bims-mihora Biomed News
on Mitohormesis, repair and aging
Issue of 2025–11–30
forty-two papers selected by
Lisa Patel, Istesso
  1. Mitochondrial Quality Control and Cell Death.
  2. Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.
  3. Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.
  4. Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.
  5. Selenoprotein H targets MTCH2 to regulate MFN2-dependent mitochondrial quality control to alleviate acute kidney injury.
  6. Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1 - and LRRK2 -Linked Parkinson's Disease.
  7. Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
  8. Mitochondrial Dynamics in Aging Heart.
  9. Cytosolic DNA sensing pathway in senescence and aging: Underlying mechanisms and targeted interventions.
  10. Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
  11. Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells.
  12. Hematopoietic Stem Cell Aging: Mechanisms, Microenvironment Influences, and Rejuvenation Strategies.
  13. Dysregulated Redox Signaling and Its Impact on Inflammatory Pathways, Mitochondrial Dysfunction, Autophagy and Cardiovascular Diseases.
  14. APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
  15. Mitochondrial Adaptation to Mechanical Stress in Cardiac Ageing and Disease.
  16. Cryo-EM reveals how ASX-173 inhibits human asparagine synthetase to activate the integrated stress response.
  17. Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations.
  18. Modulation of Nrf2 and Mitochondrial Function: Pharmacological Implications.
  19. The interplay between the immune microenvironment and bone aging: From molecular mechanisms to therapeutic interventions.
  20. Mitochondrial connexin 43 modulates metabolic stress adaptation in glioma cell lines.
  21. Rutin as a Circadian Modulator Preserves Skeletal Muscle Mitochondrial Function and Reduces Oxidative Stress to Protect Against D-Galactose-Induced Aging In Vitro and In Vivo.
  22. Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.
  23. Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
  24. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  25. Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
  26. The C. elegans immune switch proteins PALS-25 and PALS-22 localize to mitochondria and regulate fragmentation.
  27. Sirtuin downregulation mediates mitochondrial impairment causing cognitive decline in hepatic encephalopathy.
  28. Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury.
  29. A role for the Stentor syntaxin protein in post-wound cell survival.
  30. Mitochondrial crosstalk between bone marrow stromal cells and chondrocytes: implication for cartilage repair in osteoarthritis.
  31. Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.
  32. Mitochondrial NAD+ drives liver regeneration.
  33. Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche.
  34. Photobiomodulation-induced activation of Wnt signaling enhances differentiation of adipose-derived stem cells into tenocytes: Mechanistic insights into regenerative signaling pathways.
  35. Mitochondrial Protection by Astaxanthin Reduces Toxicity Caused by H2O2 and Doxorubicin in Human Cardiomyocytes.
  36. ATG7-driven mitophagy in BMSC@CS hydrogel reprograms metabolism to boost bone regeneration.
  37. Beyond ER Stress: The Pleiotropic Roles of XBP1 in Development and Regeneration.
  38. GV1001, an hTERT-Derived Peptide, Prevents Cisplatin-Induced Nephrotoxicity by Preserving Mitochondrial Function.
  39. Extracellular matrix remodeling supports Hydra vulgaris head regeneration and stem cell invasion.
  40. Role of the lncRNA MALAT1/miR-1 Pathway in Mouse Myocardial Ischemia-Reperfusion Injury.
  41. Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.
  42. Perturbation of multiprotein complexes in skeletal muscle induces protective proteases in the CNS that degrade pathogenic proteins.
  1. Int J Mol Sci. 2025 Nov 16. pii: 11084. [Epub ahead of print]26(22):
    Mitochondrial Quality Control and Cell Death.
    Zurui Zhang, Mengyuan Zhang, Hongchi Jin, Shuang Lv, Yilei Li, Yanru Li.
      Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a "spatiotemporal-threshold" model for the mitochondrial quality control-cell death axis.
    Keywords:  apoptosis; ferroptosis; mitochondrial autophagy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; pyroptosis
    DOI:  https://doi.org/10.3390/ijms262211084
  2. Biomolecules. 2025 Nov 09. pii: 1572. [Epub ahead of print]15(11):
    Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.
    Nikola Pavlović, Petar Todorović, Mirko Maglica, Marko Kumrić, Katarina Vukojević, Zenon Pogorelić, Joško Božić.
      The heart's relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD+ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients.
    Keywords:  bioenergetics; cardiomyopathy; heart failure; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/biom15111572
  3. Biochem Biophys Res Commun. 2025 Nov 24. pii: S0006-291X(25)01760-7. [Epub ahead of print]794 153044
    Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.
    Cai Sun, Liang Pan, Chengsi Tang, Yiyuan Liu, Sha Ran, Ying Li, Yan Shen.
      Acute pancreatitis (AP) is a multifactorial disease in which mitochondrial dysfunction plays a key role by triggering inflammatory cascades and necrotic cell death. Mitochondrial transplantation has been reported to alleviate AP, however its underlying mechanisms remain unclear. To investigate the effect of mitochondrial transplantation on macrophage during AP, we stimulated macrophages with supernatant of damaged pancreatic acinar cells to mimic the inflammatory microenvironment. Upon stimulation, macrophages exhibited an enhanced capacity to internalize exogenous mitochondria. These exogenous mitochondria restored mitochondrial function in damaged macrophages by maintaining mitochondrial membrane potential, suppressing excessive reactive oxygen species production, and restoring ATP levels. Furthermore, mitochondria transplantation significantly inhibited macrophages necroptosis, as evidenced by the decreased protein expression and phosphorylation levels of the necroptosis markers RIPK1 and MLKL in macrophages and pancreatic tissue, and decreased cell necrosis. In terms of inflammation, exogenous mitochondria suppressed macrophage polarization toward the pro-inflammatory M1 phenotype and reduced the expression of pro-inflammatory cytokines. Collectively, these findings demonstrate that macrophage-centered inflammatory regulation constitutes a central mechanism underlying the therapeutic effects of mitochondrial transplantation in AP, providing a theoretical foundation for developing mitochondria-based therapeutic strategies.
    Keywords:  Acute pancreatitis; Macrophage; Mitochondrial transplantation; Necroptosis
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153044
  4. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517552122
    Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Rama Aldakhlallah, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth type 2A (CMT2A). These mutations can disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR)-the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic ISR activation through the OMA1-DELE1-HRI signaling pathway as a potential strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    Keywords:  drug repurposing; integrated stress response; mitochondrial dysfunction
    DOI:  https://doi.org/10.1073/pnas.2517552122
  5. J Adv Res. 2025 Nov 26. pii: S2090-1232(25)00955-5. [Epub ahead of print]
    Selenoprotein H targets MTCH2 to regulate MFN2-dependent mitochondrial quality control to alleviate acute kidney injury.
    Dongliu Luo, Yaning Qiu, Jiahong Chu, Haodong Hu, Yanhe Zhang, Yu Xia, Fuze She, Shiwen Xu, Fating Zhu, Zhiruo Miao, Shu Li.
       INTRODUCTION: Mitochondrial dysfunction is recognized as a pivotal event in the pathogenesis of acute kidney injury (AKI). Selenoprotein (SelH), a mammalian selenoprotein, is extensively involved in regulating of diseases associated with mitochondrial dysfunction. However, its regulatory role in mitochondrial quality control during AKI remains unclear.
    OBJECTIVES: This study aims to explore the impact of SelH on AKI and potential regulatory mechanisms of SelH in AKI.
    METHODS: In vivo, a cisplatin (CP)-induced AKI model was established using SelH knockout mice to evaluate renal injury. Additionally, co-immunoprecipitation (Co-IP). combined with mass spectrometry, Co-IP assays, laser confocal microscopy, and molecular docking were employed to identify proteins interacting with SelH. In vitro, SelH/mitochondrial carrier homolog 2 (MTCH2) knockdown and overexpression models were constructed in HEK293t cells. Indicators related to oxidative stress, mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and apoptosis were analyzed.
    RESULTS: MTCH2 was identified as a potential interacting partner of SelH. Deficiency of renal SelH directly triggered oxidative stress, impaired mitochondrial biogenesis, disrupted mitochondrial dynamics, enhanced mitophagy, and promoted apoptosis. In HEK293t cells, SelH targeted MTCH2 to regulate mitofusin 2 (MFN2), thereby promoting mitochondrial fusion, alleviating mitochondrial dysfunction, maintaining mitochondrial quality control (MQC) homeostasis, and reducing renal oxidative damage and apoptosis.
    CONCLUSION: The results showed that SelH targets the MTCH2/MFN2 aixs to maintain MQC balance, alleviate oxidative stress and cell apoptosis induced by AKI. This study not only supplements kidney specific regulatory targets for the field of mitochondrial medicine but also suggests that SelH could serve as a potential molecule for proactive medicine intervention in AKI, providing experimental evidence for the early intervention of AKI.
    Keywords:  Acute kidney injury; Apoptosis; MTCH2; Restored mitochondrial homeostasis and functionality; Selenoprotein H
    DOI:  https://doi.org/10.1016/j.jare.2025.11.059
  6. medRxiv. 2025 Oct 13. pii: 2025.10.08.25337448. [Epub ahead of print]
    Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1 - and LRRK2 -Linked Parkinson's Disease.
    Daniele Mattei, Erica Brophy, Mikaela Rosen, Oriol Narcis Majos, Aloysius Domingo, Elena Meijia, Beomjin Jang, Tarek Khashan, Mengxi Yang, Deborah Raymond, Casey Young, Jack Humphrey, Elisa Navarro, Amanda Allan, Katherine Leaver, Viktoriya Katsnelson, Alexander Chung, Benjamin Muller, Matthew Swan, Vicki L Shanker, Mariel Pullman, Adina Wise, Roberto Ortega, Kelly Astudillo, Steven Frucht, Susan Bressman, Giulietta Riboldi, Laurie J Ozelius, Rachel Saunders-Pullman, Towfique Raj.
      Monocytes are increasingly implicated in Parkinson's disease (PD) pathogenesis, with idiopathic cases showing mitochondrial and lysosomal dysfunction. However, the impact of PD-associated mutations on monocytes remains unclear. To address this, we investigated transcriptomic and functional disturbances in peripheral monocytes from patients with GBA1 - and LRRK2 -associated PD and idiopathic PD. Transcriptomic data revealed shared and mutation-specific signatures, including those related to immune dysregulation, and consistent defects in lysosomal and mitochondrial pathways. Network and pathway analyses further uncovered downregulation in protein translation and enrichment of integrated stress response (ISR) signatures, alongside aberrant expression of genes linked to ER stress, proteostasis, mitophagy and type-I interferon signaling. These data suggest that monocyte immune dysfunction in PD may be, at least in part, a consequence of impaired proteostasis, organelle stress and maladaptive ISR activation. We further interrogated these signatures in functional assays in patient-derived macrophages, which revealed impaired mitochondrial potential, proteolysosomal dysfunction, and defective phagocytosis. Our findings define convergent molecular and functional abnormalities in genetic PD monocytes, implicating proteostasis failure and maladaptive ISR activation as upstream drivers of immune dysfunction, highlighting novel targetable pathways for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2025.10.08.25337448
  7. bioRxiv. 2025 Nov 06. pii: 2025.11.06.686916. [Epub ahead of print]
    Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
    Kiri Tal, Jonathan Ram, Reis Noa, Maniv Inbal, Ordureau Alban, Michael H Glickman, Sulkshane Prasad.
      Mitochondria are essential organelles responsible for cellular energy production and metabolism. Hypoxia, a pathophysiological condition, impairs the electron transport chain, disrupts mitochondrial function, and produces harmful reactive oxygen species (ROS). Ubiquitin signaling regulates mitochondrial health through several mechanisms, including protein degradation and mitophagy. Here, we show that hypoxia-induced mitophagy occurs independently of ubiquitination. However, mitochondria are heavily ubiquitinated under hypoxic stress. A significant portion of these hypoxia-induced ubiquitin chains constitute a specific type: linear head-to-tail fusions (M1), which are known for their role in NF-κB activation during cytokine signaling. We demonstrate that hypoxia-induced mitochondrial ROS leads to the accumulation of these M1 chains, activating NF-κB signaling and increasing the expression of its target genes. These findings reveal a critical internal signal that helps cells adapt to mitochondrial stress and triggers an inflammatory response.
    DOI:  https://doi.org/10.1101/2025.11.06.686916
  8. Biomedicines. 2025 Oct 24. pii: 2603. [Epub ahead of print]13(11):
    Mitochondrial Dynamics in Aging Heart.
    Pankaj Patyal, Gohar Azhar, Ambika Verma, Shakshi Sharma, Jyotsna Shrivastava, Sayed Aliul Hasan Abdi, Xiaomin Zhang, Jeanne Y Wei.
      Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD+) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population.
    Keywords:  apoptosis; cardiac aging; interventions; mitochondria; mtDNA; sirtuins
    DOI:  https://doi.org/10.3390/biomedicines13112603
  9. Biomed Pharmacother. 2025 Nov 21. pii: S0753-3322(25)00984-9. [Epub ahead of print]193 118790
    Cytosolic DNA sensing pathway in senescence and aging: Underlying mechanisms and targeted interventions.
    Elaheh Alipour-Khezri, Amin Moqadami, Sepideh Zununi Vahed, Abolfazl Barzegari.
      The global increase in the older population presents major healthcare challenges due to increased prevalence of age-related diseases. Cellular senescence is a defining feature of aging, and the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway plays a central role in orchestrating the inflammatory responses linked to senescent cells. This pathway detects cytosolic self-DNA arising from genomic instability and mitochondrial dysfunction, triggering inflammatory programs including the senescence-associated secretory phenotype (SASP). Recent studies reveal an age-dependent impairment in the canonical cGAS-STING activation, while a non-canonical signaling mode emerges that maintains chronic inflammation and senescence phenotypes. These mechanistic insights underscore the dual role of cGAS-STING in innate immunity and senescence-associated inflammation, linking DNA sensing to tissue degeneration in aging. This review aims to comprehensively summarize the underlying molecular mechanisms by which the cGAS-STING pathway regulates cellular senescence and aging. It also highlights how this axis contributes to age-related pathologies, and discusses current advances in targeted interventions that modulate this pathway. Given its critical role, the cGAS-STING axis represents a promising therapeutic target for ameliorating chronic inflammation, delaying senescence, and improving healthspan in an aging society.
    Keywords:  Age-related diseases; Antiaging; Cytoplasmic dsDNA; Senescent cells; cGAS-STING
    DOI:  https://doi.org/10.1016/j.biopha.2025.118790
  10. Cell Death Differ. 2025 Nov 25.
    Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
    Ismael Sánchez-Vera, Ana M Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T Jae, Daniel Iglesias-Serret, Joan Gil.
      Prohibitins (PHBs) are predominantly located at the inner mitochondrial membrane, displaying significant roles in tumor progression, invasion, and apoptotic resistance, often overexpressed in primary tumors. Importantly, we developed a synthetic molecule, fluorizoline, that induces apoptosis by selectively targeting PHBs in various cancer cell lines and primary samples from different hematological neoplasms. Fluorizoline induces apoptosis by activating the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, specifically via the ATF4-CHOP-NOXA axis. We identified compensatory mechanisms for four ISR-related kinases, with HRI emerging as the primary kinase responsible for the activation of the ISR and apoptosis induction, implicating mitochondrial stress in ISR activation. Here, we investigate the mitochondrial stress response signaling pathway responsible for activating HRI after targeting PHBs either by fluorizoline treatment or by PHBs downregulation in HeLa and HAP1 cancer cell lines. In this study, we describe how PHBs regulate the localization of the mitochondrial stress sensor DELE1, leading to ISR activation and apoptosis induction in HeLa and HAP1 cells. Our findings demonstrate that DELE1 promotes ISR activation upon fluorizoline treatment and PHBs downregulation. Although fluorizoline treatment activates the cleavage of long DELE1 (L-DELE1) to its cleaved form (S-DELE1), OMA1 was found to be dispensable for activating the ISR upon fluorizoline treatment. Furthermore, our findings indicate a potential impairment of the mitochondrial protein import machinery upon targeting PHBs, as the import of other mitochondrial proteins beyond DELE1 is also disrupted. These findings reveal a previously unknown physiological role of PHBs in preserving the mitochondrial protein import pre-sequence pathway, possibly due to the interaction between PHBs and DNAJC19. This novel insight underscores the potential of targeting PHBs, such as with fluorizoline, to overwhelm mitochondrial stress in cancer.
    DOI:  https://doi.org/10.1038/s41418-025-01618-0
  11. bioRxiv. 2025 Nov 11. pii: 2025.11.10.687744. [Epub ahead of print]
    Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells.
    Saran Chattopadhyaya, Stephanie Smith-Berdan, Sarah Huerta, E Camilla Forsberg.
      Aging leads to quantitative and qualitative changes in platelet (Plt) production, with increased risk for thrombosis and other adverse cardiovascular events. Recent reports showed that aging promotes the emergence of non-canonical (nc) megakaryocyte progenitors (MkPs) directly from hematopoietic stem cells (HSCs), leading to the production of hyperactive Plts. The higher engraftment potential of ncMkPs compared to both young and old canonical (c)MkPs, contrasts with the functional decline of old HSCs. Emerging reports suggest that mitochondrial function critically regulates lineage commitment and cellular functionality, but how mitochondrial activity affects aging megakaryopoiesis is unknown. Here, we demonstrate that aged MkPs sustain unique mitochondrial activity, characterized by higher mitochondrial membrane potential, higher ATP content, and lower ROS levels compared to their younger counterparts. This contrasts with the dysfunctional mitochondrial state observed in old HSCs, suggesting lineage-specific organelle adaptations upon aging. Notably, we observed that the elevated mitochondrial capacity in aged MkPs is driven selectively by the age-specific ncMkPs. Paradoxically, in vivo pharmacological enhancement of mitochondrial activity in old mice reduced in situ Plt production, but increased Plt reconstitution by transplanted HSCs. These discoveries link uniquely regulated mitochondrial capacity to the intrinsic properties of age-specific MkPs, raising the possibility of therapeutic targeting to prevent aging-induced megakaryopoiesis.
    HIGHLIGHTS: Aging-specific MkPs have elevated mitochondrial capacity, the inverse of aged HSCsMitochondrial enhancement differentially alters platelet counts in young and old miceEnhancement of mitochondrial capacity increases platelet repopulation by both young and old HSCs.
    DOI:  https://doi.org/10.1101/2025.11.10.687744
  12. Bioengineering (Basel). 2025 Oct 27. pii: 1166. [Epub ahead of print]12(11):
    Hematopoietic Stem Cell Aging: Mechanisms, Microenvironment Influences, and Rejuvenation Strategies.
    Jiaqi Cui, Xincan Li, Bin Liu, Cheng Dong, Yun Chang.
      Hematopoietic stem cells (HSCs) are essential for lifelong blood production and immune homeostasis. However, aging induces functional declines in HSCs, leading to hematological disorders, immune dysfunction, and increased susceptibility to malignancies. This review explores the biological underpinnings of HSC aging, highlighting the intrinsic and extrinsic factors that drive this process. We discuss the molecular and cellular mechanisms contributing to HSC aging, including genetic instability, epigenetic alterations, metabolic shifts, and inflammation signaling. Additionally, we examine the role of the bone marrow microenvironment in modulating HSC aging, emphasizing the impact of niche interactions, stromal cell dysfunction, and extracellular matrix remodeling. To advance our understanding of HSC aging, pluripotent stem cell differentiation platforms provide a valuable tool for modeling aged HSC phenotypes and identifying potential therapeutic targets. We review current strategies for HSC rejuvenation, including metabolic reprogramming, epigenetic modifications, pharmacological interventions, and niche-targeted approaches, aiming to restore HSC function and improve regenerative potential. Finally, we present emerging perspectives on the clinical implications of HSC aging, discussing potential translational strategies for combating age-associated hematopoietic decline. By integrating insights from stem cell biology, aging research, and regenerative medicine, this review provides a comprehensive overview of HSC aging and its therapeutic potential. Addressing these challenges will be critical for developing interventions that promote hematopoietic health and improve outcomes in aging populations.
    Keywords:  hematopoietic stem cell aging; microenvironment niche; molecular and cellular mechanisms; pluripotent stem cell; rejuvenation strategies
    DOI:  https://doi.org/10.3390/bioengineering12111166
  13. Antioxidants (Basel). 2025 Oct 24. pii: 1278. [Epub ahead of print]14(11):
    Dysregulated Redox Signaling and Its Impact on Inflammatory Pathways, Mitochondrial Dysfunction, Autophagy and Cardiovascular Diseases.
    Mehnaz Pervin, Judy B de Haan.
      Dysregulated redox signaling, mitochondrial dysfunction and impaired autophagy form an interconnected network that drives inflammatory and immune responses in cardiovascular disease. Among these, disturbances in redox balance, largely mediated by reactive oxygen species (ROS), serve as key drivers linking inflammatory signaling to adverse cardiovascular outcomes. Mitochondria are essential for energy production and cellular homeostasis, but their dysfunction leads to the accumulation of excessive ROS, which triggers inflammation. This pro-oxidative milieu disrupts immune regulation by activating inflammasomes, promoting cytokine secretion, triggering immune cell infiltration and ultimately contributing to cardiovascular injury. Conversely, intracellular degradation processes such as mitophagy alleviate these effects by selectively eliminating dysfunctional mitochondria, thereby decreasing ROS levels and maintaining immune homoeostasis. These interconnected processes influence myeloid cell function, including mitochondrial reprogramming, macrophage polarization and autophagic activity. The modulation of these immune responses is crucial for determining the severity and resolution of cardiac and vascular inflammation, and consequently the extent of cellular injury. This review examines the latest developments and understanding of the intricate relationships between redox signaling, mitochondrial dysfunction, autophagy and oxidative stress in modulating inflammation and immune responses in cardiovascular diseases. Understanding these interrelationships will inform future studies and therapeutic solutions for the prevention and treatment of cardiovascular diseases.
    Keywords:  autophagy; cardiovascular disease; inflammation; mitochondrial dysfunction; oxidative stress; redox signaling
    DOI:  https://doi.org/10.3390/antiox14111278
  14. Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01385-1. [Epub ahead of print]243 245-259
    APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
    Firoz Akhter, Asma Akhter, Donghui Zhu.
      APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.
    Keywords:  APOE4; Alzheimer's disease (AD); Mito-nuclear communication; Mitochondrial stress; Mitophagy; Nrf2-PINK/Parkin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.040
  15. Adv Sci (Weinh). 2025 Nov 28. e16736
    Mitochondrial Adaptation to Mechanical Stress in Cardiac Ageing and Disease.
    Aishwarya Prakash, Thomas Iskratsch.
      Cardiomyocytes are highly specialized cells that depend on a finely tuned interplay between mechanical forces and metabolic activity to sustain continuous contraction throughout life. While the role of mitochondria in supporting cardiac biomechanics through ATP production, calcium buffering, and redox signaling is well established, the reverse relationship, namely how mechanical forces influence mitochondrial behavior, remains comparatively understudied. This review explores the emerging concept of biomechanical feedback on mitochondrial dynamics in cardiomyocytes. Mechanical cues are shown to regulate mitochondrial morphology, positioning, and function via diverse mechanotransduction pathways. Key mechanisms include integrin signaling, stretch-activated ion channels, and cytoskeletal networks, alongside mechanical stimuli such as cyclic stretch, pressure overload, and shear stress, which modulate mitochondrial fusion/fission processes, membrane potential, calcium handling, and reactive oxygen species production. The implications of these interactions are considered in the context of cardiac pathologies, including hypertrophy, ischemia-reperfusion injury, and heart failure. By integrating perspectives from mitochondrial biology and cardiac mechanobiology, this review aims to foster interdisciplinary research and inform novel therapeutic approaches for cardiovascular disease.
    Keywords:  cardiac mechanobiology; heart failure; mechanotransduction; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/advs.202516736
  16. bioRxiv. 2025 Oct 17. pii: 2025.10.16.682859. [Epub ahead of print]
    Cryo-EM reveals how ASX-173 inhibits human asparagine synthetase to activate the integrated stress response.
    Kirk A Staschke, Nicholas T Walda, Lucciano A Pearce, Ronald C Wek, Wen Zhu, Yuichiro Takagi.
      Targeting asparagine metabolism is a promising strategy for treating asparaginase-resistant acute lymphoblastic leukemia (ALL), sarcoma, and potentially other solid tumors. Here, we characterize the molecular mechanism by which a cell-penetrable small molecule, ASX-173, inhibits human asparagine synthetase (ASNS), the enzyme that catalyzes intracellular asparagine biosynthesis. ASX-173 reduces cellular asparagine levels, induces the integrated stress response (ISR), and reduces cell growth in HEK-293A cells. A cryo-EM structure reveals that ASX-173 engages a unique, hydrophobic pocket formed by AMP, Mg 2+ , and pyrophosphate in the C-terminal synthetase domain of ASNS, thereby enabling multivalent, high-affinity binding. Based on in vitro kinetic and thermal shift assays, we find that ASX-173 binds to the ASNS/Mg 2+ /ATP complex and is therefore a rare example of an uncompetitive enzyme inhibitor with potential therapeutic use. These findings provide a structural and mechanistic basis for targeting ASNS with small molecules, which have application in treating cancer and other human diseases.
    DOI:  https://doi.org/10.1101/2025.10.16.682859
  17. Stem Cell Res Ther. 2025 Nov 28. 16(1): 669
    Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations.
    Mayu Morita, Eshan B Damle, Issei Shinohara, Masatoshi Murayama, Yosuke Susuki, Qi Gao, Chao Ma, Simon Kwoon-Ho Chow, Stuart Barry Goodman.
       BACKGROUND: With the global population aging, optimizing bone regeneration is becoming increasingly important for enhancing the quality of life among elderly individuals. Progenitor cell-based therapies, such as mesenchymal stromal cells and induced pluripotent stem cells for bone regeneration have shown challenges due to cellular senescence and the control of the differentiation processes remain significant hurdles. In particular, elevated expression of senescence markers may play a pivotal role in limiting bone regeneration. This systematic review examines how these senescence markers influence the efficacy of progenitor cell therapies and whether targeting them could improve outcomes.
    METHODS: We conducted a systematic literature review following the PRISMA guidelines, using the PubMed, Web of Science, Embase and Scopus with the algorithm of "bone regeneration AND senescence AND marker". Data synthesis focused on human cell sources and specifically examined senescence markers related to bone regeneration.
    RESULTS: Studies using human cells were discussed in 101 papers. Based on our inclusion and exclusion criteria, 13 papers remained for our review on senescence markers in human cells within the context of bone regeneration and senescence, with and without interventional strategies. More than half of the cell sources in current aging-related studies are derived from bone marrow. Markers of aging relevant to bone regeneration include changes in cell size and morphology, increased levels of β-galactosidase (β-Gal) and Reactive Oxygen Species (ROS), and the presence of a senescence-associated secretory phenotype (SASP). Additionally, distinct senescence markers such as p16Ink4a, p21, and p53, and mitochondrial dysfunction were associated with reduced osteogenic potential and impaired regenerative capacity.
    CONCLUSION: Bone marrow is the most common source of cells for studies of senescence. Cellular senescence characterized by elevated expression of specific markers was consistently shown to be negatively associated with osteogenic capacity and regenerative outcomes. The most common strategies to rejuvenate senescent cells include targeting of senescence markers and oxidative stress. Among these, modulation of p53, p21, and p16 signaling pathways has been highlighted as a potential therapeutic approach for mitigating cell senescence in bone-related conditions.
    Keywords:  Bone regeneration; Cellular senescence; ROS; Senescence marker; p16; p21; p53
    DOI:  https://doi.org/10.1186/s13287-025-04767-8
  18. Pharmaceuticals (Basel). 2025 Nov 08. pii: 1698. [Epub ahead of print]18(11):
    Modulation of Nrf2 and Mitochondrial Function: Pharmacological Implications.
    Luciano Saso, Ilker Ates, Ramazan Tunc, Beyza Yilmaz, Marialucia Gallorini, Simone Carradori, Sibel Suzen.
      Mammalians are constantly exposed to exogenous and endogenous sources of free radicals that have both favorable and harmful effects on the cellular systems. Oxidative stress (OS) is an imbalance of reactive oxygen species (ROS) and antioxidants in the body that can lead to serious cell damage. It is associated with many diseases such as cancer, Alzheimer's disease and heart disease. Background/Objectives: The Nuclear factor-2 erythroid-related factor-2 (Nrf2) is a transcription factor that controls the cellular oxidation state using antioxidant systems in the body and affects mitochondrial activities. Increased Nrf2 levels serve to protect cells from mitochondrial toxins; however, Nrf2 activity is inhibited in mitochondria-related diseases. In addition, Nrf2 is involved in mitochondrial activities for OS control. Methods: As mitochondrial wellbeing and activity is the chief controller for cellular metabolism, Nrf2 is a critical regulator for metabolic pathways. Thus, Nrf2 is the chief organizer of protection against OS in the cells. Nrf2 activator molecules support mitochondrial activity by stimulating mitophagy and helping to battle OS-related permeability transition. Conclusions: This review describes the influence of Nrf2 on OS and the way Nrf2 modulates mitochondrial function. Furthermore, we highlight recent studies of Nrf2 regarding its possible role in cell systems as well as pharmacological implications. Furthermore, this review emphasizes the importance of the mitochondria in the development of life-threatening diseases; pharmacological activation of Nrf2 is an important strategy to counter mitochondrial dysfunction.
    Keywords:  Nrf2; ROS; antioxidant; mitochondrial function; oxidative stress
    DOI:  https://doi.org/10.3390/ph18111698
  19. Exp Gerontol. 2025 Nov 24. pii: S0531-5565(25)00303-1. [Epub ahead of print]212 112974
    The interplay between the immune microenvironment and bone aging: From molecular mechanisms to therapeutic interventions.
    Jianxu Wang, Yijun Xin, Zihao Dong, Siying Li, Guang Yang.
      The core mechanism of skeletal aging lies in the comprehensive disruption of microenvironmental homeostasis, involving a multidimensional interactive network comprising immune cells, mesenchymal stem cells, and their differentiated lineages. Although osteoporosis (OP) and osteoarthritis (OA) have traditionally been viewed as distinct degenerative disorders, recent breakthroughs in osteoimmunology reveal their shared immune-aging mechanism: immune cell dysfunction within the bone marrow microenvironment triggers inflammaging, subsequently driving a vicious cycle of bone formation and resorption through the senescence-associated secretory phenotype (SASP). This review not only integrates the molecular landscape of osteoclast-osteoblast-immune triangular crosstalk but also highlights emerging mechanisms such as mitochondrial dysfunction, exosomal communication, and cell death mechanisms, systematically establishing the pivotal role of the immune microenvironment in bone aging and providing a theoretical framework for developing next-generation targeted therapies against skeletal aging.
    Keywords:  Bone aging; Bone cells; Immune cells; Immune microenvironment; Therapy
    DOI:  https://doi.org/10.1016/j.exger.2025.112974
  20. Cell Commun Signal. 2025 Nov 27. 23(1): 512
    Mitochondrial connexin 43 modulates metabolic stress adaptation in glioma cell lines.
    Anna Gervasi, Simona Denaro, Simona D'Aprile, Maja Potokar, Jernej Jorgačevski, Robert Zorec, Daniele Tibullo, Agata Zappalà, Angela Maria Amorini, Rosalba Parenti, Nunzio Vicario.
       BACKGROUND: Connexin 43 (CX43) is a hemichannel (HC)- and gap junction (GJ)-forming protein that mediates the exchange of small molecules between the intracellular and extracellular environments, as well as intercellular communication. In addition to this canonical role, recent studies have shown that its functions range from transcriptional regulation to intracellular homeostasis. The ability of CX43 to translocate into mitochondria suggests its involvement in energy metabolism. However, the functions of mitochondrial CX43 (mt-CX43) in neural cells remain unexplored.
    METHODS: Our study investigated the expression and localisation of mt-CX43 through western blot and immunofluorescence analyses in four immortalised human glioma cell lines: T98-G, A-172, CCF-STTG1, and U-87 MG. Additionally, targeted metabolomic analysis was conducted to assess changes in key metabolic pathways.
    RESULTS: Basal CX43 expression and extracellular stress factors, particularly cell density and extracellular pH fluctuations, significantly modulated the mitochondrial localisation of CX43. Inhibition of the heat shock protein 90 (HSP90) chaperone system by geldanamycin (GA) resulted in a marked reduction in mt-CX43, suggesting an import mechanism involving HSP90 and the translocase of the outer membrane (TOM) complex. In addition, the assessment of key metabolites revealed increased purine biosynthesis in T98-G cells exposed to GA treatment, characterised by lower basal CX43 expression and reduced mt-CX43 levels under stress conditions. Conversely, U-87 MG cells exhibited a stable NAD+/NADH ratio and a significant increase in NADH levels, indicating a metabolic shift towards a more resilient state.
    CONCLUSIONS: Our results suggest that mt-CX43 serves as a multifunctional regulator of metabolic adaptation and stress response in glioma cell lines. Our results extend the role of mt-CX43 as an essential factor in cellular metabolic plasticity, providing new insights into the modulation of metabolic imbalances and mitochondrial dysfunction.
    Keywords:  CX43; Geldanamycin; Glioblastoma; Metabolism; Purine; pH
    DOI:  https://doi.org/10.1186/s12964-025-02523-2
  21. Nutrients. 2025 Nov 15. pii: 3571. [Epub ahead of print]17(22):
    Rutin as a Circadian Modulator Preserves Skeletal Muscle Mitochondrial Function and Reduces Oxidative Stress to Protect Against D-Galactose-Induced Aging In Vitro and In Vivo.
    Yoonha Choi, Suhyeon Lee, Eunju Kim.
      Background: Skeletal muscle aging is characterized by impaired myogenic differentiation, disrupted circadian rhythms, elevated oxidative stress, and mitochondrial dysfunction. Rutin, a natural flavonoid with antioxidant properties, has been suggested to mitigate aging processes; however, its effects on circadian regulation and muscle homeostasis remain unclear. Methods: In vitro, differentiated C2C12 myotubes were treated with D-galactose (D-gal, 20 g/L) with or without rutin (20 μM). In vivo, C57BL/6 mice were supplemented with rutin (100 mg/kg b.w.) via oral gavage in a D-gal-induced aging mouse model (150 mg/kg b.w., i.p.). Results: D-gal induced cellular senescence, impaired myogenic differentiation, disrupted circadian oscillations, increased oxidative stress, and compromised mitochondrial function. Rutin treatment restored myotube formation, enhanced circadian rhythmicity of differentiation-related genes, and corrected the antiphase patterns of Per2 and Rorc. It also reduced reactive oxygen species and malondialdehyde levels; increased superoxide dismutase, catalase, and glutathione peroxidase activity; improved ATP production and membrane potential; and decreased mitochondrial oxidative aging, as confirmed by pMitoTimer imaging. Furthermore, rutin reinstated the rhythmic expression of oxidative phosphorylation proteins and Pgc1α. In vivo, rutin supplementation enhanced muscle performance (prolonged hanging time) and oxidative capacity, particularly at night (ZT14-ZT16), without altering muscle fiber-type distribution, and normalized circadian rhythmicity of core clock genes. Conclusions: Rutin attenuates D-gal-induced cellular senescence by modulating circadian rhythms, reducing oxidative stress, and improving mitochondrial function. Importantly, its in vivo effects on muscle performance and circadian regulation suggest that rutin is a promising therapeutic strategy to counteract skeletal muscle aging and sarcopenia.
    Keywords:  circadian rhythm; mitochondrial function; muscle senescence; oxidative stress; rutin
    DOI:  https://doi.org/10.3390/nu17223571
  22. Res Sq. 2025 Oct 09. pii: rs.3.rs-7476559. [Epub ahead of print]
    Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.
    Jin Young Huh, Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan Saltiel.
      Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here, we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1 knockout (LTKO) mice, we show that TBK1 loss leads to the accumulation of depolarized, ROS-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal acidification. Therapeutic restoration of TBK1 expression via AAV8 delivery enhanced mitophagy, reduced mitochondrial burden, and ameliorated liver fibrosis. Notably, both human samples and murine steatohepatitis models exhibited a significant decline in TBK1 kinase activity. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.
    DOI:  https://doi.org/10.21203/rs.3.rs-7476559/v1
  23. Int J Mol Sci. 2025 Nov 13. pii: 10977. [Epub ahead of print]26(22):
    Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
    Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss.
      Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.
    Keywords:  mitochondrial dynamics; skeletal muscle; statin; translocase of outer mitochondrial membrane; transmission electron microscopy
    DOI:  https://doi.org/10.3390/ijms262210977
  24. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  25. Exp Gerontol. 2025 Nov 20. pii: S0531-5565(25)00299-2. [Epub ahead of print] 112970
    Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
    Shota Uebo, Yoshiyuki Ikeda, Yoshihiro Uchikado, Yuichi Sasaki, Yuichi Akasaki, Takuro Kubozono, Mitsuru Ohishi.
      Aim Sarcopenia, a major cause of frailty in postmenopausal women, is linked to mitochondrial dysfunction, but the underlying mechanisms remain unclear. This study aimed to clarify whether mitophagy, a mitochondrial quality control mechanism, contributes to postmenopausal sarcopenia, to elucidate its underlying mechanism, and to assess whether it can be rescued.
    METHODS: C57BL/6 mice (12-week-old females) underwent ovariectomy to establish a menopause mouse model, or sham surgery, and the therapeutic effects of nicotinamide mononucleotide (NMN) were assessed. Human skeletal muscle myoblasts (HSMMs) differentiated under postmenopausal conditions with or without 17β-estradiol (E2), and Rab9 expression was modulated using CRISPR activation.
    RESULTS: Ovariectomized mice exhibited decreased muscle mass and strength. E2 deficiency in HSMMs inhibited skeletal muscle cell differentiation, promoted senescence, impaired mitochondrial function, and reduced mitophagy. However, E2 deficiency did not modulate light chain 3 and autophagy-related 7 but reduced Rab9 expression and the colocalization of Rab9 with lysosomal-associated membrane protein 2, suggesting that E2 mediates mitophagy through Rab9-dependent alternative autophagy. Furthermore, overexpression of Rab9 in E2-deficient HSMMs enhanced mitophagy, improved mitochondrial function, suppressed cellular senescence, and promoted skeletal muscle cell differentiation. The administration of NMN to ovariectomized mice increased Rab9 expression and improved sarcopenia through increased mitophagy.
    CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.
    Keywords:  Alternative autophagy; Estrogen; Menopause-induced sarcopenia; Mitochondria; Mitophagy; Nicotinamide mononucleotide; Rab9
    DOI:  https://doi.org/10.1016/j.exger.2025.112970
  26. bioRxiv. 2025 Oct 15. pii: 2025.10.13.682198. [Epub ahead of print]
    The C. elegans immune switch proteins PALS-25 and PALS-22 localize to mitochondria and regulate fragmentation.
    Spencer S Gang, Max W Strul, Emily R Troemel.
      The nematode C. elegans controls immunity against intracellular pathogens like microsporidia using the pals gene family, which has expanded in C. elegans compared to mammals. pals-22 is a negative regulator that restrains pals-25 , which serves as a positive regulator of immunity. pals-22 and pals-25 encode proteins that bind each other and can act in the intestine and epidermis, but their subcellular localization and mechanism of action have not been described. Here we show that PALS-22 and PALS-25 proteins localize to mitochondria, with PALS-25 being required for PALS-22 localization to mitochondria. The C-terminus of PALS-25 is both necessary and sufficient for mitochondrial localization. Loss of PALS-22 causes mitochondrial fragmentation, which occurs after activating the Intracellular Pathogen Response (IPR), a transcriptional program induced by intracellular infection. Mitochondrial fragmentation induced in an independent manner increases resistance against microsporidia infection. Thus, PALS-22/25-mediated fragmentation of mitochondria appears to increase immunity against intracellular infection.
    DOI:  https://doi.org/10.1101/2025.10.13.682198
  27. Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01394-2. [Epub ahead of print]243 300-317
    Sirtuin downregulation mediates mitochondrial impairment causing cognitive decline in hepatic encephalopathy.
    Shiwangi Gupta, Vikas Rishi, Aanchal Aggarwal.
      Hepatic encephalopathy (HE) induced cognitive decline has long been associated with mitochondrial dysfunction. Therefore, the present study aimed to characterize mitochondrial alterations in HE and also examining the regulatory role of Sirtuins. Using both in vitro (NH4Cl induced SH-SY5Y) and in vivo (bile duct ligation, BDL) models, mitochondrial analysis revealed pronounced abnormalities, including reduced membrane potential, elevated oxidative stress, and swelling. Moreover, spatial memory was also significantly impaired in BDL rats. Following HE, nuclear Sirtuins (Sirtuin 1, 6, and 7) were significantly downregulated, whereas Sirtuin 2-5 remained largely unchanged. Reduced Sirtuin 1 expression in HE resulted in decreased occupancy at the HIF-1α promoter, diminishing transcriptional repression and leading to aberrant HIF-1α upregulation. Elevated HIF-1α in turn enhanced transcriptional activation of VDAC1 in both HE models. Pharmacological activation of Sirtuin 1 with SRT2104 suppressed HIF-1α levels reduced VDAC1 expression, while inhibition with EX-527 exhibited the reverse effect and worsened mitochondrial dysfunction. Furthermore, selective VDAC1 inhibition by VBIT-12 effectively restored mitochondrial integrity in NH4Cl-treated cells. In addition to the Sirtuin 1-HIF-1α mechanism, a separate regulatory pathway involving Sirtuin 6 was also uncovered. Loss of Sirtuin 6 amplified HIF-1α transcriptional activity by reducing its interaction with Sirtuin 6 and diminishing Sirtuin 6-mediated repression, thereby promoting increased expression of the downstream target VDAC1. Together, these observations identify reduced nuclear Sirtuin 1 and Sirtuin 6 as converging upstream regulators of the HIF-1α-VDAC1 axis, contributing to mitochondrial dysfunction in HE.
    Keywords:  HIF-1α; Hepatic encephalopathy; Mitochondria; Oxidative stress; Sirtuin; VDAC1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.049
  28. Redox Biol. 2025 Nov 08. pii: S2213-2317(25)00433-1. [Epub ahead of print]88 103920
    Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury.
    Duo Jin, Xinran Ge, Li Liu, Yujie Jia, Chang Liu, Ke Meng, Xiaowei Zhang.
       BACKGROUND: Mitochondrial dysfunction and excessive reactive oxygen species (ROS) generation play a pivotal role in ischemic neuronal injury. The Activator of 90kDa heat shock protein ATPase homolog 1 (AHSA1/AHA1) has been implicated in regulating ATP synthesis and energy metabolism. Yet, its role in neurological functional impairment and mitophagy under pathological conditions remains unclear.
    METHODS: We utilized in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) neuronal cell models. The study integrated bioinformatics, molecular biology techniques, histological analyses, behavioral tests, and genetic knockdown (siRNA) to elucidate the underlying mechanisms.
    RESULTS: Our findings demonstrate that I/R stress induces the transcription factor STAT3 to upregulate AHA1 expression. AHA1 then translocates to the mitochondria and directly interacts with the ATP synthase subunit ATP5A1. This interaction disrupts the cellular ATP/AMP ratio and increases ROS production, leading to mitochondrial damage. The resulting energy stress triggers the aberrant activation of the AMPK/mTOR/ULK1 signaling pathway, culminating in an excessive and detrimental flux of PINK1/Parkin-mediated mitophagy. Critically, silencing of AHA1 reversed these effects, suppressing pathological mitophagy, reducing infarct volume, and improving neurological outcomes.
    CONCLUSION: This study reveals a novel, non-canonical function for AHA1 as a pathological driver in ischemic stroke. By directly interacting with ATP5A1, AHA1 links transcriptional stress responses to mitochondrial bioenergetic failure and excessive autophagy. Targeting the AHA1-ATP5A1 axis represents a promising therapeutic strategy to inhibit maladaptive mitophagy and protect against neurological outcomes.
    Keywords:  AHA1; ATP5A1; Ischemic stroke; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2025.103920
  29. bioRxiv. 2025 Nov 05. pii: 2025.11.04.686591. [Epub ahead of print]
    A role for the Stentor syntaxin protein in post-wound cell survival.
    Ambika V Nadkarni, Ulises Diaz, Kevin S Zhang, Sindy Ky Tang, Wallace F Marshall.
      Wound healing is an essential biological process that occurs both in tissues and single cells. In free-living single-celled ciliates such as Stentor coeruleus , rapid wound healing is necessary to repair breaches to the plasma membrane, where any delays represent the difference between life and death. In order to discover novel molecular pathways that are important for healing in Stentor , we carried out a targeted RNA interference-based perturbation genetic screen combined with microsurgical wounding using a microfluidic guillotine to introduce reproducible bisection wounds. We identified a Stentor syntaxin gene that was necessary for cell survival, particularly post-wounding, with only ∼37% of the syntaxin-deficient cells surviving compared with ∼98% of the control cells. Syntaxin-deficient cells were more susceptible to hyposmotic shock and became increasingly vacuolated in the hours post-wounding, eventually leading to cell death. Osmotic stabilization of the cells during and after bisection partially restored the post-wound survival in knockdown cells. These results support the interpretation that syntaxin-deficient cells lack essential membrane fusion machinery, which manifests in vacuolar defects, and are deficient in maintaining osmotic homeostasis necessary for their survival post-wounding. This study provides a template for the discovery of new wound healing biology in emerging model systems.
    Significance: Stentor is a single-celled ciliate with prodigious healing ability, yet the molecular mechanisms by which the cell rapidly heals wounds are not fully characterized. Through a targeted microfluidics genetic screen, we identified a novel syntaxin-like protein that is essential for Stentor survival post-wounding. Syntaxin-deficient cells were more susceptible to osmotic shock. Wounding cells in osmotically balanced conditions reduced the degree of hyposmotic stress associated with wounding and enabled more cells to survive. Our discovery highlights the rebalancing of intracellular osmolarity as an important step in wound repair in freshwater-dwelling organisms.
    DOI:  https://doi.org/10.1101/2025.11.04.686591
  30. Connect Tissue Res. 2025 Nov 25. 1-17
    Mitochondrial crosstalk between bone marrow stromal cells and chondrocytes: implication for cartilage repair in osteoarthritis.
    Baihui Zhang, Jiasi Zhang, Danyang Yue, Xiao Huang, Jun Pan.
       PURPOSE/AIM: Mitochondria are vital dynamic organelles released by cells into extracellular space, endocytosed in or transferred between cells in contact. Mitochondria from healthy bone marrow stem cells (MSCs) show rescue effects on chondrocytes, accordingly a concept of using healthy MSC mitochondria for cartilage regeneration is put forward. Therefore, whether mitochondria from healthy MSCs help to save chondrocytes in damaged cartilage microenvironment is intriguing. We answered this question by considering coexistent MSCs and chondrocytes, and their released mitochondria in damaged joint.
    MATERIALS AND METHODS: Mitochondria were extracted from primarily cultured MSCs and chondrocytes of osteoarthritis (OA) human patients to represent mitochondria released endogenously by MSCs and chondrocytes in damaged joint. While mitochondria were extracted from healthy rats to represent mitochondria exogenously added during MSC mitochondrial repair for the inaccessibility of healthy human. The mitochondria were co-cultured with another type of cells. Endocytosing and afterward positioning of exogenous mitochondria, as well as induced alterations in mitochondria and cellular behaviors of recipient cells were assayed.
    RESULT: Our results suggested that although mitochondria from healthy MSCs advantaged remedy for inflammatory chondrocytes, mitochondria from healthy and OA chondrocytes, as well as from OA MSCs disadvantaged chondrocytes remedy, no matter the mitochondria were from the same or different species. However, reactive oxygen species (ROS) modulation alleviated the disadvantage.
    CONCLUSIONS: Our results provide a reminder for careful consideration of mitochondrial therapy, and explanation for unsuccessful repair of damaged cartilage by MSCs from aspect of mitochondria, as well as potential remedy through ROS modulation.
    Keywords:  Mitochondrial therapy; ROS; cartilage regeneration; differentiation; stem cells
    DOI:  https://doi.org/10.1080/03008207.2025.2590044
  31. Commun Biol. 2025 Nov 24. 8(1): 1650
    Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.
    Aeowynn J Coakley, Adam J Hruby, Jing Wang, Andrew Bong, Tripti Nair, Carmen M Ramos, Athena Alcala, Daniel Hicks, Maxim Averbukh, Naibedya Dutta, Darius Moaddeli, Camilla Pearson, Cynthia J Siebrand, Mattias de Los Rios Rogers, Arushi Sahay, Sean P Curran, Peter J Mullen, Bérénice A Benayoun, Gilberto Garcia, Ryo Higuchi-Sanabria.
      The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissues to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while more modest changes were detected in GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.
    DOI:  https://doi.org/10.1038/s42003-025-09036-1
  32. Nat Metab. 2025 Nov 24.
    Mitochondrial NAD+ drives liver regeneration.
      
    DOI:  https://doi.org/10.1038/s42255-025-01414-7
  33. bioRxiv. 2025 Oct 15. pii: 2025.10.15.682539. [Epub ahead of print]
    Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche.
    Bingqing Zou, Qiuyun Chen, Junjun Zheng, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou.
      Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome, yet strategies to enhance lymphocyte regeneration are limited. We studied the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We revealed that PERK activation is a prominent feature of BM endothelium in leukemia patients and is a hallmark response in mouse BM following ionizing irradiation. Ablating endothelial Perk boosted Notch ligand DLL4 expression and promoted DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis shows that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment and niche cytokine production. NOTCH3 is critical for the upregulation of IL7 following irradiation and for supporting the expansion of lymphoid progenitors in mesenchymal sphere cultures. These findings not only unveil a previously unrecognized ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising therapeutic strategy to improve immune recovery after myeloablative transplantation.
    Summary: Zou et al unravel that the adaptive ER stress response in bone marrow blood vessels restricts the post-transplant regeneration of immune progenitor cells by attenuating the expression of Notch ligand DLL4. Targeting ER stress sensor PERK can accelerate immune recovery after transplantation by enhancing DLL4-NOTCH3 signaling and IL7 cytokine production.
    DOI:  https://doi.org/10.1101/2025.10.15.682539
  34. Cell Transplant. 2025 Jan-Dec;34:34 9636897251372397
    Photobiomodulation-induced activation of Wnt signaling enhances differentiation of adipose-derived stem cells into tenocytes: Mechanistic insights into regenerative signaling pathways.
    Mbali Mpanza, Heidi Abrahamse, Anine Crous.
      The differentiation of adipose-derived stem cells (ADSCs) into tendon cells is a key process in tissue engineering and regenerative medicine. The Wnt signaling pathway plays a key role in regulating cell fate and tissue-regeneration decisions, making it a promising target for improving tendon differentiation. Photobiomodulation (PBM) is a non-invasive therapeutic approach that has been shown to modulate cellular processes, including stem cell differentiation. The aim of this review is to provide an understanding of the effects of PBM and Wnt signaling on ADSC differentiation. The complexities of interactions between PBM and dynamic Wnt pathway exist in different ways during the differentiation of ADSCs into tendon cells. The results highlight the potential therapeutic application of PBM in promoting tendon healing and regeneration. This review explores the clinical importance of PBM-mediated Wnt signaling regulation in tendon injuries. The results of this review will provide valuable information for the rational design of therapeutic strategies to enhance tendon differentiation and improve clinical outcomes and will also contribute to increasing knowledge of the synergistic relationship between PBMs, Wnt signaling pathways, and stem cell differentiation.
    Keywords:  Wnt pathway; adipose stem cells; photobiomodulation; tenocyte differentiation
    DOI:  https://doi.org/10.1177/09636897251372397
  35. Cells. 2025 Nov 12. pii: 1772. [Epub ahead of print]14(22):
    Mitochondrial Protection by Astaxanthin Reduces Toxicity Caused by H2O2 and Doxorubicin in Human Cardiomyocytes.
    Yulia Baburina, Aleksey Lomovsky, Yana Lomovskaya, Roman Sotnikov, Linda Sotnikova, Olga Krestinina.
      Astaxanthin (AST) is a xanthophyll carotenoid known for its cardioprotective effects. In this study, we investigated the impact of AST on the survival of AC16 human cardiomyocytes under cardiotoxic conditions induced by hydrogen peroxide (H2O2) and doxorubicin (DOX). We assessed a series of parameters associated with cell death signaling, including: changes in cytosolic Ca2+ levels and reactive oxygen species (ROS) production; alterations in mitochondrial function (membrane potential ΔΨm and the content of key subunits of complexes I and II); and the levels of key apoptotic and ER stress markers. Our findings show that AST prevented the cytotoxic effects of both H2O2 and DOX. In the presence of AST, the number of viable cells increased, while Ca2+ levels, ROS production, and ΔΨm remained comparable to those in the control group. Furthermore, AST prevented the H2O2-induced decrease in the levels of the main subunits of respiratory chain complexes I and II. AST prevented the H2O2-induced increase in the levels of apoptotic caspases-8 and -3. It also protected against ER stress by counteracting the H2O2-mediated upregulation of BIP, CHOP, and ERO1α proteins. These results lead us to conclude that AST exerts a protective effect by inhibiting mitochondrial dysfunction.
    Keywords:  astaxanthin; doxorubicin; human AC16 cardiomyocytes; hydrogen peroxide; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/cells14221772
  36. Mater Today Bio. 2025 Dec;35 102483
    ATG7-driven mitophagy in BMSC@CS hydrogel reprograms metabolism to boost bone regeneration.
    Qiumei Lan, Mengtian Fan, Fengmei Zhang, Qian Gong, Jiayan Zhong, Miao Yi, Qiqi Zeng, Jianqiang Chen, Yiming Pan, Nana Geng, Biao Kuang, Yu Du, Chuanrong Zhao, Deping Zeng, Chunliang Zhao, Zhen Li, Guixue Wang, Fengjin Guo.
      Bone regeneration remains a formidable challenging due to impaired energy metabolism and the limited osteogenic potential of transplanted stem cells. Mitochondrial homeostasis orchestrates osteogenesis, with mitophagy maintaining the metabolic rhythm essential for bone formation. However, the role of autophagy related gene 7(ATG7), a pivotal regulator of mitochondrial function, in bone regeneration remains elusive. In this study, we developed a ATG7-overexpressing bone marrow mesenchymal stem cells (ATG7-BMSCs) encapsulated within a thermoresponsive chitosan (CS) hydrogel, creating a biocompatible, living platform capable of adapting to physiological conditions. The hydrogel exhibited excellent injectability, physiological gelation at 37 °C, and prolonged biocompatibility, providing a favorable microenvironment for stem cell survival and proliferation. The system was evaluated through in vitro assays for mitochondrial function and osteogenic differentiation, as well as in vivo using rat cranial and femoral defect models. Mechanistically, ATG7 activation enhanced mitophagy, preserved mitochondrial integrity, reduced reactive oxygen species (ROS) accumulation, and reactivated oxidative phosphorylation via the PI3K-AKT signaling pathway, thereby reprogramming osteogenic metabolism and promoting differentiation. Conversely, ATG7 deficiency led to mitochondrial dysfunction, glycolytic dependence, and impaired bone formation. In vivo, the ATG7-BMSC@CS hydrogel markedly accelerated new bone formation and mineral density recovery while maintaining excellent injectability, biocompatibility, and systemic safety. Collectively, this study identifies ATG7-driven mitophagy as a critical regulator of osteogenic metabolism and bone formation, and establishes a smart, living hydrogel platform that seamlessly integrates metabolic reprogramming with stem cell delivery. This strategy provides a conceptual blueprint for next-generation, metabolism-oriented bone repair at the intersection of cell biology, biomaterials, and precision medicine.
    Keywords:  ATG7-BMSC@CS; Bone formation; Metabolic reprogramming; Mitophagy; Osteogenesis
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102483
  37. Biomedicines. 2025 Oct 30. pii: 2663. [Epub ahead of print]13(11):
    Beyond ER Stress: The Pleiotropic Roles of XBP1 in Development and Regeneration.
    Delan Huang, Fan Gu, Jingzhi Ma, Zhi Chen.
      This review synthesizes current knowledge on the roles of X-box binding protein 1 (XBP1) in development and regenerative medicine. XBP1 is defined as a key transcription factor that regulates biological processes from embryogenesis to adult tissue homeostasis via both endoplasmic reticulum(ER) stress-dependent and independent mechanisms. Evidence for its regulatory role in cell fate determination and tissue maintenance across multiple systems is presented. The therapeutic potential of targeting XBP1 is explored, particularly for the regeneration of skeletal muscle, skin, and bone. Critical future research priorities are outlined, such as deciphering the precise functions of the Inositol requiring enzyme 1 (IRE1α)/XBP1 signaling axis and evaluating the long-term safety of its modulation. XBP1 is thus confirmed as a prime target for advancing developmental biology and pioneering new regenerative therapies.
    Keywords:  ER stress; XBP1; development; regeneration; tissue homeostasis
    DOI:  https://doi.org/10.3390/biomedicines13112663
  38. Cells. 2025 Nov 19. pii: 1818. [Epub ahead of print]14(22):
    GV1001, an hTERT-Derived Peptide, Prevents Cisplatin-Induced Nephrotoxicity by Preserving Mitochondrial Function.
    Wei Chen, Cheyenne Beheshtian, Seojin Kim, Reuben Kim, Sangjae Kim, No-Hee Park.
      GV1001, a multifunctional peptide, has shown numerous biomedical activities, including antioxidant, anti-inflammatory, anti-Alzheimer's, and anti-atherosclerotic effects, and protects mitochondria from cytotoxic agents. Cisplatin is a widely used chemotherapeutic agent against cancers, but its clinical utility is limited by nephrotoxicity driven by mitochondrial dysfunction in renal epithelial cells. Here, we investigated whether GV1001 protected against cisplatin-induced nephrotoxicity (CIN) in vivo and preserved mitochondrial integrity in human renal epithelial cells in vitro. In mice, GV1001 substantially mitigated CIN by significantly reducing histological damage, kidney injury marker expression, macrophage infiltration, endothelial-to-mesenchymal transition, inflammation, and apoptosis. In cultured renal epithelial cells, GV1001 maintained mitochondrial membrane potential, preserved ATP production, and prevented mitochondrial membrane peroxidation possibly by binding to cardiolipin. GV1001 also reduced the level of reactive oxygen species (ROS), suppressed cytochrome c release into the cytosol, and inhibited activation of apoptosis-related pathways elicited by cisplatin. Collectively, these findings demonstrated that GV1001 might protect kidney from cisplatin through maintaining mitochondrial structure and function and suppressing downstream injury cascades in renal epithelial cells. By directly targeting the mitochondrial mechanisms underlying cisplatin toxicity, GV1001 represents as a promising therapeutic strategy to mitigate CIN and improve the safety of cisplatin-based chemotherapy.
    Keywords:  GV1001; cisplatin; mitochondria; nephrotoxicity; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells14221818
  39. bioRxiv. 2025 Nov 10. pii: 2025.11.07.687297. [Epub ahead of print]
    Extracellular matrix remodeling supports Hydra vulgaris head regeneration and stem cell invasion.
    Ben D Cox, Jasmine Mah, Angel Perez, Celina E Juliano.
      The small freshwater cnidarian Hydra vulgaris is a classic model for investigating the genetic regulation of whole-body regeneration, but the underlying cell biology is comparatively underexplored. Hydra has a simple body plan consisting of two epithelial monolayers separated by an extracellular matrix (ECM). This ECM contains conserved components such as collagen and laminin, making Hydra well suited for dissecting ECM function during regeneration. Following head amputation and wound closure, we observe a retraction of ECM proteins from the wound site, creating a region of low ECM protein accumulation that persists for several days during head regeneration. Several matrix metalloproteinase (MMP) genes are expressed during this process, and MMP inhibition reduces the size of the ECM gap and results in a regenerative outcome with gross morphological defects. We further find that interstitial stem cells (ISCs), which originate in the ectoderm, localize in the regenerating head endoderm near regions of reduced ECM. This suggests that the ECM gap facilitates stem cell invasion to populate the new head with neurons and gland cells. However, inhibition of collagen cross-linking reveals that collagen synthesis is also required for regeneration, indicating that Hydra must balance ECM degradation and synthesis to complete regeneration. Together, these findings highlight ECM remodeling as a critical and conserved feature of regeneration.
    Summary statement: This study uses Hydra vulgaris , a highly regenerative freshwater cnidarian, to study remodeling of extracellular matrix proteins and stem cell invasion during tissue regeneration.
    DOI:  https://doi.org/10.1101/2025.11.07.687297
  40. Endocr Metab Immune Disord Drug Targets. 2025 Nov 24.
    Role of the lncRNA MALAT1/miR-1 Pathway in Mouse Myocardial Ischemia-Reperfusion Injury.
    Jiangen Liu, Bin Zhang, Jinlei Li, Zhongfeng Chen, Yangxue Li.
       INTRODUCTION: The interplay between LncRNA MALAT1 and hsa-miR-1 plays a crucial role in Myocardial Ischemia-Reperfusion Injury (MIRI), offering insights into the molecular mechanisms underlying cardiovascular pathologies. This study sought to elucidate their regulatory relationship and functional impact on MIRI progression.
    MATERIALS AND METHODS: Using an H9C2 cardiomyocyte cell line subjected to ischemia-reperfusion (I/R) modeling, we analyzed alterations in LncRNA MALAT1 and hsa-miR-1 expression and their downstream effects on apoptosis, reactive oxygen species (ROS) accumulation, and myocardial injury markers.
    RESULTS: Our findings demonstrated that siRNA-mediated knockdown of MALAT1 or modulation of hsa-miR-1 (via mimics and inhibitors) effectively attenuated oxidative stress and reduced cardiomyocyte apoptosis. Furthermore, in vivo experiments using a murine MIRI model corroborated the regulatory roles of MALAT1 and hsa-miR-1, identifying them as potential therapeutic targets for mitigating reperfusion injury.
    DISCUSSION: Our findings highlight the importance of the MALAT1/miR-1 axis in MIRI pathogenesis. The observed reduction in ROS and apoptosis upon modulation of these molecules suggests their involvement in key cellular stress responses. These results align with previous studies on lncRNA- miRNA interactions in cardiovascular diseases.
    CONCLUSION: These results not only highlight the significance of the MALAT1/miR-1 axis in MIRI but also propose novel molecular intervention strategies for the treatment of cardiovascular disease.
    Keywords:  LncRNA MALAT1; apoptosis.; hasa-miR-1; myocardial ischemia-reperfusion injury; oxidative stress
    DOI:  https://doi.org/10.2174/0118715303439119251106075344
  41. Pharmacol Res. 2025 Nov 21. pii: S1043-6618(25)00468-2. [Epub ahead of print]222 108043
    Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.
    Chenrong Jin, Juhui Qiao, Huilin Gong, Xiaorui Yu, Xinran Wang, Jiao Xi, Runying Mi, Shiting Yu, Daian Pan, Siming Wang, Xiaolin Tong, Daqing Zhao, Meichen Liu.
      Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in Drosophila. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and Drosophila Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.
    Keywords:  Brain aging; Drp1 mutants; Ginsenoside Re; Mitochondrial dynamics; Mitophagy axis
    DOI:  https://doi.org/10.1016/j.phrs.2025.108043
  42. NPJ Aging. 2025 Nov 27. 11(1): 97
    Perturbation of multiprotein complexes in skeletal muscle induces protective proteases in the CNS that degrade pathogenic proteins.
    Mamta Rai, Helen J E Baddeley, Chia-Lung Chuang, Anna Platt, Michelle Curley, David Finkelstein, Fabio Demontis.
      Many cellular functions rely on multiprotein complexes and their stoichiometric assembly. Reducing the levels of individual complex components can perturb this process and induce corrective stress responses. In addition to local outcomes, cellular stress in one tissue can induce long-distance responses in other tissues. Here, we used muscle-targeted RNAi to examine the systemic stress responses induced by muscle-specific genetic perturbation of four distinct multiprotein complexes: the sarcomere, mitochondrial respiratory complex I, proteasome, and VCP (valosin-containing protein) complex. Muscle-specific disruption of these four complexes produced largely overlapping transcriptional adaptations in the central nervous system (CNS), and these responses were centered on the upregulation of many proteases and peptidases. Testing in a retinal model of Huntington's disease demonstrated that several stress-induced proteases limit the accumulation of huntingtin-polyQ aggregates during aging, indicating that these proteases protect from pathogenic proteins. We next examined whether the myokine Amyrel is a possible mediator of this stress-initiated muscle-to-CNS signaling because of its previously reported role in inducing protease expression. Consistent with this model, Amyrel expression was transcriptionally induced in muscle by perturbation of each of the four multiprotein complexes. Moreover, experimental upregulation of Amyrel in muscle reduced the amount of pathogenic huntingtin-polyQ aggregates in the retina. Taken together, these findings indicate that Amyrel and protective proteases improve CNS proteostasis following the perturbation of multiprotein complexes in skeletal muscle. Thus, this study provides insight into a muscle-to-CNS signaling axis that conveys information on the stress status of multiprotein complexes.
    DOI:  https://doi.org/10.1038/s41514-025-00288-z
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