
    Shi-Yao Chang, Yu-Ting Li, Hong-Yang Zhu, Zhi-Xian He, Yu You, Yu-Hui Liu.
       OBJECTIVE: This study explores the anti-atherosclerosis (AS) effects of Buyang Huanwu Decoction (BYHWD), focusing on its regulatory effects on the TLR4/NF-κB/NLRP3 inflammatory pathway, gut microbiota metabolites, and mitochondrial autophagy. Through the triple regulatory mechanisms of gut microbiota, the TLR4/NF-κB/NLRP3 inflammatory pathway, and mitochondrial autophagy, this study explores a novel strategy for stabilizing vulnerable AS plaques.
    MATERIALS AND METHODS: The active components of Buyang Huanwu Decoction (BYHWD) were detected using LC-MS/MS. By feeding a high-fat diet (HFD) and adding 1.3 % choline chloride to the drinking water to induce ApoE-/- mice gut microbiota dysbiosis, an AS mouse model with vulnerable plaques was established. The treatment groups were administered low, medium, and high doses of BYHWD, as well as broad-spectrum antibiotics. The effects of BYHWD on the vulnerable plaque area in the aorta, collagen content, macrophage and α-SMA protein expression, levels of inflammatory cytokines, reactive oxygen species (ROS), LC3 and NLRP3 expression, gut microbiota composition and abundance, serum trimethylamine-N-oxide (TMAO) levels, and the total bile acid content in the liver, serum, and gallbladder, as well as mitochondrial autophagy, were evaluated applying hematoxylin-eosin (HE) staining, Oil Red O staining, Sirius Red staining, immunohistochemistry, ELISA, immunofluorescence, 16S rRNA sequencing, biochemical analysis, and LC-MS detection. Western blot for TLR4, MyD88, ASC, pro-caspase-1, caspase-1, NLRP3, p-NF-κB/NF-κB, GPR41, GPR43, CYP7A1, CYP27A1, FMO3, FXR, TGR5, NIX, BNIP3, FUNDC1, PINK1, and Parkin proteins expression level.
    RESULTS: A total of 31 major active components were identified in Buyang Huanwu Decoction (BYHWD). BYHWD significantly reduced the vulnerable plaque area in the ApoE-/- mouse model of AS, decreased the expression of inflammatory cytokines, inhibited the protein expression of TLR4, MyD88, p-NF-κB/NF-κB, ASC, pro-caspase-1, NLRP3, FMO3, NIX, BNIP3, FUNDC1, and PINK1/Parkin in aortic tissues, downregulated ROS levels and mitochondrial autophagy activity, regulated gut microbiota abundance, reduced serum TMAO levels, and up-regulated the expression of gut microbiota-related proteins, including GPR41, GPR43, CYP7A1, CYP27A1, FXR, and TGR5.
    CONCLUSION: BYHWD exerts anti-AS effects through the inhibition of the TLR4/NF-κB/NLRP3 inflammatory pathway, modulating the gut microbiota, and stabilizing mitochondrial autophagy. The in-depth investigation of this mechanism effectively expands the therapeutic potential of BYHWD in the prevention and treatment of cardiovascular diseases and provides new theoretical insights and therapeutic targets for AS-related research.
    Keywords:  Atherosclerosis; Buyang Huanwu Decoction; Gut microbiota; Mitophagy; TLR4-NF-κB-NLRP3 inflammatory pathway
    DOI:  https://doi.org/10.1016/j.phymed.2025.156751
  19. Chem Biol Drug Des. 2025 Apr;105(4): e70109
    Correction to "Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin RPB5 Interactor 1-Mediated Mitophagy".
      
    DOI:  https://doi.org/10.1111/cbdd.70109
  20. Cell Signal. 2025 Apr 22. pii: S0898-6568(25)00242-6. [Epub ahead of print] 111829
    Deficiency of FUN14 domain-containing 1 enhances the migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis through mitochondrial dysregulation.
    Ye Lu, Ya-Xiong Fang, Zhi-Ming Ou-Yang, Tao Wu, Qian Zhang, Yao-Wei Zou, Hu-Wei Zheng, Jun Jing, Le-Hang Lin, Jian-Da Ma, Zhuoyi Liang, Lie Dai.
       BACKGROUND: Fibroblast-like synoviocytes (FLS) display aggressive phenotypes contributing to synovitis and joint destruction in rheumatoid arthritis (RA). Disrupted mitochondrial homeostasis has been proposed to aggravate the RA pathogenesis, however, the underlying mechanism remains to be elucidated. This study aimed to elucidate the role of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) on RA-FLS migration and invasion.
    METHODS: We analyzed the correlation of synovial FUNDC1 expression with joint destruction and disease activity in RA patients. Single cell sequencing data analysis combined with immunofluorescence indicated the specific expression and localization of FUNDC1 in synovial tissue and RA-FLS. The roles of FUNDC1 in the migration, invasion, and cytokine secretion of RA-FLS were examined by patient-derived primary culture as well as SCID mouse models. We investigated the effects and mechanism of FUNDC1 on mitophagy and mitochondrial quality control network in primary RA-FLS.
    RESULTS: We found that the FUNDC1 was mainly expressed in FLS and exhibited a decreased level in RA synovium, which was correlated with severe joint destruction. Deficiency of FUNDC1 enhanced migration, invasion as well as secretion of matrix metalloproteinases in RA-FLS. On the contrary, overexpression of FUNDC1 in RA-FLS with low FUNDC1 inhibited the migration, invasion and secretion capacity of RA-FLS. Mechanistically, repressed FUNDC1 level in RA-FLS impaired mitophagy, imbalanced mitochondrial quality control, and increased mitochondrial reactive oxygen species (mtROS) production, leading to the overactivation of the MAPK pathway. Treatment with mtROS scavenger mtTEMPO can reverse this process and diminish the invasiveness of RA-FLS.
    CONCLUSIONS: Deficiency of FUNDC1 dysregulates mitochondrial quality-control system and induces aggressive phenotype of RA-FLS, resulting in joint destruction during RA progression.
    Keywords:  FUN14 domain-containing 1; Mitochondrial homeostasis; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111829
  21. Eur J Neurosci. 2025 Apr;61(8): e70118
    S-9-PAHSA Attenuates Aβ Accumulation and Improves Cognitive Deficits by Promoting Mitochondrial Autophagy in 5xFAD Mice.
    Chenyu Lu, Jiaoqi Ren, Shanshan Huang, Meng Wang, Houguang Zhou, Jingchun Guo.
      Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by significant cognitive impairment and predominantly affects the elderly. With no effective cure available, research continues to explore novel therapeutic and preventive strategies. Recently, palmitic acid-hydroxystearic acids (PAHSAs), especially their stereochemistry S-configuration, have shown potential as a dietary supplement with anti-inflammatory and anti-diabetic properties. We previously found that one of the PAHSAs, 9-PAHSA, could improve cognitive impairment in the high-fat-diet mice, however, whether it has an equal effect on AD-like mice remains unclear. Since mitochondrial dysfunction is recognized as a significant pathological feature of AD, with impaired mitophagy leading to the accumulation of dysfunctional mitochondria, thus exacerbating disease progression, in this study, we evaluated the effects of the chiral isomer of 9-PAHSA, S-9-PAHSA, on cognitive dysfunction and mitochondrial dysfunction in 5xFAD mice. Three-month-old mice were treated with S-9-PAHSA 30 mg/kg in their drinking water for 3 months. Behavioral studies were conducted using the Morris Water Maze (MWM) and Y-maze tests, followed by assessments of amyloid-beta (Aβ) plaque deposition, neuronal apoptosis, and mitochondrial function. We found that S-9-PAHSA significantly enhanced spatial learning and memory abilities, reduced amyloid plaque deposition, decreased neuronal apoptosis, and improved mitochondrial homeostasis and autophagy in 5xFAD mice. These findings suggest that S-9-PAHSA holds promise as a supplementary preventive and therapeutic strategy for AD treatment.
    Keywords:  Alzheimer's disease; S‐9‐PAHSA; amyloid‐beta; cognition; mitochondrial autophagy
    DOI:  https://doi.org/10.1111/ejn.70118
  22. Front Neurol. 2025 ;16 1533092
    Acupuncture alleviates hemorrhagic transformation after delayed rt-PA treatment for acute ischemic stroke by regulating the mitophagy-NLRP3 inflammasome pathway.
    Tao Jiang, Qianqian Liu, Huanhuan Liu, Zheng Huang, Mengning Yang, Peiyan Huang, Yiting Shen, Yangyang Song, Wentao Xu, Xinchang Zhang, Guangxia Ni.
       Background: The clinical application of recombinant tissue plasminogen activator (rt-PA) is significantly constrained by hemorrhagic transformation (HT), a common and severe complication following thrombolysis for ischemic stroke. Notably, the mitochondrial injury-mediated NLRP3 inflammasome plays a crucial role in HT after delayed rt-PA thrombolysis in acute ischemic stroke. Although acupuncture has demonstrated antioxidant and anti-inflammatory effects in acute cerebral infarction, its impact on delayed rt-PA thrombolysis, especially concerning mitophagy and the NLRP3 inflammasome, remains unclear. This study investigates how acupuncture protects against HT resulting from mitochondrial damage and NLRP3 inflammasome activation after delayed rt-PA thrombolysis in acute cerebral stroke.
    Methods: We selected an embolic stroke model in rats and assessed brain injury after delayed rt-PA in acute ischemic stroke using neurological deficit score, volume of brain infarct, the permeability assay of the blood-brain barrier (BBB), and HT. Then, the levels of proteins and mRNA involved in mitophagy and the NLRP3 inflammasome pathway were measured by western blot and real-time PCR. The levels of interleukin-18 (IL-18) and interleukin-1β (IL-1β) were assessed using enzyme-linked immunosorbent assay (ELISA). Morphological changes in the BBB and mitochondria of neurons were observed via transmission electron microscopy.
    Results: Acupuncture significantly improved neurological deficit scores, volume of cerebral infarction, BBB destruction, and HT in an embolic stroke model rat. Furthermore, acupuncture induced mitophagy and substantially downregulated the activity of the NLRP3 inflammasome. Additionally, the use of mitochondrial inhibitors significantly reversed the suppressive impact of acupuncture on the NLRP3 inflammasome.
    Conclusion: Acupuncture can promote mitophagy and suppress NLRP3 inflammasome activation to decrease HT after delayed rt-PA therapy for acute ischemic stroke.
    Keywords:  NLRP3 inflammasome; acupuncture; acute ischemic stroke; hemorrhagic transformation; mitophagy; rt-PA thrombolysis
    DOI:  https://doi.org/10.3389/fneur.2025.1533092
  23. J Med Invest. 2025 ;72(1.2): 66-75
    Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.
    Yuki Nagara, Kentaro Tsuji, Yuki Kamei, Mitsugu Akagawa.
      Aging and obesity trigger liver mitochondrial decline, impairing liver function and energy metabolism. Effective hepatic mitochondrial biogenesis helps maintain and restore hepatocyte function. The effects of bergenin, a polyphenol with various pharmacological effects, on hepatic mitochondrial biogenesis remain unclear. Therefore, we aimed to determine its effects on mitochondrial biogenesis in hepatocytes. We measured mitochondrial content in human HepG2 hepatocytes using MitoTracker Green FM ; intracellular ATP content using an ATP assay kit ; and mitochondrial DNA (mtDNA) using the ratio of mtDNA to nuclear DNA by qPCR. Protein levels were analyzed using immunoblotting. Nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assessed by immunofluorescence staining and immunoblotting. In human HepG2 hepatocytes, bergenin increased mitochondrial content, elevated mitochondrial DNA and constituent proteins, and enhanced intracellular ATP levels and PGC-1α nuclear translocation, possibly promoting mitochondrial biosynthesis. SIRT1 expression was induced in bergenin-treated cells and may be responsible for bergenin-inducible mitochondrial biogenesis, which was abolished by the SIRT1 inhibitor EX-527. Furthermore, bergenin activated AMP-activated protein kinase (AMPK). Compound C, an AMPK inhibitor, abolished bergenin-induced SIRT1 expression and mitochondrial biogenesis. Overall, bergenin activates hepatic mitochondrial biogenesis through the AMPK / SIRT1 axis, which could help to prevent and ameliorate serious aging- and obesity-related liver diseases. J. Med. Invest. 72 : 66-75, February, 2025.
    Keywords:  bergenin; biogenesis; hepatocytes; mitochondria
    DOI:  https://doi.org/10.2152/jmi.72.66
  24. J Biochem Mol Toxicol. 2025 May;39(5): e70245
    Mechanism of Nano-Microplastics Exposure-Induced Myocardial Fibrosis: DKK3-Mediated Mitophagy Dysfunction and Pyroptosis.
    Liang Xiong, Ziyi Xiong, Juan Hua, Qi Chen, Dandan Wang.
      Nano-microplastics (NMPs), as environmental pollutants, are widely present in nature and pose potential threats to biological health. This study aims to investigate the mechanisms by which NMPs inhibit mitophagy through the suppression of dickkopf-related protein 3 (DKK3) expression, leading to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated cardiomyocyte pyroptosis and promoting myocardial fibrosis. Healthy adult male C57BL/6 mice were administered NMP solution via gavage, and their cardiac function was monitored. The results showed that NMP exposure significantly reduced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and increased the extent of myocardial fibrosis. Transcriptome sequencing identified 14 differentially expressed genes (DEGs), including MYL7. Using the random forest algorithm and functional enrichment analysis, DKK3 was identified as a key gene. In Vitro experiments further confirmed that NMPs downregulate DKK3 expression, thereby inhibiting mitophagy and promoting cardiomyocyte pyroptosis. This study elucidates the molecular mechanisms by which NMPs induce myocardial fibrosis and provides new theoretical bases and molecular targets for the diagnosis and treatment of heart diseases.
    Keywords:  Dickkopf‐related protein 3; NOD‐like receptor family; mitophagy; myocardial fibrosis; nano‐microplastics
    DOI:  https://doi.org/10.1002/jbt.70245
  25. Sci Rep. 2025 Apr 19. 15(1): 13585
    SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
    Brahim Chaqour, Jacob B Rossman, Miranda Meng, Kimberly E Dine, Ahmara G Ross, Kenneth S Shindler.
      Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.
    Keywords:  Experimental autoimmune encephalomyelitis; Optic neuritis; SIRT1
    DOI:  https://doi.org/10.1038/s41598-025-97456-8
  26. ACS Nano. 2025 Apr 23.
    Gestational Exposure to Black Phosphorus Nanoparticles Induces Placental Trophoblast Dysfunction by Triggering Reactive Oxygen Species-Regulated Mitophagy.
    Changqing Zhang, Li Xiao, Zhenya Fang, Shuxian Li, Chao Fan, Ruolan You, Chunying Wang, Anna Li, Xietong Wang, Meihua Zhang.
      As a type of two-dimensional nanomaterial, black phosphorus (BP) has attracted considerable interest for applications in various fields. Despite its advantages, including biodegradability and biocompatibility, recent studies have shown that BP exhibits cytotoxicity in different types of cells. However, no studies have investigated the effects of BP exposure during pregnancy. Herein, we first investigated the effect of gestational exposure to BP nanoparticles (BPNPs) in a mouse model. Our findings indicated that BPNPs exposure restricted fetal growth and hindered placental development. In HTR8/SVneo trophoblast cells, BPNPs inhibited cell proliferation, migration, and invasion and caused apoptosis in a dose-dependent manner. Furthermore, BPNPs induced intracellular reactive oxygen species (ROS) overproduction and extensive mitochondrial damage. We further demonstrated that BPNPs promoted mitophagy via the PINK1/Parkin signaling pathway. Parkin siRNA knockdown rescued BPNPs-induced trophoblast dysfunction, while ROS inhibition attenuated BPNPs-induced cytotoxicity by reducing mitochondrial damage. Finally, treatment with mdivi-1, a mitophagy inhibitor, mitigated mitochondrial membrane potential reduction, excessive mtROS production, and the resulting trophoblast dysfunction. In vivo model investigation indicated that the application of mdivi-1 ameliorated embryonic resorption and fetal growth by alleviating placental damage. In summary, gestational exposure to BPNPs impairs fetal growth by inducing placental trophoblast dysfunction through ROS-regulated, PINK1/Parkin-dependent mitophagy.
    Keywords:  ROS; black phosphorus; mitophagy; nanoparticles; placental trophoblast
    DOI:  https://doi.org/10.1021/acsnano.4c18731
  27. Mitochondrion. 2025 Apr 17. pii: S1567-7249(25)00038-8. [Epub ahead of print]84 102041
    MiR-718-mediated inhibition of prohibitin 1 influences mitochondrial dynamics, proliferation, and migration of keratinocytes.
    Himani Rani, Neeru Saini.
      Keratinocyte hyperproliferation is a key characteristic of psoriasis. Prohibitins (PHB) are known to be associated with keratinocyte proliferation and cell cycle regulation, influenced by mitochondrial processes. The objective of this study was to examine the impact of miR-718 overexpression and downregulation on the various PHB1-mitochondria-driven activities in HaCaT keratinocytes. We demonstrated that PHB1 expression is downregulated through direct targeting by miR-718, which then leads to a reduction in the expression of MFN1, MFN2, and OPA1 in miR-718-transfected cells, as evidenced by western blot analysis. Mitochondrial fusion and DRP1-mediated fission, as indicated by western blot results, were further validated using confocal imaging with CMXRoS labeling, contrasting with the effects of AM-718. JC-1 dye staining results demonstrated the miR-718 overexpression facilitates the mitochondrial membrane depolarization that highlighting the PHB1-OPA1 mediated depolarization. Moreover, OPA1 maintains mitochondrial cristae structure and its dysfunction can trigger cell death. Further PHB1 is known to regulate OPA1 function, alters mitochondrial morphology and significantly influences epithelial cell migration. Herein, our data demonstrated a reduction in keratinocyte proliferation and migration, as evidenced by the CCK assay and wound healing assay, respectively, following 24 h of transfection. Ultimately, our data indicates the potential involvement of miR-718 in the mitochondria-mediated suppression of cell proliferation and migration in HaCaT keratinocytes, likely due to modified mitochondrial processes via PHB1.
    Keywords:  Keratinocytes; Mitochondria; PHB1; miR-718
    DOI:  https://doi.org/10.1016/j.mito.2025.102041
  28. J Virol. 2025 Apr 23. e0026825
    LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.
    Sen Zeng, Zipeng Luo, Wenhui Zhu, Zhanhui Zhang, Ruibo Zhao, Shuaiqi Zhu, Qi Qiu, Nan Cao, Xinliang Fu, Wenjun Liu, Shuangqi Fan, Cheng Fu.
      Lactate dehydrogenase A (LDHA) plays a crucial role in regulating lactate synthesis in various biological processes. Lactate, a byproduct of glycometabolism, has been recognized as a unique molecule with implications in both metabolism and immunity. Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and severe infectious disease that primarily affects pigs. Prior research has shown that CSFV infection disrupts the normal glycolytic process, leading to an accumulation of lactate within the host. Nevertheless, it remains unclear whether there is mutual regulation between the CSFV and LDHA-lactate axis. Here, we have found that CSFV infection increases LDHA expression in vivo and in vitro, which may be attributed to attenuated ISGylation of LDHA. Furthermore, CSFV infection induces L-lactate production via LDHA dependence in vitro. The cellular biology research on LDHA has revealed that LDHA not only localizes to the mitochondria but also inhibits PINK1-Parkin-mediated mitophagy. Through various experimental techniques such as western blot to detect mitophagy marker proteins, laser confocal microscopy to observe the flow of mitophagy, and transmission electron microscopy to assess changes in the number of mitochondria enclosed within autophagosome-like vesicles, it has been discovered that the addition of exogenous lactate can inhibit PINK1-Parkin-mediated mitophagy. Importantly, we have observed that lactate activates the JAK1-STAT1-ISG15 network and suppresses CSFV replication by antagonizing CCCP-induced mitophagy. These results represent the first report on the mechanisms through which the LDHA-lactate axis regulates mitophagy, the JAK-STAT pathway, and CSFV replication. This study provides novel insights into the roles of the LDHA-lactate axis in glycometabolism and viral replication.
    IMPORTANCE: This research unveils how CSFV interacts with cellular metabolism through LDHA. By revealing LDHA's dual role and how lactate influences cellular processes during CSFV infection, this study uncovers new pathways for viral replication. These findings not only deepen our understanding of viral-host interactions but also open doors for innovative antiviral strategies centered around manipulating cellular metabolism.
    Keywords:  CSFV; JAK-STAT; LDHA; lactate; mitophagy
    DOI:  https://doi.org/10.1128/jvi.00268-25
  29. J Inherit Metab Dis. 2025 May;48(3): e70029
    YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
    Anthi Demetriadou, Olga Grafakou, Theodoros Georgiou, Daniela Burska, Anna Malekkou, Jana Krizova, Efstathia Paramera, Gavriella Mavrikiou, Maria Dionysiou, Athina Theodosiou, Carolina Sismani, Violetta Anastasiadou, Ioannis Ioannou, Evangelos Papakonstantinou, Hana Hansikova, Anthi Drousiotou, Petros P Petrou.
      3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.
    Keywords:  3‐methylglutaconic aciduria; YME1L1; inherited metabolic disorders; mitochondrial disorders; mitochondrial dysfunction; mitochondrial fragmentation
    DOI:  https://doi.org/10.1002/jimd.70029
  30. J Funct Biomater. 2025 Apr 21. pii: 147. [Epub ahead of print]16(4):
    MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy.
    Rita Alonaizan, Ujang Purnama, Sophia Malandraki-Miller, Mala Gunadasa-Rohling, Andrew Lewis, Nicola Smart, Carolyn Carr.
      The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.
    Keywords:  cardiac progenitor cells; cell therapy; heart regeneration; hypoxia; ischaemia; miR-210; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.3390/jfb16040147
  31. Int Immunopharmacol. 2025 Apr 18. pii: S1567-5769(25)00668-X. [Epub ahead of print]156 114678
    TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy.
    Chun-Lian Huang, Shen Qi-En, Xu-Feng Cen, Ting Ye, Hang-Shuai Qu, Si-Jia Chen, Dong Liu, Hong-Guang Xia, Cheng-Fu Xu, Jian-Sheng Zhu.
       BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a liver disease accompanied by inflammatory cell infiltration. There is growing evidence that insufficient mitophagy can exacerbate inflammation and liver fibrosis (LF). TJ0113 is a novel mitophagy inducer. The study aimed to explore the role of TJ0113 in ameliorating fibrosis in MASH and its mechanisms.
    METHODS: A high-fat diet (HFD)-induced MASH mice model and a transforming growth factor (TGF)-β1-induced LX-2 cells model were used, and then they were treated with TJ0113. Changes in hepatocyte damage were observed using electron microscopy. Expression of key molecules related to mitophagy, mitochondrial damage and inflammation in liver was detected by immunofluorescence staining (IF), immunohistochemistry (IHC) and western blotting (WB).
    RESULT: TJ0113 induces mitophagy through parkin/PINK1 and ATG5 signaling pathways and reduces lipid accumulation, inflammation and fibrosis in the liver of MASH mice. TJ0113 attenuated hepatic injury and lowered serum ALT, AST, TC and TG levels. TJ0113 reduced pro-inflammatory factors (IL-1β, IL-6, TNF-α), TGF-β1/Smad pathway activation and typical fibrosis-related molecules (α-SMA, Collagen-1) expression. In addition, NF-κB/NLRP3 signaling pathway activation after MASH was significantly attenuated by enhanced Mitophagy. We found that TJ0113 was able to effectively and safely induce mitophagy in vitro and reduce TGF-β1/Smad signaling and downstream pro-fibrotic responses in TGF-β1-treated LX-2 cells.
    CONCLUSION: TJ0113 enhances mitophagy to inhibit lipid accumulation, inflammation and fibrosis formation in MASH, and is a candidate for MASH treatment.
    Keywords:  Liver fibrosis; Metabolism dysfunction-associated steatohepatitis (MASH); Mitophagy; TGF-β1; TJ0113
    DOI:  https://doi.org/10.1016/j.intimp.2025.114678
  32. Biochem Biophys Res Commun. 2025 Apr 19. pii: S0006-291X(25)00571-6. [Epub ahead of print]765 151857
    Role of IP3R2-Mediated mitochondrial calcium homeostasis in early hypoxic stress injury of retinal pigment epithelial cells.
    Li Xu, Jingjing Jiang, Yuchen Wang, Fang Wei, Hong Zhu.
       OBJECTIVE: To investigate the regulatory role of IP3R2 on mitochondrial function in retinal pigment epithelial cells during the early stage of hypoxic stress preceding apoptosis.
    METHODS: ARPE-19 cell line was cultured in 1 % oxygen to establish an in vitro hypoxic model. The presence of hypoxia and absence of significant apoptosis in RPE cells were confirmed through hypoxia-inducible factor HIF-1α expression and apoptosis assays respectively. Mitochondrial function was evaluated using an ATP assay kit and flow cytometry. Immunoblotting was conducted to ascertain the expression levels of mitochondrial dynamics proteins (MFN2, DRP1, TOMM20) and mitochondrial calcium-related proteins (IP3R1, IP3R2, IP3R3, VDAC1). Mitochondrial morphology was observed using confocal microscopy. The impact of small interfering RNA (siRNA)-mediated IP3R2 knockdown on apoptosis and mitochondrial function was assessed in RPE cells.
    RESULTS: Under hypoxic stress before the onset of apoptosis in RPE cells, mitochondrial dysfunction and significant increase in mitochondrial calcium flux were observed, accompanied by a notable upregulation of IP3R2 expression under hypoxia. Knockdown of IP3R2 during the pre-apoptotic stage further impaired RPE function under hypoxia.
    CONCLUSION: IP3R2-mediated mitochondrial calcium overload is crucial for maintaining RPE function and mitochondrial homeostasis during the pre-apoptotic stage triggered by hypoxic stress.
    Keywords:  Early hypoxic stress; IP3R2; Mitochondrial function; Retinal pigment epithelial cells
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151857
  33. Int Immunopharmacol. 2025 Apr 21. pii: S1567-5769(25)00664-2. [Epub ahead of print]156 114674
    Stibene glucoside prevents PM2.5 caused pulmonary fibrosis by Pseudo hypoxia, autophagy and NF-κB signal pathways.
    Huifang Niu, Fei Guo, Wen Li.
      Although the association between PM2.5 exposure and pulmonary fibrosis is well-documented, the underlying molecular mechanisms remain poorly understood, and effective preventive strategies against PM2.5-induced pulmonary toxicity are yet to be established‌. This study investigated the role of reactive oxygen species (ROS)-mediated pseudo-hypoxia signaling and NF-κB pathway activation in PM2.5-triggered epithelial-mesenchymal transition (EMT) and fibrosis, alongside the therapeutic potential of the antioxidant compound stilbene glucoside (TSG). ‌In vivo‌, C57BL/6 mice exposed to PM2.5 for two months developed pulmonary fibrosis, with transcriptomic analysis revealing significant alterations in pathways associated with carbohydrate metabolism, cancer signaling, and immune-related diseases‌. Concurrently, upregulated expression of EMT markers (fibronectin, vimentin), glycolysis-related genes (PKM, LDHA), and inflammatory cytokines (TGF-beta) was observed in lung tissues‌. ‌In vitro‌, PM2.5 induced EMT in BEAS-2B cells via ROS-driven mitochondrial membrane potential collapse, mitophagy, HIF-1α activation, and NF-κB-mediated inflammation, which collectively promoted a metabolic shift toward glycolysis‌. Notably, TSG treatment attenuated PM2.5-induced pulmonary fibrosis by suppressing ROS accumulation, pseudo-hypoxia signaling, and NF-κB pathway activation. These effects correlated with restored mitochondrial function and normalized glucose metabolism in cellular models‌. ‌We come to the conclusion that PM2.5 exacerbates pulmonary fibrosis through ROS/HIF-1α and NF-κB axis-driven EMT and metabolic reprogramming. TSG, as a multifunctional antioxidant, represents a promising prophylactic agent against PM2.5-associated pulmonary damage‌.
    Keywords:  EMT; Mitophagy; PM(2.5); Stibene glucoside; pseudo hypoxia
    DOI:  https://doi.org/10.1016/j.intimp.2025.114674
  34. Plant Cell Environ. 2025 Apr 21.
    Mitochondrial Energy Homeostasis and Membrane Interaction Regulate the Rapid Growth of Moso Bamboo.
    Yanli Gao, Anjing Chen, Dongmei Zhu, Mingbing Zhou, Huahong Huang, Ronghui Pan, Xu Wang, Lei Li, Jinbo Shen.
      The rapid growth of moso bamboo is primarily attributed to the swift elongation of its internodes. While mitochondria are known to provide energy for various cellular processes, the specific mechanisms by which they facilitate rapid growth in bamboo remain elusive. In this study, we optimised the procedures for mitochondria isolation and performed a comprehensive analysis of mitochondrial dynamics and proteomics from internodes at various growth stages, including the initial growth (IG) stage, the starting of cell division (SD), and the rapid elongation (RE). Confocal observation demonstrated that cells in the RE stage have a higher mitochondrial density and increased mitochondrial motility compared to other stages. Proteomic analysis of isolated mitochondria revealed an upregulation of the tricarboxylic acid cycle, along with a synchronous increase in both mitochondrial- and nuclear-encoded components of oxidative phosphorylation in RE cells. Moreover, the upregulation of various mitochondrial membrane transporters in RE cells suggests an enhanced exchange of metabolic intermediates and inorganic ions with the cytosol. Intriguingly, ultrastructural analysis and pharmacological treatments revealed membrane interactions between the endoplasmic reticulum (ER) and mitochondria in RE cells. In conclusion, our study provides novel insights into mitochondrial function and the intracellular dynamics that regulate the rapid growth of moso bamboo.
    Keywords:  ER‐mitochondria interaction; TCA cycle; bamboo; fast growth; mitochondrial dynamics; mitochondrial proteome; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/pce.15559
  35. J Cell Mol Med. 2025 Apr;29(8): e70566
    rhCC16 Suppresses Cellular Senescence and Ameliorates COPD-Like Symptoms by Activating the AMPK/Sirt1-PGC-1-α-TFAM Pathway to Promote Mitochondrial Function.
    Ying-Jie Ren, Tian-Qi Sun, Yu Lu, Dan-Li Liu, Rui Gao, Ting Li, Min Guo, Qing-Hua Liu, Hai-Long Wang, Min Pang.
      Chronic obstructive pulmonary disease (COPD) is a widespread lung disease marked by alveolar wall damage, leading to inflammation and fibrosis. Key risk factors include age, smoking, sex, and education, with smoking being the most crucial. These factors are globally consistent and linked with aging. Club cell secretory protein 16 (CC16), primarily secreted by non-ciliated bronchial epithelial cells, is crucial for pulmonary health, offering anti-inflammatory and antioxidant benefits. CC16 levels are notably reduced in COPD, suggesting its enhancement as a potential treatment. In this study, cellular senescence of BEAS-2B cells was stimulated using cigarette smoke extract (CSE) and the function of recombinant human CC16 protein (rhCC16) in cellular senescence was assessed by detecting the levels of β-galactosidase, p16, p21, ROS and the underlined mechanism was revealed by measuring mitochondrial biogenesis and metabolism. Additionally, COPD mice were prepared, and rhCC16's role on the cellular senescence of lung tissues was examined. Our findings showed that rhCC16 ameliorated cellular senescence in BEAS-2B cells and lung tissues of COPD mice accompanied by lower levels of β-galactosidase, p16, p21 and ROS. Mechanically, rhCC16 mitigated senescence via triggering PGC-1α expression through the AMPK/SIRT1 pathway and fostering mitochondrial biogenesis and metabolism to reduce the levels of ROS. Furthermore, the results also indicated that rhCC16 exerted its effect via both integrin α4β1 and clathrin-mediated endocytosis. Collectively, rhCC16 suppresses cellular senescence and ameliorates COPD-like symptoms by activating the AMPK/Sirt1-PGC-1-α-TFAM pathway to foster mitochondrial function.
    Keywords:  AMPK; COPD; cellular senescence; mitochondrial function; rhCC16
    DOI:  https://doi.org/10.1111/jcmm.70566
  36. Stem Cell Res Ther. 2025 Apr 20. 16(1): 198
    Correction: CircSPG21 ameliorates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells and mitigates intervertebral disc degeneration through the miR-217/SIRT1 axis and mitophagy.
    Yongbo Zhang, Sheng Yang, Xuan You, Zhengguang Li, Liuyang Chen, Rui Dai, Hua Sun, Liang Zhang.
      
    DOI:  https://doi.org/10.1186/s13287-025-04337-y
  37. Curr Cardiol Rev. 2025 Apr 18.
    Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.
    Samir Bolivar Gonzalez, César Vásquez Trincado, Karen Patricia Torres Rodríguez, Lizeth Paola Forero Acosta, Maria Fernanda Perez García, Steffy Saavedra Castro, Sara Camila Castiblanco Arroyave, Gerardo Manríquez Higuera, Luis Antonio Díaz Ariza, Héctor Rodríguez Ortiz, Evelyn Mendoza-Torres.
      Cardiovascular diseases (CVD) are the leading cause of death worldwide, creating the need for new therapeutic strategies targeting the pathological processes involved. Mitochondria, which comprise one-third of cardiac cell volume, maybe a potential therapeutic target for CVD. Known primarily for energy production, mitochondria are also involved in other processes including intermediary metabolism, mitophagy, calcium homeostasis, and regulation of cell apoptosis. Mitochondrial function is closely linked to morphology, which is altered through mitochondrial dynamics, including processes such as fission and fusion, which ensure that the energy needs of the cell are met. Recent data indicate that mitochondrial dysfunction is involved in the pathophysiology of several CVDs, including cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and cardiac fibrosis. Furthermore, mitochondrial dysfunction is associated with oxidative stress related to atherosclerosis, hypertension, and pulmonary hypertension. In this review, we first briefly present the physiological mechanisms of mitochondrial function in the heart and then summarize the current knowledge on the impact of mitochondrial dysfunction on CVD. And finally, we highlight the evidence from in vitro, in vivo, and clinical studies of the cardioprotective effects of drugs that preserve mitochondrial function in CVD. It is hoped that this review may provide new insights into the need to discover new pharmacological targets with direct actions on mitochondria that may provide combined therapeutic strategies to optimally treat these pathologies.
    Keywords:  Cardiovascular disease; angiotensins; cardiac hypertrophy; heart failure; ischemia; metformin; mitochondrial dynamics; nicotinamide riboside.
    DOI:  https://doi.org/10.2174/011573403X372565250331190001
  38. Cell Rep. 2025 Apr 21. pii: S2211-1247(25)00381-X. [Epub ahead of print]44(5): 115610
    Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
    Benjamin A S Willett, Scott B Thompson, Vincent Chen, Anza Dareshouri, Conner L Jackson, Tonya Brunetti, Angelo D'Alessandro, Jared Klarquist, Travis Nemkov, Ross M Kedl.
      Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.
    Keywords:  CD8; CP: Immunology; Mitofusins; Opa1; T cell; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.115610
  39. Cell Mol Neurobiol. 2025 Apr 21. 45(1): 38
    Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
    Donghui Na, Zechen Zhang, Meng Meng, Meiyu Li, Junyan Gao, Jiming Kong, Guohui Zhang, Ying Guo.
      Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.
    Keywords:  Brain aging; Energy metabolism; Mitochondrial quality control; Neurons
    DOI:  https://doi.org/10.1007/s10571-025-01555-z
  40. Cells. 2025 Apr 11. pii: 573. [Epub ahead of print]14(8):
    Correction: Zhou et al. Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy. Cells 2019, 8, 213.
    Ping Zhou, Weijie Xie, Xiangbao Meng, Yadong Zhai, Xi Dong, Xuelian Zhang, Guibo Sun, Xiaobo Sun.
      In the original publication [...].
    DOI:  https://doi.org/10.3390/cells14080573
  41. Sci Rep. 2025 Apr 21. 15(1): 13811
    Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
    Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.
      Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.
    Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L
    DOI:  https://doi.org/10.1038/s41598-025-98397-y
  42. Pediatr Res. 2025 Apr 23.
    Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.
    Madori T Osawa, Yasunori Fujita, Kazuki Kagami, Masataka Ito, Yoshiteru Tamura, Shoichiro Tateishi, Junya Take, Fumi Hirose, Hidetoshi Hagiwara, Kohsuke Imai, Daisuke Yoshinaga, Shiro Baba, Mitsujiro Osawa, Hiroko Harashima, Kei Murayama, Yuko Akioka, Akira Ohtake, Ikuro Suzuki, Takeshi Adachi, Takeru Yamazaki, Satoshi Arai, Shiro Matsumoto, Tetsuya Kitaguchi, Megumu K Saito, Ikuroh Ohsawa, Shigeaki Nonoyama.
       BACKGROUND: DNM1L encodes dynamin-related protein 1, which plays an important role in mitochondrial and peroxisomal division. The DNM1L mutation leads to cardiac dysfunction in patients and animal models. However, the mechanism of cardiac dysfunction caused by DNM1L mutation has not been elucidated clearly at least in the studies of human cardiomyocytes.
    METHODS: We established human induced pluripotent stem cells (hiPSCs) from two pediatric patients with DNM1L mutation. The hiPSCs were differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). Mitochondrial morphology and function, cardiomyocyte Ca2+ dynamics, and contractile and diastolic function of hiPS-CMs were analyzed.
    RESULTS: The morphology of the mitochondria was abnormally elongated in patient-derived hiPS-CMs. The mitochondrial membrane potential and oxygen consumption rate were significantly decreased, resulting in reduced ATP production. In the analysis of Ca2+ dynamics, the 50% time to decay was significantly longer in patient-derived hiPS-CMs than in healthy control. High-precision live-imaging system analysis revealed that contractile and diastolic function was significantly impaired under isoproterenol stimulation.
    CONCLUSION: DNM1L mutations cause mitochondrial impairment with less production of ATP in cardiomyocytes. This leads to abnormal intracellular Ca2+ dynamics, resulting in contractile and diastolic dysfunction.
    IMPACT: DNM1L mutations was identified in two pediatric patients who developed cardiac dysfunction and human induced pluripotent stem cells (hiPSCs) were established from these two patients and differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). DNM1L mutations induced abnormal mitochondrial morphology, mitochondrial dysfunction, and insufficient ATP production in hiPS-CMs. In addition, hiPS-CMs with DNM1L mutation showed abnormal Ca2+ kinetics and impaired contractile and diastolic function. This is the first study that elucidate the mechanism of cardiac dysfunction caused by DNM1L mutations by using hiPSCs.
    DOI:  https://doi.org/10.1038/s41390-025-04045-6
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