bims-mihora 2025-11-23 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–11–23
24 papers selected by
Lisa Patel, Istesso

Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
Aging as the wound that fails to heal: a bioenergetic continuum of resolution failure.
Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
The Integrated Stress Response Pathway Improves Aged Murine Muscle Stem Cell Activation and in vivo Regeneration.
Multi-target synergistic anti-aging: QG extends Caenorhabditis elegans lifespan through DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming.
Mitochondrial homeostasis via Pink1 control alleviates nickel nanoparticle-induced reproductive damage in mouse spermatocyte GC-2 cells.
Developmental hepatotoxicity induced by flusilazole in zebrafish: Mechanistic insights into mitochondrial dysfunction, oxidative stress, ferroptosis, and regenerative impairment.
Targeting the Powerhouse: A Critical Review of Mitochondrial Inhibitors as a Therapeutic Strategy in Lung Cancer.
Active mitochondria in healthy spiny mouse fibroblasts resemble megamitochondria and remain resilient across lifespan.
RAF inhibitors activate the integrated stress response by direct activation of GCN2.
Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.
Cell phenotypic conversion and fate change during the host defense response, tissue injury and repair.
From The Integrated Stress Response to Oxidative Stress; A Historical Perspective.
PSMD4 Alleviates Aβ₁₋₄₂-Induced Mitochondrial Dysfunction and Oxidative Stress via the PGC-1α/Nrf Axis in Alzheimer's Disease Models.
Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer's disease.
Organ-specific rewiring of mitochondrial integrity through COX7A dictates cellular ploidy control.
Mfn2 Regulates Scleral Remodeling in Myopia by Maintaining Endoplasmic Reticulum Homeostasis in Scleral Fibroblasts.
How cells die determines the consequences of tissue repair: roles of programmed cell death in lung injury on the progression of pulmonary fibrosis.
Electron Microscopy and Multi-Omics Reveal Mitochondrial Dysfunction and Structural Remodeling in the Hearts of Elderly Mice.
Mitochondrial stress bridge: Could muscle-derived extracellular vesicles be the missing link between sarcopenia, insulin resistance, and chemotherapy-induced cardiotoxicity?
Sphingosine-1-phosphate activates ICl,swell in ventricular myocytes via mitochondrial reactive oxygen production.
Complex II inhibition suppresses RSL3-induced ferroptosis by restoring mitochondrial bioenergetics.
Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.

Int Rev Immunol. 2025 Nov 17. 1-30

Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.

Thao Hoang Nhu Le, Van Thi Tuong Nguyen.

  Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.

Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer

DOI:  https://doi.org/10.1080/08830185.2025.2577986
Biogerontology. 2025 Nov 20. 27(1): 7

Aging as the wound that fails to heal: a bioenergetic continuum of resolution failure.

Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang, Prayfan Tippairote.

  Aging may be conceptualized as a wound that fails to heal, characterized by persistent, unresolved inflammation. Building on Ogrodnik's "unhealed wound" model, this Perspective extends the Exposure-Related Malnutrition (ERM) framework to propose a bioenergetic interpretation of aging. ERM links chronic stress adaptation, nutrient misallocation, and mitochondrial insufficiency to sustained bioenergetic debt that impedes the transition from catabolic containment to anabolic repair. Across tissues, this energetic shortfall manifests as metabolic inflexibility, lipid-droplet accumulation, and a continuum of adaptive mitochondrial dysfunction that remains reversible until the threshold of senescence-the terminal stage of unresolved adaptation. Recognizing bioenergetic availability as the principal determinant of regenerative success reframes mitochondrial dysfunction and senescence not as primary causes of aging but as downstream consequences of chronic energetic exhaustion. Within this continuum, aging reflects a progressive loss of rhythmic catabolic-anabolic cycling that supports metabolic adaptation. Transient metabolic stress normally induces hormetic activation followed by anabolic recovery, but when this oscillation fails, adaptive hormesis gives way to maladaptive exhaustion. Aging thus emerges from the erosion of bioenergetic rhythm-a transition from recovery with renewal to endurance without repair.

Keywords:  Aging; Energy metabolism; Exposure-related malnutrition (ERM); Metabolic adaptation; Regeneration; Wound healing

DOI:  https://doi.org/10.1007/s10522-025-10356-2
J Transl Med. 2025 Nov 19. 23(1): 1321

Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.

Cristina Algieri, Salvatore Nesci, Francesca Oppedisano.

  Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.

Keywords:  Complex diseases; Immunity; Inflammation; Metabolism; Mitochondria

DOI:  https://doi.org/10.1186/s12967-025-07392-4
bioRxiv. 2025 Sep 29. pii: 2025.09.26.678822. [Epub ahead of print]

The Integrated Stress Response Pathway Improves Aged Murine Muscle Stem Cell Activation and in vivo Regeneration.

Alexander D Brown, Annarita Scaramozza, Hanzhi Zhang, Samiha Mahin, Nivedita Suresh, Takeshi Tsusaka, Susan Eliazer, Xuhui Liu, Brian Feeley, Andrew S Brack.

  For efficient regeneration, muscle stem cells (MuSCs) transition out of quiescence through a series of progressively more activated states. During MuSC aging, transition through the earliest steps is the slowest and delayed, with the molecular regulators that govern this transition not well characterized. By analyzing the dynamic changes of MuSCs at the molecular (scRNA-Seq and Cell Painting) and phenotypic (heteromotility) level at single cell resolution we found that the Integrated Stress Response (ISR) Pathway is a critical regulator of MuSC transition states. Aged MuSCs have increased baseline ISR activity in quiescence that does not increase during activation to levels observed in adult MuSCs. Rapid and transient pharmacological ISR activation in vitro was sufficient to increase aged MuSC activation rate and migratory behavior as well as alter the transcriptional states toward a younger phenotype. ISR activation also improved aged MuSC potency and aged mouse muscle regeneration in vivo. Therefore, pharmacological activation of the ISR has therapeutic potential to improve MuSC function and skeletal muscle repair during aging.

Keywords:  Aging; ISRIB; Sal003; activation dynamics; integrated stress response; muscle stem cells; state transitions

DOI:  https://doi.org/10.1101/2025.09.26.678822
Biogerontology. 2025 Nov 18. 27(1): 6

Multi-target synergistic anti-aging: QG extends Caenorhabditis elegans lifespan through DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming.

Jiahui Wang, Shuqi Li, Zichen Lei, Yantao Xing, Jieshu Li, Jie Guo, Boshi Duan, Yonggang Liu.

  Aging not only significantly reduces the quality of life for the elderly but also poses multifaceted challenges to society. Its progression involves the synergistic interaction of multidimensional, multipathway molecular mechanisms, including mitochondrial dysfunction, oxidative stress accumulation, chronic inflammation, and genomic damage. Quercetagetin (QG), as a natural flavanol monomer, exhibits significant potential in anti-aging due to its simultaneous targeting of key aging pathways such as oxidative stress and chronic inflammation. We first evaluated QG's safety profile, finding that 0.02 mg/ml QG did not adversely affect motility, feeding, growth, and reproductive capacity in Caenorhabditis elegans (C. elegans). At this concentration, in vivo experiments using wild-type C. elegans confirmed QG's ability to extend lifespan and enhance oxidative stress resistance. The antioxidant and anti-aging effects of QG were further validated using the daf-16 mutant C. elegans DR26. Subsequently, observation of QG's impact on C. elegans mitochondrial morphology revealed significant reductions in area/perimeter and mitochondria coverage ratio following treatment. This indicates that QG treatment shifts the mitochondrial network from fusion toward fission and reduces overall mitochondrial content. QG can also improve age-related dopaminergic, 5-hydroxytryptaminergic and cholinergic neuron degeneration. Mass spectrometry metabolome analysis revealed that QG significantly affected citrate cycle and glycerophospholipid metabolism. Collectively, QG extends C. elegans lifespan by regulating redox homeostasis, DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming. This multi-target regulatory capacity positions QG as an ideal candidate molecule for anti-aging drug development.

Keywords:   C. elegans ; Anti-aging; DAF-16/FOXO pathways; Metabolic reprogramming; Mitochondrial homeostasis; Quercetagetin

DOI:  https://doi.org/10.1007/s10522-025-10347-3
Environ Int. 2025 Nov 08. pii: S0160-4120(25)00661-0. [Epub ahead of print]206 109910

Mitochondrial homeostasis via Pink1 control alleviates nickel nanoparticle-induced reproductive damage in mouse spermatocyte GC-2 cells.

Lu Kong, Jiahui Dong, Yán Wāng.

  Nickel nanoparticles (Ni NPs), increasingly utilized in environmental energy, electronics, and biomedical fields, have raised growing concern due to their emerging reproductive toxicity. Our prior investigations revealed that Ni NPs trigger oxidative stress and apoptosis in male germ cells, contributing to compromised fertility in rodent models. Given the central role of mitochondria in cellular homeostasis, and mitophagy in maintaining mitochondrial integrity, we hypothesized that mitochondrial stress may mediate Ni NPs-induced spermatocyte injury. In the present study, we employed GC-2 mouse spermatocyte cells to elucidate the role of PINK1/Parkin-mediated mitophagy in Ni NPs-induced reproductive toxicity. Ni NPs exposure (25-100 μg/mL) led to significant reductions in cell viability and mitochondrial membrane potential (MMP), along with increases in apoptosis, reactive oxygen species (ROS) accumulation, and ATP depletion. Western blot analyses demonstrated elevated expression of mitophagy- and apoptosis-related proteins including PINK1, Parkin, LC3BII, P62, BAX, Caspase9, and Caspase3, with concurrent downregulation of LC3BI and the anti-apoptotic protein BCL2. Pharmacological inhibition of mitophagy using cyclosporin A (CsA, 3 μM) partially restored mitochondrial function, suppressed apoptosis, and ameliorated overall cytotoxicity. Moreover, lentivirus-mediated knockdown of Pink1 further reversed Ni NPs-induced cellular damage by reducing ROS levels, recovering ATP production and MMP, and downregulating mitophagy and apoptosis-related markers. These findings identify aberrant mitophagy as a critical driver of Ni NPs-induced reproductive toxicity and highlight PINK1 as a potential molecular target for therapeutic intervention. This study offers novel mechanistic insights into Ni NPs-induced male reproductive damage, with implications for occupational health and nanoparticle safety assessment.

Keywords:  Cyclosporin A; Germ cell; Metal nanoparticle; Mitochondrial dysfunction; PINK1/Parkin; Reproductive toxicology

DOI:  https://doi.org/10.1016/j.envint.2025.109910
Comp Biochem Physiol C Toxicol Pharmacol. 2025 Nov 18. pii: S1532-0456(25)00274-1. [Epub ahead of print] 110393

Developmental hepatotoxicity induced by flusilazole in zebrafish: Mechanistic insights into mitochondrial dysfunction, oxidative stress, ferroptosis, and regenerative impairment.

Hojun Lee, Jisoo Song, Garam An, Seung-Min Bae, Gwonhwa Song, Whasun Lim, Sunwoo Park.

  Flusilazole is a triazole-based fungicide that persists in various environments because of its high stability and solubility, raising concerns about its developmental and ecological impacts. Although numerous studies have reported flusilazole-induced toxicity, the specific effects and mechanisms of flusilazole-induced hepatotoxicity during development remain unclear. In this study, we examined the in vivo and in vitro toxicities in Danio rerio (zebrafish) and zebrafish-derived liver (ZFL) cells. Morphological changes in the liver and alterations in liver regeneration were evaluated using fabp10a:dsRed and fabp10a:CFP-NTR transgenic models. Flusilazole exposure was shown to deteriorate hepatic structure and regenerative capacity, with potential long-term consequences for aquatic organisms. Moreover, in ZFL cells, flusilazole treatment induced oxidative stress, mitochondrial malfunction, and disruption of calcium and iron homeostasis, leading to the induction of apoptosis and ferroptosis. Transcriptomic analysis supported these findings. Additionally, disturbances in ERK and Akt signaling indicated interference with pathways central to cell survival, growth, and tissue repair. Together, these findings establish that flusilazole exerts developmental hepatotoxic effects and highlight its potential hazards to ecosystems.

Keywords:  Ferroptosis; Flusilazole; Hepatotoxicity; Liver regeneration; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.cbpc.2025.110393
Eur J Pharmacol. 2025 Nov 18. pii: S0014-2999(25)01136-7. [Epub ahead of print] 178382

Targeting the Powerhouse: A Critical Review of Mitochondrial Inhibitors as a Therapeutic Strategy in Lung Cancer.

Woo Hyun Park.

  Lung cancer therapy is constrained by profound intrinsic and acquired resistance to targeted therapies and immunotherapy. To overcome this, a new therapeutic paradigm is emerging that targets the unique metabolic and survival dependencies of cancer cells. Mitochondria, the central hubs of metabolism, cell death, and signaling, represent a critical vulnerability. This review provides a new conceptual framework for understanding and targeting mitochondrial pathways in lung cancer. First, this review outlines the key "mitochondrial hallmarks" of lung cancer that create therapeutic windows, emphasizing the critical role of metabolic heterogeneity. Second, it provides a novel, mechanism-based classification of mitochondrial inhibitors into four major classes: (1) electron transport chain (ETC) inhibitors, (2) metabolic enzyme modulators, (3) apoptosis pathway modulators, and (4) mitochondrial quality control (MQC) disruptors. Third, this review critically analyzes the molecular mechanisms by which these inhibitors activate regulated cell death pathways (apoptosis, ferroptosis) and, most importantly, their potential in overcoming therapeutic resistance to standard-of-care. Fourth, it explores the mechanisms of mitochondrial crosstalk within the tumor microenvironment (TME), including intercellular transfer via tunneling nanotubes. Finally, this review presents a systematic review of the clinical landscape, synthesizing data from preclinical models and ongoing clinical trials. This review concludes by highlighting key limitations and future perspectives, positioning MQC and the mitochondrial unfolded protein response (UPRmt) as next-generation targets to improve patient outcomes.

Keywords:  Ferroptosis; Lung Cancer; Mitochondria; Mitochondrial Inhibitors; Mitochondrial Quality Control (MQC); Therapeutic Resistance

DOI:  https://doi.org/10.1016/j.ejphar.2025.178382
bioRxiv. 2025 Oct 04. pii: 2025.10.02.680123. [Epub ahead of print]

Active mitochondria in healthy spiny mouse fibroblasts resemble megamitochondria and remain resilient across lifespan.

Ebenezer Aryee, Ajoy Aloysius, Sandeep Saxena, Hemendra Vekaria, Patrick G Sullivan, Ashley W Seifert.

Although they exhibit limited regenerative ability of some tissues and organs shortly after birth or towards the end of fetal development, humans and laboratory mammals quickly transition to producing scar tissue for tissue repair. In contrast, spiny mice exhibit complex tissue regeneration as adults and provide a blueprint for how regeneration can occur throughout adulthood in mammals. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit extreme resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from highly regenerative and non-regenerative mammals, we find that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting a lower ROS-producing basal state. Uniquely, spiny mouse fibroblasts exhibit large, spherical, depolarized mitochondria similar to megamitochondria identified in pathological tissues. The megamitochondria phenotype was present across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype which ultimately helps supports tissue regeneration.

DOI: https://doi.org/10.1101/2025.10.02.680123
Nat Commun. 2025 Nov 17. 16(1): 10033

RAF inhibitors activate the integrated stress response by direct activation of GCN2.

Rebecca Gilley, Andrew M Kidger, Graham Neill, Eve Morrison, Paul Severson, Dominic P Byrne, Niall S Kenneth, Gideon Bollag, Chao Zhang, Taiana Maia de Oliveira, Patrick A Eyers, Richard Bayliss, Glenn R Masson, Simon J Cook.

Paradoxical activation of wild type RAF by chemical RAF inhibitors (RAFi) is a well-understood 'on-target' biological and clinical response. In this study, we show that a range of RAFi drive ERK1/2-independent activation of the Unfolded Protein Response (UPR), including expression of ATF4 and CHOP, that requires the translation initiation factor eIF2α. RAFi-induced ATF4 and CHOP expression was not reversed by inhibition of PERK, a known upstream activator of the eIF2α-dependent Integrated Stress Response (ISR). Rather, RAFi exposure activated GCN2, an alternate eIF2α kinase, leading to eIF2α-dependent (and ERK1/2-independent) ATF4 and CHOP expression. The GCN2 kinase inhibitor A-92, GCN2 RNAi, GCN2 knock-out or ISRIB (an eIF2α antagonist) all reversed RAFi-induced expression of ATF4 and CHOP indicating that RAFi require GCN2 to activate the ISR. RAFi also activated full-length recombinant GCN2 in vitro and in cells, generating a characteristic 'bell-shaped' concentration-response curve, reminiscent of RAFi-driven paradoxical activation of WT RAF dimers. Activation of the ISR by RAFi was abolished by a GCN2 kinase dead mutation. A M802A GCN2 gatekeeper mutant was activated at lower RAFi concentrations, demonstrating that RAFi bind directly to the GCN2 kinase domain; this is supported by mechanistic structural models of RAFi interaction with GCN2. Since the ISR is a critical pathway for determining cell survival or death, our observations may be relevant to the clinical use of RAFi, where paradoxical GCN2 activation is a previously unappreciated off-target effect that may modulate tumour cell responses.

DOI: https://doi.org/10.1038/s41467-025-65376-w
Cell Regen. 2025 Nov 16. 14(1): 45

Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.

Wenxin Li, Guo Shao, Ruifang Qi.

  Hypoxia-ischemia plays a role in the physiological and pathological processes of various diseases and presents a common challenge for humans under extreme environmental conditions. Neurons are particularly sensitive to hypoxia-ischemia, and prolonged exposure may lead to irreversible brain damage. The primary mechanisms underlying this damage include energy depletion, mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Mitochondria serve as primary organelles for adenosine triphosphate (ATP) production, and mitochondrial dysfunction plays a crucial role in mediating hypoxic pathophysiological processes. Hypoxic-ischemic preconditioning (H/IPC) is an endogenous cellular protective mechanism that reduces the damage caused by lethal hypoxic stressors. In this review, we summarize the potential role of H/IPC and its protective effects on mitochondrial quality control and function. This perspective offers a new approach for treating diseases caused by hypoxia-ischemia.

Keywords:  Hypoxia; Hypoxic/ischemic preconditioning; Ischemia; Mitochondrial; Neuroprotection

DOI:  https://doi.org/10.1186/s13619-025-00268-4
Pharmacol Ther. 2025 Nov 18. pii: S0163-7258(25)00171-8. [Epub ahead of print]277 108959

Cell phenotypic conversion and fate change during the host defense response, tissue injury and repair.

Xin Shi, Gabriel Mekis, Kevin J Simms, Bin Gao, Ping Zhang.

  In the process of host response to insults of serious injury/intense stressor, many types of somatic cells can undergo phenotypic conversion and fate change. The typical feature of cell conversion in this circumstance is to acquire the status of upstream precursors, which commonly accompanies transcriptional alteration to enhance cell proliferation and increase the plasticity of differentiation toward the lineage(s) needed in urgency for defending host against injury as well as maintaining/restoring the integrity of organ tissue function. The extent of cell conversion varies dependent on cell types and insult properties. Pattern ligands derived from pathogens and damaged tissues as well as the dynamic changes in systemic neurohumoral environment and local niche cue mediate cell conversion. Distinctive signaling interplays are involved in regulating various types of cell conversion. Better understanding the phenomena of cell conversion and their underlying regulatory mechanisms is critical for advancing regenerative medicine and developing novel therapeutic strategies to promote host defense as well as optimal repair of organ tissue injury. This article reviews recent progress in investigation on cell conversion and state change in different organ tissue environments with focus on bone marrow, vascular endothelium, lung, liver, and intestine. Discussion on delineating the signaling mechanisms is extended. Efforts in exploring the correlated therapeutic approaches are addressed to highlight the substantial potential in clinical application for this field of regenerative medicine.

Keywords:  Cell signaling; Direct reprogramming; Fate change; Host defense response; Phenotypic conversion; Stem/progenitor; Tissue injury repair

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108959
J Biol Chem. 2025 Nov 19. pii: S0021-9258(25)02810-8. [Epub ahead of print] 110958

From The Integrated Stress Response to Oxidative Stress; A Historical Perspective.

Mehdi Amiri, Phoenix Toboz, Michael A Bellucci, Soroush Tahmasebi, Nahum Sonenberg.

  Oxidative stress has exerted fundamental evolutionary pressure since the emergence of aerobic life. Its impact on the physiology and function of all organisms is profound and consequential for cell survival. The integrated stress response (ISR) plays a critical role in counteracting oxidative stress via translational control of a subset of mRNAs. Here, we summarize the fundamental discoveries that shaped our understanding of the ISR pathway's role in cellular adaptation to oxidative stress from studies of protein synthesis in reticulocyte lysates to the regulation of glutathione metabolism downstream of the ISR pathway. We describe recent advances in studying mRNA translation changes in response to oxidative stress based on high throughput translatome analyses.

Keywords:  Glutathione; ISR; Oxidative Stress; eIF2; mRNA Translation

DOI:  https://doi.org/10.1016/j.jbc.2025.110958
Mol Neurobiol. 2025 Nov 21. 63(1): 117

PSMD4 Alleviates Aβ₁₋₄₂-Induced Mitochondrial Dysfunction and Oxidative Stress via the PGC-1α/Nrf Axis in Alzheimer's Disease Models.

Min Yuan, Xiao-Jian Han, Chao-Qun Luo, Hai-Li Pan, Huang-Yan Zhou.

  This study aimed to investigate the role of 26S proteasome non-ATPase regulatory subunit 4 (PSMD4) in regulating mitochondrial function and oxidative stress in Alzheimer's disease (AD) and to explore its potential molecular mechanism in Aβ-induced neurotoxicity. An in vitro AD model was established by treating Neuro-2a cells with Aβ₁₋₄₂, and PSMD4 was overexpressed using a lentiviral vector. Flow cytometry was employed to assess reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm). Quantitative PCR and Western blotting were utilized to examine the expression of mitochondrial biogenesis-associated regulators, including PGC-1α, Nrf1, Nrf2, and TFAM. For the in vivo study, APP/PS1 double-transgenic mice served as the AD model. Histological analyses (HE and Nissl staining), immunofluorescence, and Western blotting were performed to evaluate hippocampal neuronal morphology and the expression of PSMD4 and mitochondrial marker TOM20. Aβ₁₋₄₂ significantly increased ROS levels, reduced ΔΨm, and downregulated the expression of PGC-1α, Nrf1, Nrf2, and TFAM in Neuro-2a cells. PSMD4 overexpression attenuated these changes, suggesting a protective role against mitochondrial dysfunction and oxidative stress. In APP/PS1 mice, hippocampal neurons showed morphological damage with reduced Nissl substance and decreased PSMD4 and TOM20 expression. Immunofluorescence revealed cytoplasmic PSMD4 localization and enhanced co-localization with MAP2, TOM20, and Aβ₁₋₄₂ in transgenic mice. PSMD4 is downregulated in AD models, and its overexpression ameliorates Aβ-induced oxidative stress and mitochondrial impairment, potentially by promoting mitochondrial biogenesis. These findings suggest that PSMD4 may serve as a novel therapeutic target for AD intervention.

Keywords:  Alzheimer’s disease; Aβ₁₋₄₂; Mitochondrial dysfunction; Oxidative stress; PGC-1α; PSMD4

DOI:  https://doi.org/10.1007/s12035-025-05445-9
Brain Res. 2025 Nov 18. pii: S0006-8993(25)00603-1. [Epub ahead of print] 150040

Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer's disease.

Maryam Sardari, Oveis Hosseinzadeh Sahafi, Ameneh Rezayof.

  Alzheimer's disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.

Keywords:  Alzheimer’s disease; Glial cells; Mitochondrial dynamics; Neuroinflammation

DOI:  https://doi.org/10.1016/j.brainres.2025.150040
bioRxiv. 2025 Sep 30. pii: 2025.09.29.678879. [Epub ahead of print]

Organ-specific rewiring of mitochondrial integrity through COX7A dictates cellular ploidy control.

Archan Chakraborty, Sophia DeLuca, Meera Gangasani, Stephen Rogers, Nenad Bursac, Donald T Fox.

To achieve proper cell and tissue size, cytoplasmic and nuclear growth must be coordinated. Disrupting this coordination causes birth defects and disease. In nature's largest cells, nuclear growth occurs through polyploidization (whole-genome-duplication). How the massive nuclear growth of polyploid cells is coordinated with cytoplasmic growth processes such as mitochondrial biogenesis is relatively unclear. Here, focusing on one of nature's most commonly polyploid organs-the heart-we uncover cross-talk between cytoplasmic mitochondrial biogenesis/integrity and nuclear growth/polyploidy. From a human-to-fly screen, we uncover novel regulators of cardiomyocyte ploidy, including mitochondrial integrity regulators. In comparing these cardiac hits with a parallel screen in another polyploid tissue, the salivary gland, we discovered two opposing roles for Cytochrome-c-oxidase-subunit-7A (COX7A). While salivary gland COX7A preserves mitochondrial integrity to promote polyploidy and optimal organ growth, cardiac COX7A instead suppresses mitochondrial biogenesis to repress polyploidy and prevent hypertrophic organ growth. Among all electron transport chain genes, only COX7A functions as a cardiac growth repressor. Fly hearts with compromised COX7A show abnormally high cardiac output. Human COX7A1, a mitochondrial-localized protein, similarly represses polyploidy of human iPSC-derived cardiomyocytes. In summary, our human-fly-human approach reveals conserved rewiring of mitochondrial integrity in heart tissue that switches COX7A's role from ploidy promotion to repression. Our findings reveal fundamental cross-talk between mitochondrial biogenesis and genome duplication that are critical in growing metazoan tissues.

DOI: https://doi.org/10.1101/2025.09.29.678879
Invest Ophthalmol Vis Sci. 2025 Nov 03. 66(14): 40

Mfn2 Regulates Scleral Remodeling in Myopia by Maintaining Endoplasmic Reticulum Homeostasis in Scleral Fibroblasts.

Yiyan Wang, Shuting Liu, Qiong Huang, Yang Cheng.

Purpose: Endoplasmic reticulum (ER) stress participates in the development of various disorders by regulating tissue remodeling and apoptosis. This study aimed to explore the regulatory role of mitofusin 2 (Mfn2)-mediated ER stability in scleral remodeling in myopia.
Methods: Myopia was induced in rats by form deprivation and hyperopic defocus. Scleral remodeling, ER stress, oxidative stress, and Mfn2 protein expression were examined in vivo. ER and mitochondrial ultrastructure were assessed by electron microscopy, and tissue apoptosis was evaluated. Primary rat scleral fibroblasts (SFs) were exposed to hypoxia to establish an in vitro myopia model, and Mfn2 expression in SFs was interfered by cell transfection. The extent of SFs transdifferentiation, extracellular-matrix remodeling, ER stress, mitochondrial damage, and cell apoptosis were assessed.
Results: In this study, we discovered that tissue remodeling was accompanied by ER stress and oxidative stress in the sclera of myopic rats. Concomitantly, Mfn2 expression levels were significantly decreased, and the structures of the ER and mitochondria were damaged, along with tissue apoptosis. In vitro study showed that both hypoxia induction and MFN2 knockdown significantly increased hypoxia-inducible factor-1α expression in SFs. Mfn2 overexpression inhibited the transdifferentiation of hypoxia-induced SFs into myofibroblasts and upregulated the expression of collagen Iα1. Additionally, Mfn2 overexpression alleviated ER stress and mitochondrial damage in hypoxia-induced SFs, and reduced apoptosis of SFs.
Conclusions: Our study revealed a critical role of Mfn2 in maintaining ER homeostasis in SFs, which conferred protective effects during scleral remodeling and provided a new therapeutic target for myopia.

DOI: https://doi.org/10.1167/iovs.66.14.40
Mol Cell Biochem. 2025 Nov 18.

How cells die determines the consequences of tissue repair: roles of programmed cell death in lung injury on the progression of pulmonary fibrosis.

Linying Zhou, Xi Zhu, Ershi Hua, Liqin Xu, Jian Feng.

  Pulmonary fibrosis (PF) is a pathological change in the development of end-stage lung disease, referring to an irreversible lesion in which lung tissue undergoes an abnormal repair response during injury repair, resulting in the replacement of normal alveolar structure by fibrous scarring. The main mechanisms of pulmonary fibrosis progression are activation of epithelial cell and macrophage repair after oxidative stress, fibroblast proliferation leading to extracellular matrix deposition in the lung, and a repair process involving multiple modes of death and molecular mechanisms that cross-talk in macrophages and alveolar epithelial cells, accelerating extracellular matrix deposition. Cell death is controlled by programmed cell death (PCD), which mainly includes apoptosis, necrotic apoptosis, pyroptosis, ferroptosis and autophagy. There is increasing evidence that PCD plays an important role in the pathogenesis of pulmonary fibrosis progression. In this review, we discuss recent advances in the role of PCD in lung injury-accelerated fibrosis, show how the mode of death of alveolar epithelial cells, macrophages, and fibroblasts promotes or inhibits the progression of lung injury, and explore associations between different types of PCD, with the aim of exploring the molecular mechanisms underlying the progression of recurrent lung injury and searching for new therapeutic targets.

Keywords:  Lung injury; Programmed cell death; Pulmonary fibrosis

DOI:  https://doi.org/10.1007/s11010-025-05431-8
Aging Cell. 2025 Nov 18. e70286

Electron Microscopy and Multi-Omics Reveal Mitochondrial Dysfunction and Structural Remodeling in the Hearts of Elderly Mice.

Manuela Giovanna Basilicata, Marco Malavolta, Serena Marcozzi, Eduardo Sommella, Lucia Scisciola, Fabrizio Merciai, Gianluca Fulgenzi, Valentina Golino, Giovanni Tortorella, Tatiana Spadoni, Laura Graciotti, Tania Ciaglia, Leonardo Schirone, Valentina Valenti, Sebastiano Sciarretta, Ceereena Ubaida-Mohien, Carmine Pizzi, Rafael De Cabo, Pietro Campiglia, Lucia Altucci, Michelangela Barbieri, Fabiola Olivieri, Luigi Ferrucci, Giuseppe Paolisso.

  Aging is a key driver of cardiac dysfunction, promoting structural remodeling, metabolic alterations, and loss of cellular resilience. In aged hearts, extracellular matrix remodeling and collagen accumulation reduce ventricular compliance, impairing both diastolic function and stress adaptability. Cardiomyocytes exhibit diminished regenerative capacity and dysregulated stress responses, with mitochondrial dysfunction emerging as a central contributor to energy imbalance, oxidative stress, and fibrosis. Traditional single-omics approaches are insufficient to capture the complexity of these interconnected changes. To address this, we employed an integrative multi-omics strategy-combining spatial transcriptomics, proteomics, and metabo-lipidomics with electron microscopy-to investigate cardiac aging in mice at three life stages: adult (12 months), middle-aged (24 months), and elderly (30 months). Electron microscopy revealed enlarged, structurally compromised mitochondria. Spatial transcriptomics showed reduced expression of cardioprotective genes (MANF, CISH, and BNP) and increased expression of profibrotic markers like CTGF. Proteomics revealed widespread mitochondrial dysregulation and impaired ATP production. Metabolic and lipidomic profiling identified reduced antioxidant metabolites and accumulation of lipotoxic species, such as ceramides and diacylglycerols. This multiscale analysis highlights key molecular and metabolic alterations driving cardiac aging, identifying potential therapeutic targets to mitigate age-related functional decline. Overall, our findings highlight the value of integrated, system-level approaches for uncovering the complex mechanisms that drive organ aging. Although our study was conducted in mice, validation in human models will be crucial to establish the translational relevance of these results and to guide future research with potential impact across diverse biomedical fields.

Keywords:  aging; cardiac dysfunction; heart; mitochondria; multi‐omics approach

DOI:  https://doi.org/10.1111/acel.70286
Biomed Pharmacother. 2025 Nov 19. pii: S0753-3322(25)01008-X. [Epub ahead of print]193 118814

Mitochondrial stress bridge: Could muscle-derived extracellular vesicles be the missing link between sarcopenia, insulin resistance, and chemotherapy-induced cardiotoxicity?

Okechukwu Paul-Chima Ugwu, Fabian C Ogenyi, Chinyere Nneoma Ugwu, Mariam Basajja, Michael Ben Okon.

  Sarcopenia is currently considered a systemic condition that goes beyond muscle atrophy to include multifunctional metabolic and cardiovascular dysfunction. The mediators between skeletal muscle loss and entire body insulin resistance and increased vulnerability to cardiotoxicity caused by chemotherapy are not clear. We hypothesise that mitochondrial-enriched, muscle-secreted extracellular vesicles (EVs) of mtDNA/mitoproteins, stress-regulated microRNAs (miR-1/133/206; miR-29 family), and ROS-modified damage-associated molecular patterns (DAMPs) are a mitochondrial stress bridge that secretes danger signals from sarcopenic muscle to the liver/adipose and heart. EV cargo mechanistically impairs insulin signaling (IRS-1 → PI3K-AKT → GLUT4) and cardiomyocyte pre-injury (loss of Δpsm, antioxidant repression, apoptosis), increasing the toxicity of doxorubicin. Should this framework be valid, it describes the clustering of sarcopenic patients with metabolic dysfunction and disproportional cardiotoxic incidents throughout cancer therapy and places circulating EV cargo as an indicator of outcomes and therapeutic interventions.

Keywords:  Cardiotoxicity; Chemotherapy; Extracellular vesicles; Insulin resistance; Mitochondrial stress; Sarcopenia

DOI:  https://doi.org/10.1016/j.biopha.2025.118814
J Mol Cell Cardiol. 2025 Nov 19. pii: S0022-2828(25)00214-7. [Epub ahead of print]211 18-27

Sphingosine-1-phosphate activates ICl,swell in ventricular myocytes via mitochondrial reactive oxygen production.

Frank J Raucci, Adolfo G Mauro, Edward J Lesnefsky, Clive M Baumgarten.

   AIMS: We previously demonstrated that bacterial sphingomyelinase (SMase), which converts plasmalemmal sphingomyelin to long-chain ceramides, activates the swelling-activated chloride current (ICl,swell) in rabbit ventricular myocytes in a reactive oxygen (ROS)-dependent manner under isosmotic conditions. Ceramides can be converted to sphingosine by ceramidase and, in turn, phosphorylated by sphingosine kinase to yield sphingosine-1-phosphate (S1P), which binds to multiple cytoplasmic targets and activates S1P receptors via inside-out transport. This study was designed to determine the cellular source of ROS production elicited by SMase, the sphingolipid species responsible, and thereby, the mechanism of activation of ICl,swell by sphingolipids.
METHODS AND RESULTS: Whole-cell patch clamp experiments were conducted using freshly isolated rabbit ventricular myocytes. Inhibition of ceramidase with D-erythro-MAPP, which increases the concentration of endogenous ceramides in the cell membrane, prevented activation of ICl,swell upon exposure to SMase. Similarly, inhibition of sphingosine kinase with DL-threo-dihydrosphingosine to prevent SIP formation by phosphorylation of sphingosine also completely inhibited SMase-induced Cl- current. In contrast, addition of S1P to the bath solution elicited ICl,swell. ROS generated by both NADPH oxidase 2 (NOX2) and mitochondria previously were implicated in triggering ICl,swell. SMase-induced ICl,swell activation was abrogated by blocking mitochondrial electron transport at Complex I with rotenone but was insensitive to blockade of NOX2 with either apocynin or gp91ds-tat. Moreover, diazoxide, which augments mitochondrial ROS production, evoked ICl,swell, and 5-HD, an inhibitor of this pathway, reversed the SMase and diazoxide-induced currents. Flow cytometry using C-H2DCFDA-AM to assess cytoplasmic ROS in HL-1 myocytes confirmed the effects of the interventions on ROS production.
CONCLUSIONS: Taken together, these data suggest S1P is the sphingolipid that triggers ICl,swell in cardiomyocyte, and activation of ICl,swell by SMase and S1P is due to ROS produced by mitochondria and appears independent of NOX2.
TRANSLATIONAL PERSPECTIVE: ICl,swell modulates apoptosis, cell volume, action potential duration, and participation in mechanoelectrical feedback in cardiomyocytes. Persistent activation of ICl,swell is seen in several forms of cardiac disease, including dilated cardiomyopathy [1] and models of heart failure [2]. Additionally, it has been implicated in metabolic syndrome and subsequent development of type 2 diabetes (DM2) [3]. This implies a complex relationship, in which there may be both direct effects on damaged cardiomyocytes and indirect effects on the cardiovascular system in general leading to chronic cellular stress such as that seen in DM2. This report demonstrates, for the first time, that S1P augments ICl,swell activation in cardiomyocytes via disruption of the mitochondrial respiratory chain resulting in ROS release. This presents potential therapeutic targets for the treatment of cardiovascular diseases, such as dilated cardiomyopathy or metabolic syndrome, characterized by alterations in sphingolipid metabolism.

Keywords:  Cardiomyocytes; Mitochondria; Reactive oxygen species; Sphingosine-1-phosphate; Volume-sensitive chloride current

DOI:  https://doi.org/10.1016/j.yjmcc.2025.11.009
Biochem Biophys Res Commun. 2025 Nov 14. pii: S0006-291X(25)01686-9. [Epub ahead of print]792 152970

Complex II inhibition suppresses RSL3-induced ferroptosis by restoring mitochondrial bioenergetics.

Sun Chul Lee, Soo Kyung Lee, Hyun Kim, Kyu-Sang Park.

  The mitochondrial electron transport chain (ETC) serves as the main site of cellular energy production and a major source of reactive oxygen species (ROS) generation, which can contribute to the lipid peroxidation associated with ferroptosis. However, the critical roles of mitochondria in ferroptosis are still being debated, and the consequences for cell survival vary depending on different ferroptosis inducers or mitochondrial modulators. In the neuroblastoma clonal cells SH-SY5Y, we demonstrated that inhibition of mitochondrial Complex II by 2-thenoyltrifluoroacetone (TTFA) markedly suppressed RSL3-induced ferroptotic lipid peroxidation and cell death. RSL3, a known inhibitor of glutathione peroxidase 4 (GPX4), significantly increased the mitochondrial membrane potential and superoxide production while reducing ATP-linked oxygen consumption. Co-treatment with TTFA effectively attenuated RSL3-induced mitochondrial hyperpolarization, lowered mitochondrial ROS generation, and restored respiratory activities - particularly enhanced ATP-linked oxygen consumption and reduced proton leak. Consistently, TTFA restored ATP production suppressed by RSL3. In contrast, inhibition of Complex I by rotenone did not suppress superoxide production and lipid peroxidation induced by RSL3, although it provided some protection against RSL3-mediated cytotoxicity. These findings suggest that inhibition of Complex II confers protection against ferroptosis by maintaining mitochondrial redox balance and protecting mitochondrial energy metabolism. In addition, our results uncover a novel mitochondrial mechanism underlying RSL3-induced oxidative stress and ferroptosis that can be modulated through targeted regulation of the ETC.

Keywords:  2-thenoyltrifluoroacetone; ATP-linked respiration; Ferroptosis; Mitochondrial electron transport chain; Mitochondrial superoxide; RSL3

DOI:  https://doi.org/10.1016/j.bbrc.2025.152970
Exp Physiol. 2025 Nov 19.

Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.

Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle plays an important role in whole-body health, quality of life and regulation of metabolism. The maintenance of a healthy mitochondrial pool is imperative for the preservation of skeletal muscle quality and is mediated through mitochondrial quality control consisting of mitochondrial turnover mediated by a balance between organelle synthesis and degradation. The selective tagging and removal of dysfunctional mitochondria is essential for maintaining mitochondrial quality control and is termed mitophagy. The mechanisms of the initial stages of mitophagy involving the recognition and tagging of mitochondria within skeletal muscle are well established, but our understanding of the terminal step involving organelle degradation mediated via lysosomes is in its infancy. An assessment of the proteolytic functions to facilitate the removal and breakdown of dysfunctional mitochondria is crucial for our understanding of the mechanisms of mitophagy, which is essential for maintaining skeletal muscle health. The aim of this review is to address the current knowledge surrounding mitophagy and lysosomal function, alongside distinct physiological conditions, such as ageing, exercise and disuse, that have varying effects on mitophagy and lysosomal adaptations within skeletal muscle.

Keywords:  Parkin; adaptation; lysosomes; mitophagy; skeletal muscle; transcription factor EB

DOI:  https://doi.org/10.1113/EP093041
Stem Cell Reports. 2025 Nov 20. pii: S2213-6711(25)00324-8. [Epub ahead of print] 102720

Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.

Eunkyu Sung, Shohei Murakami, Masanobu Morita, Tomoaki Ida, Takaaki Akaike, Hozumi Motohashi.

  Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment of hematopoietic progenitors, we utilized Cars2-mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, while the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to the MEP lineage selection, acting as a "mitochondrial navigation" for lineage commitment.

Keywords:  CARS2; MEP; differentiation; erythropoesis; megakaryocyte; megakaryocyte-erythroid progenitor; mitochondria; mouse; persulfide; sulfur metabolism

DOI:  https://doi.org/10.1016/j.stemcr.2025.102720