bims-mihora 2026-01-11 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–01–11
24 papers selected by
Lisa Patel, Istesso

Integrated Stress Response (ISR) Modulators in Vascular Diseases.
AUF1 Restrains Hepatocyte Senescence by Maintaining Mitochondrial Homeostasis in AML12 Hepatocyte Model.
Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.
Mitochondria-targeted co-assembled nanosystem with multimodal mitochondrial DNA level control to alleviate inflammation and promote chronic wound healing.
Mitochondrial presequences harbor variable strengths to maintain organellar function.
Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.
Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.
Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.
The many faces of p97/Cdc48 in mitochondrial homeostasis.
Islet regeneration protein Reg3g promotes macrophage clearance of β cell-derived dysfunctional mitochondria-rich vesicles to mitigate T2DM.
Mitophagy in the pathogenesis and management of disease.
Multi-omics analysis identifies mitochondrial dysfunction in CD83+ macrophages as a key event in diabetic peripheral neuropathy progression.
Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
Adaptive inter-tissue proteostasis networks in aging and neurodegeneration.
Mitochondrial dynamics and signaling in stem cell differentiation.
Inhibiting SHP2 improves ventricular remodeling by restoring AMPK phosphorylation and mitochondrial homeostasis.
Black phosphorus in theragenerative medicine: a multi-organ perspective on disease modulation and tissue repair.
SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response.
Photobiomodulation Activates Coordinated Signaling Networks to Modulate Inflammation, Adaptive Stress, and Tissue Healing via Redox-Mediated NFκB-TGF-β1-ATF-4 Axis.
Uncovering the role of integrated stress in Alzheimer's disease through single-cell and transcriptomic analysis.
Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response.
Mitochondrial integrity modulates mTOR signaling and podocyte function.
Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.

Cells. 2025 Dec 19. pii: 2. [Epub ahead of print]15(1):

Integrated Stress Response (ISR) Modulators in Vascular Diseases.

Alexander Kalinin, Ekaterina Zubkova, Irina Beloglazova, Yelena Parfyonova, Mikhail Menshikov.

  Vascular dysfunction lies at the core of cardiovascular diseases-the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The integrated stress response (ISR), an evolutionarily conserved signaling network activated by diverse stressors, represents a critical but underexplored mechanism in vascular biology. This review examines the dual roles of the core ISR kinases-PERK, GCN2, HRI and PKR-in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We develop a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators-including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157-which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention.

Keywords:  GCN2; PERK; PKR; cardiovascular diseases; integrated stress response; pulmonary arterial hypertension; pulmonary capillary hemangiomatosis; pulmonary veno-occlusive disease; restenosis; thrombosis

DOI:  https://doi.org/10.3390/cells15010002
Cells. 2025 Dec 26. pii: 48. [Epub ahead of print]15(1):

AUF1 Restrains Hepatocyte Senescence by Maintaining Mitochondrial Homeostasis in AML12 Hepatocyte Model.

Myeongwoo Jung, Sukyoung Han, Seungyeon Ryu, Seongho Cha, Ye Eun Sim, Se Hoon Jung, Hyosun Tak, Wook Kim, Eun Kyung Lee.

  Cellular senescence, a hallmark of aging, involves irreversible growth arrest and an enhanced senescence-associated secretory phenotype (SASP). It is often accompanied by mitochondrial dysfunction and altered inter-organelle communication. Using a chronic oxidative stress model in AML12 hepatocytes, we confirmed senescence by canonical assays (e.g., SA β-gal positivity and proliferation arrest) and observed a decline in the RNA-binding protein AUF1 (hnRNP D). AUF1 knockdown further amplified senescent phenotypes, including elongation of mitochondrial network, loss of mitochondrial membrane potential, reduced ATP level, and elevated mitochondrial reactive oxygen species (ROS). In addition, AUF1 knockdown weakened mitochondria-endoplasmic reticulum coupling and reduced mitochondrial Ca2+ load. At the molecular level, AUF1 binds to the 3' untranslated regions (3'UTRs) of Opa1 and Mfn2 and limits their abundance, thereby coupling post-transcriptional control to mitochondrial dynamics. In gain-of-function experiments, ectopic expression of AUF1 attenuated Opa1/Mfn2 induction, restored mitochondrial network architecture, and preserved bioenergetic function under pro-senescent stimuli. Collectively, these findings support a model in which AUF1 preserves mitochondrial homeostasis and thereby restrains the mitochondria-senescence axis in hepatocytes.

Keywords:  AUF1; fusion; mitochondria; reactive oxygen species; senescence

DOI:  https://doi.org/10.3390/cells15010048
Biogerontology. 2026 Jan 06. 27(1): 33

Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.

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

  Chronic stress has been linked to mitochondrial dysfunction and impaired telomere maintenance, yet the mechanistic relationships connecting these pathways in humans remain poorly resolved. Using longitudinal findings from the Guillén-Parra cohort as a motivating human example, this Perspective offers a reinterpreted framework that proposes a unifying energetic interpretation in which bioenergetic insufficiency-defined as a mismatch between stress-induced energetic demand and mitochondrial throughout-rather than accumulated molecular damage, forms the upstream constraint linking stress physiology, mitochondrial performance, and telomerase regulation. In this cohort, lower baseline mitochondrial energetic capacity predicted greater longitudinal declines in telomerase activity, while telomere length remained stable across the short observation window, supporting the view that telomerase activity represents an early, energy-sensitive marker of unresolved stress adaptation, whereas telomere shortening is a delayed structural consequence. Interpreted within the Exposure-Related Malnutrition (ERM) framework, these patterns suggest that repeated activation of stress-response pathways without adequate metabolic recovery limits mitochondrial throughput and progressively compromises genome maintenance. In contrast, repeated exposure to mild stressors followed by sufficient recovery promotes adaptive strengthening of mitochondrial function and telomeric maintenance, consistent with physiological hormesis. We outline a roadmap integrating telomerase activity with dynamic indices of mitochondrial and redox function, including NAD⁺ availability, and emerging biomarkers of systemic energetic strain, such as circulating cell-free mitochondrial DNA and GDF15. By reframing aging phenotypes as early-stage failures of energetic resolution, this model highlights modifiable windows of vulnerability and hormesis-informed strategies-including exercise-induced adaptive stress, circadian alignment, and nutritional sufficiency-as actionable pathways for preserving mitochondrial resilience and telomere maintenance.

Keywords:  Bioenergetic stress; Cellular senescence; Mitochondrial energetics; Psychological stress; Telomerase activity

DOI:  https://doi.org/10.1007/s10522-025-10377-x
Biomaterials. 2026 Jan 03. pii: S0142-9612(26)00005-0. [Epub ahead of print]329 123981

Mitochondria-targeted co-assembled nanosystem with multimodal mitochondrial DNA level control to alleviate inflammation and promote chronic wound healing.

Xueyan Mao, Chuanwen Wang, Shufan Yu, Kai Zhang, Zheng Wang, Jing Du, Ying Kong, Alberto Bianco, Shaohua Ge, Baojin Ma.

  Mitochondrial dysfunction, particularly when associated with the mitochondrial DNA (mtDNA) activated cGAS-STING signaling pathway, represents a key pathogenic mechanism contributing to excessive inflammation. Therapeutic targeting of mitochondrial homeostasis coupled with precise modulation of mtDNA release emerges as a promising yet underexplored strategy to suppress pathological inflammation and promote chronic wound healing. Herein, epigallocatechin gallate-quercetin co-assembled nanoparticles (EQ NPs) were engineered to inhibit mtDNA-mediated inflammatory cascades through mitochondria-targeted multimodal mtDNA level control. Primarily, EQ NPs reduced the formation of oxidized mtDNA fragments (Ox-mtDNA). Then, EQ NPs inhibited the excessive opening of the mitochondrial permeability transition pore, preventing Ox-mtDNA cytoplasmic leakage. Subsequently, the escaped mtDNA fragments were neutralized by EQ NPs through polyphenol-mediated adsorption. Finally, mitophagy was upregulated to selectively eliminate damaged mitochondria. This well-designed strategy significantly inhibited the activation of the mtDNA-mediated cGAS-STING pathway, relieved the release of inflammatory factors, and promoted anti-inflammatory phenotype polarization of macrophages. In vivo, EQ NPs promoted chronic wound healing by bacteriostasis, anti-inflammation, immunomodulation, and accelerated angiogenesis. Overall, the study establishes a sequential mitochondrial quality control paradigm in which the inflammatory cascade is interrupted by multimodal and full-chain mtDNA scavenging, providing a promising candidate for the treatment of inflammatory diseases and chronic wound healing.

Keywords:  Co-assembly; Immunomodulation; Mitochondrial homeostasis; Oxidative stress; Polyphenol

DOI:  https://doi.org/10.1016/j.biomaterials.2026.123981
J Cell Biol. 2026 Apr 06. pii: e202507116. [Epub ahead of print]225(4):

Mitochondrial presequences harbor variable strengths to maintain organellar function.

Youmian Yan, Baigalmaa Erdenepurev, Thiago N Menezes, Ian Collinson, Natalie M Niemi.

Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.

DOI: https://doi.org/10.1083/jcb.202507116
Int J Mol Sci. 2025 Dec 23. pii: 175. [Epub ahead of print]27(1):

Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.

Jan Krekora, Elzbieta Pawlowska, Marcin Derwich, Jarosław Drożdż, Janusz Blasiak.

  Atrial fibrillation (AF) is the most common cardiac arrhythmia. Yet, its treatment has serious challenges and is unsuccessful in a considerable fraction of patients. One reason may be a limited understanding of the molecular mechanisms underlying AF. Recent studies suggest that oxidative stress is involved in AF pathogenesis. Enhanced oxidative stress is largely determined by disrupted mitochondrial homeostasis, as cardiomyocytes heavily rely on mitochondrial energy production and calcium transfer between mitochondria and the sarcoplasmic reticulum. Atrial fibrillation involves metabolic, structural, and electrical remodeling, all of which are influenced by mitochondrial mechanisms. Mitochondrial homeostasis is controlled by mitochondrial quality control (mtQC), which is a multi-pathway mechanism to maintain integrity and functionality of mitochondria. Impaired mtQC may result in disturbed mitochondria-related calcium handling, decreased energy production, mitochondria-related inflammation and fibrosis, and impaired mitophagy. Sirtuins (SIRTs) are a family of seven members of histone deacetylases which have antioxidant properties, and three of them are localized to mitochondria. Therefore, at least some SIRTs may ameliorate enhanced oxidative stress related to damaged mitochondria. SIRTs have shown potential to improve AF outcomes in studies on AF patients and animal models. Therefore, SIRTs may have potential to ameliorate AF by decreasing oxidative stress and restoring mitochondrial homeostasis disrupted in AF. In this narrative review, we provide information on how mitochondrial dysfunctions, expressed as a disturbance in mtQC, contribute to AF through oxidative stress, calcium handling abnormalities, energy deficiency, inflammation and fibrosis, and genetic changes. In addition, we present the protective potential of sirtuins in AF.

Keywords:  AF; atrial fibrillation; calcium handling; fibrosis; inflammation; metabolic remodeling; mitochondrial quality control; mitophagy; oxidative stress; sirtuins

DOI:  https://doi.org/10.3390/ijms27010175
Basic Clin Pharmacol Toxicol. 2026 Feb;138(2): e70188

Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.

Luling Li, Xiuting Huang, Pei Li.

  Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.

Keywords:  atherosclerosis; inflammation; macrophage senescence; metformin; ox‐LDL

DOI:  https://doi.org/10.1111/bcpt.70188
Cell Death Dis. 2026 Jan 08. 17(1): 9

Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.

Tsung-Hsien Chen, Chu-Kuang Chou, Kurt Ming-Chao Lin.

Heat shock protein 60 (HSP60) plays a vital role in maintaining mitochondrial homeostasis and essential functions and requires ATP for its assembly into chaperone complexes. This study aimed to investigate the long-term effects of HSP60 induction on mitochondrial homeostasis at varying doses and durations using HSP60 transgenic mice. In this study, we generated transgenic mice with elevated levels of native HSP60 using the LoxP-Cre system. These mice exhibited impaired postnatal development, skeletal muscle dystrophy, and increased mortality. Initially, excess HSP60 enhanced the mitochondrial oxidative respiratory capacity, which was later compensated for by increased glycolysis. Surplus HSP60 primarily accumulated in the mitochondria, likely due to insufficient ATP availability, leading to the buildup of HSP60 heptamers. Consequently, mitochondrial number and morphology were altered, protein levels in electron transport chain complexes were reduced, and oxidative phosphorylation was impaired. Additionally, reactive oxygen species accumulated, contributing to mitochondrial dysfunction in skeletal muscles. The upregulation of Pink-1/Parkin triggered enhanced autophagy, while increased Bax and poly (ADP-ribose) polymerase (PARP) cleavage mediated heightened apoptosis; both mechanisms aimed at eliminating damaged mitochondria. However, prolonged HSP60 accumulation overwhelmed these protective processes, ultimately leading to skeletal muscle dystrophy and premature death. Our findings demonstrated that excessive mitochondrial HSP60 initially boosts oxidative respiration; however, over time, it contributes to mitochondrial dysregulation and myopathy. This study provides novel insights into how excessive HSP60 affects mitochondrial oxidative respiration and glycolysis, with potential links to certain mitochondria-related diseases.

DOI: https://doi.org/10.1038/s41419-025-08260-1
Aging Cell. 2026 Jan;25(1): e70355

Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.

Steve D Guzman, Paula M Fraczek, Klimentini Itsani, Esraa K Furati, Devin Juros, Grace Kenney, Gregorio Valdez, Joe V Chakkalakal, Carlos A Aguilar.

Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10-two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

DOI: https://doi.org/10.1111/acel.70355
Essays Biochem. 2025 Dec 22. pii: EBC20253045. [Epub ahead of print]69(5):

The many faces of p97/Cdc48 in mitochondrial homeostasis.

Jonathan Ram, Michael H Glickman.

  Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.

Keywords:  Cdc48; ERAD; MAD; P97; VCP; mitochondria; mitostasis; proteasome; ubiquitin

DOI:  https://doi.org/10.1042/EBC20253045
Redox Biol. 2025 Dec 25. pii: S2213-2317(25)00509-9. [Epub ahead of print]89 103996

Islet regeneration protein Reg3g promotes macrophage clearance of β cell-derived dysfunctional mitochondria-rich vesicles to mitigate T2DM.

Senlin Li, Mengheng Wang, Hong Zhou, Jia Liu, Mengxuan Wang, Huimin Yuan, Mengzhu Zheng, Xin Li, Xiangling Zhu, Ming Xiang.

  Under metabolic stress in type 2 diabetes mellitus (T2DM), β cells accumulate damaged mitochondria, and proinflammatory macrophages infiltrate pancreatic islets. In several tissues, mitochondrial transfer between macrophages and parenchymal cells has been shown to alleviate inflammation and sustain cellular function reponse to stress. However, whether a similar process occurs between pancreatic β cells and macrophages remains unclear. Here, we identified a form of intercellular communication mediated by damaged mitochondrial-rich extracellular vesicles (mEVs) from β cells to macrophages within the inflammatory islets, promoted by Reg3g. Using time-lapse confocal microscopy, flow cytometry and split-GFP mitochondrial fusion assays, we demonstrated that stressed β cells release damaged mitochondria via mEVs, which were internalized by macrophages through a heparan sulfate (HS)-dependent mechanism and subsequently degraded through mitophagy. Under metabolic stress, β cells increased mEVs release, but macrophage uptake was impaired due to reduced HS biosynthesis. The protein Reg3g restored this process by binding macrophage exostosin-like glycosyltransferase 3 (EXTL3) receptors, promoting HS synthesis. Mechanically, increased HS enhanced mEVs uptake and strengthened the heparan sulfate proteoglycan (HSPG)-NF-κB interaction, sequestering NF-κB in the cytoplasm and suppressing purinergic receptor P2X7 (P2RX7) expression. P2RX7 downregulation subsequently promoted metabolic remodeling and an anti-inflammatory shift in macrophages. Collectively, our study identifies a Reg3g-orchestrated transcellular mitophagy pathway, wherein macrophages clear mEVs from β cells, promoting islet homeostasis. Targeting this axis may offer new therapeutic strategies for T2DM.

Keywords:  Heparan sulfate; Macrophage; Mitochondria-rich extracellular vesicles; Reg3g; Transcellular mitophagy

DOI:  https://doi.org/10.1016/j.redox.2025.103996
Cell Res. 2026 Jan;36(1): 11-37

Mitophagy in the pathogenesis and management of disease.

Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx.

Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy - from receptors and stress-responsive triggers to lysosomal degradation - illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.

DOI: https://doi.org/10.1038/s41422-025-01203-7
Neurobiol Dis. 2026 Jan 06. pii: S0969-9961(26)00006-9. [Epub ahead of print] 107262

Multi-omics analysis identifies mitochondrial dysfunction in CD83+ macrophages as a key event in diabetic peripheral neuropathy progression.

Yumin Lin, Yuanyuan Shen, Jiahua Wu, Yucheng Wang, Yijin Zhao, Caixia Yao, Jiale Lin, Hanbing Zhao, Hongman Zhang, Yucong Chen, Jianbo Li.

   BACKGROUND: Diabetic peripheral neuropathy (DPN) is a debilitating diabetic complication marked by progressive nerve fiber loss and dysfunction. While extensive studies have focused on the onset of DPN, the mechanisms underlying its progression remain poorly understood. Once DPN progression occurs, it can render nerve damage irreversible and make treatment more challenging. Emerging evidence suggests that immune and mitochondrial metabolic dysregulation play critical roles in disease exacerbation, yet the specific cell subtype and molecular mediators driving DPN progression have not been systematically identified.
METHODS: Constructed a progressive DPN mouse model for bulk sequencing to explore progression-related mechanisms. Integrated Scissor and multi-omics analyses identified key cell subtypes and hub genes. TIMM23's role in DPN progression and mitochondrial function was validated in vitro in bone marrow-derived macrophages (BMDMs) and in vivo via adeno-associated virus-mediated overexpression.
RESULTS: Mitochondrial metabolic dysfunction is a potential core mechanism underlying the progression of DPN. CD83+ macrophages were identified as the most prominent and specific subset associated with mitochondrial dysfunction and the DPN progression. Accordingly, we constructed a progressive DPN-related mitochondrial score, which enabled quantitative evaluation of DPN progression, inflammation, and immune infiltration. In vitro, high-glucose or high-fat intervention in BMDMs resulted in reduced expression of TIMM23. TIMM23 overexpression increased ATP production and mitochondrial mass, while reducing reactive oxygen species. In vivo, TIMM23 overexpression in the sciatic nerve improved nerve conduction velocity and nociceptive responses.
CONCLUSION: This study highlights the first discovery of CD83+ macrophages in DPN progression and identifies TIMM23 as a potential diagnostic and therapeutic marker.

Keywords:  CD83+ macrophage; Mitochondria; Multi-omics; Progressive diabetic neuropathy; TIMM23

DOI:  https://doi.org/10.1016/j.nbd.2026.107262
Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00492-6. [Epub ahead of print]89 103979

Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.

William M Curtis, Patrick C Bradshaw.

  The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O2-•), hydrogen peroxide (H2O2), nitric oxide (NO•), peroxynitrite (ONOO-), carbonate radicals (•CO3-), nitrogen dioxide radicals (•NO2), hydroxyl radicals (•OH), oxygen (•O2• or O2), and carbon dioxide (CO2). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O2-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O2-• is mainly produced by the reaction of O2 with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O2-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H2O2. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O2-• readily reacts with NO• to form ONOO-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O2-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.

Keywords:  DJ-1; Mitophagy; NADPH; Nitric oxide synthase; Parkinson's disease; Superoxide sentinel hypothesis

DOI:  https://doi.org/10.1016/j.redox.2025.103979
Biosci Rep. 2026 Jan 09. pii: BSR20254097. [Epub ahead of print]46(1):

Adaptive inter-tissue proteostasis networks in aging and neurodegeneration.

Carlos A Vergani-Junior, Matheus Antonio V de C Ventura, Evandro A De-Souza.

  The maintenance of proteostasis is essential for cellular function and organismal health. Its decline with age is a key contributor to neurodegenerative diseases, metabolic disorders, and other chronic conditions. Eukaryotic cells respond to proteotoxic stress through compartment-specific pathways, including the heat shock response (HSR), the unfolded protein response of the endoplasmic reticulum (UPRER), and the mitochondrial UPR (UPRmt). While these pathways have been extensively studied in cell-autonomous contexts, recent evidence reveals that neurons and glial cells can co-ordinate these responses across tissues through cell-non-autonomous mechanisms. Neuronal signals, including neuropeptides, biogenic amines, and possibly extracellular vesicles, can activate stress responses in distal cells, modulating lipid metabolism and impacting longevity. Emerging data also suggest a role for glial cells in systemic proteostasis regulation, though their mechanisms remain relatively uncharacterized. This review discusses both classical and emerging concepts of proteostasis stress-response pathways, their integration with neural signaling, and how their modulation influences aging and disease. Understanding how intercellular communication governs proteostasis could open new avenues for therapeutic interventions in age-related and neurodegenerative disorders.

Keywords:  aging; cell-non-autonomous signaling; heat shock response (HSR); proteostasis network; unfolded protein response (UPR)

DOI:  https://doi.org/10.1042/BSR20254097
J Cell Sci. 2026 Jan 01. pii: jcs263847. [Epub ahead of print]139(1):

Mitochondrial dynamics and signaling in stem cell differentiation.

Rahul Kumar Verma, Somya Madan, Richa Rikhy.

  Mitochondrial dynamics are defined by the continuous processes of fusion and fission that regulate mitochondrial shape, distribution and activity. They are also involved in cellular functions of mitochondria, such as energy production, metabolic adaptation, apoptosis and cellular stress responses. Consequently, these organelle dynamics play a crucial role in development, growth, differentiation and disease. Mitochondrial morphology is controlled by Drp1 (also known as DNM1L) and Fis1, which drive fission, whereas Opa1, Mfn1 and Mfn2 mediate fusion. The transcription, activation and degradation of these proteins are often regulated by signaling cascades that are crucial for stem cell maintenance and differentiation. In turn, mitochondrial dynamics regulate key outcomes of these pathways. We explore the interplay between mitochondrial fusion and fission proteins and such signaling pathways, including Notch, receptor tyrosine kinase, JNK, Hippo and mTOR signaling, finding that stem cell renewal and differentiation states are dependent on the regulation of signaling pathways by mitochondrial morphology and activity. Overall, this Review highlights how mitochondrial morphology and activity crucially regulate stem cell division for renewal and differentiation, examining their impact across diverse systems.

Keywords:  Drp1; Marf; Mfn; Mitochondria; Opa1; Signaling; Stem cells

DOI:  https://doi.org/10.1242/jcs.263847
Cell Commun Signal. 2026 Jan 07.

Inhibiting SHP2 improves ventricular remodeling by restoring AMPK phosphorylation and mitochondrial homeostasis.

Qiao-Juan Shi, Wei-Qi Li, Ya-Nan Liu, Guo-Xuan Liu, Jia-Ning Zheng, Ming-Yang He, Chen-Lu Liu, Yu-Rou Wu, Jie Tong, Meng Zhang, Guang Liang, Hua-Zhong Ying, Xue Han.

   BACKGROUND: Although mitochondrial dysfunction is an established hallmark of ventricular remodeling, the molecular mechanisms governing this process remain incompletely characterized. This study systematically investigates the regulatory role of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) in AMPK-mediated mitochondrial dysfunction and its pathological consequences in ventricular remodeling.
METHODS: Ventricular remodeling was induced by angiotensin II (Ang II) or isoproterenol (ISO) in vivo and in vitro, with assessment of hypertrophy and fibrosis using echocardiography, molecular analyses and histopathology. Bulk RNA-seq demonstrated that SHP099, an SHP2 inhibitor, modulated the AMPK pathway. LC-MS/MS and Co-IP confirmed the interaction between AMPK and SHP2. We constructed SHP2 mutant plasmids and employed AAV9-mediated cardiac SHP2 overexpression together with AMPK activator A769662 administration to validate the functional significance of this interaction.
RESULTS: SHP2 expression is upregulated in Ang II- or ISO-induced ventricular remodeling models. Both SHP099 (pharmacological inhibition) or siSHP2 (genetic knockdown) ameliorated cardiac hypertrophy and mitochondrial dysfunction, whereas SHP2 overexpression exacerbated these pathological changes. Mechanistically, SHP2 directly interacts with AMPK via its protein tyrosine phosphatase (PTP) domain at cysteine 459, dephosphorylating AMPK at Thr172. AAV9-mediated SHP2 overexpression aggravated ventricular remodeling, which was rescued by AMPK activator A769662.
CONCLUSIONS: This study demonstrates that SHP2 acts as a key phosphatase directly dephosphorylates AMPK, thereby triggering mitochondrial dysfunction and exacerbating ventricular remodeling. Our findings provide novel mechanistic insights into heart failure progression and highlight SHP2 as a potential therapeutic target for heart failure treatment.

Keywords:  AMPK dephosphorylation; Mitochondrial function; Protein tyrosine phosphatase family; SHP2; Ventricular remodeling

DOI:  https://doi.org/10.1186/s12964-025-02620-2
Bioact Mater. 2026 Apr;58 422-471

Black phosphorus in theragenerative medicine: a multi-organ perspective on disease modulation and tissue repair.

Ashkan Bigham, Anna Mariano, Aldo R Boccaccini, Luigi Ambrosio, Maria Grazia Raucci.

  Black phosphorus (BP) has attracted considerable attention as a biodegradable, stimuli-responsive 2D nanomaterial, emerging as a powerful theragenerative platform that integrates disease modulation with tissue regeneration. While earlier studies focused mainly on its anticancer properties, this review provides the first comprehensive analysis of BP as a theragenerative agent, unifying its disease-modulating capacity with its ability to stimulate tissue regeneration across multiple organs. BP exhibits several shared advantages: its degradation releases bioactive phosphate ions that support tissue repair; its highly reactive surface promotes cell interactions and enables efficient drug loading and delivery; its responsiveness to external stimuli, such as Near-infrared (NIR) light, ultrasound, and electrical signals, allows precise, on-demand therapeutic activation; and its ability to modulate reactive oxygen species (ROS) and immune modulation helps balance inflammation and regeneration. These properties collectively enhance osteogenesis and implant integration in bone, accelerate wound healing in skin, promote neural repair and redox homeostasis, protect cardiac tissue, and support recovery in kidney and liver injuries. By highlighting these mechanisms, this review emphasizes BP's versatility as a multifunctional nanomaterial capable of addressing pathological conditions while simultaneously stimulating endogenous regenerative pathways, thereby laying the foundation for its translation into next-generation theragenerative platforms.

Keywords:  2D nanomaterials; Black phosphorus; Disease therapy; Stimuli-responsive; Tissue regeneration

DOI:  https://doi.org/10.1016/j.bioactmat.2025.12.019
bioRxiv. 2025 Dec 29. pii: 2025.12.28.696697. [Epub ahead of print]

SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response.

Nicholas A Parenti, Renee Cusic, David M Renner, Nathaniel Jackson, Chengjin Ye, Li Hui Tan, Jessica J Pfannenstiel, Anthony R Fehr, Noam A Cohen, Luis Martinez-Sobrido, James M Burke, Susan R Weiss.

Coronaviruses pose a serious threat to public health, driving the need for antiviral therapeutics and vaccines. Therefore, it is paramount to understand how this family of viruses evades cellular antiviral responses and establishes productive infection. The conserved coronavirus non-structural protein (nsp)1 has been shown to inhibit host protein synthesis and promote host mRNA degradation while viral mRNAs are protected. We showed previously that SARS-CoV-2 induces activation of host integrated stress response (ISR) kinases PKR and PERK, which promote phosphorylation of eIF2α and consequent inhibition of host protein synthesis. In contrast, eIF2α remains unphosphorylated during MERS-CoV infection. To investigate the interactions of nsp1 and the ISR kinases, we utilized recombinant SARS-CoV-2 and MERS-CoV expressing nsp1 with mutations in each of two conserved domains. Upon infection with SARS-CoV-2 nsp1 mutants, translation was shut down in wildtype (WT) and PKR knockout (KO) cells but rescued in PERK KO cells, likely due to reduced p-eIF2α. In contrast, translation was rescued during infection with the analogous MERS-CoV nsp1 mutants even in WT cells. Moreover, SARS-CoV-2 WT suppressed expression of GADD34, a negative regulator of eIF2α phosphorylation, while SARS-CoV-2 nsp1 mutants induced GADD34. In contrast MERS-CoV WT induced GADD34. Utilizing single-molecule fluorescence in situ hybridization, we found that SARS-CoV-2 and MERS-CoV nsp1 promote host mRNA degradation during WT, but not nsp1 mutant, infection. Finally, while SARS-CoV-2 WT suppressed stress granule formation, nsp1 mutants induced stress granules containing host RNA. Thus, SARS-CoV-2 and MERS-CoV differ in interactions with the ISR and nsp1 control of host protein synthesis.
Significance: Coronaviruses cause disease across a wide range of animal species, and the human coronaviruses SARS-CoV-2 and MERS-CoV have caused epidemics of severe respiratory illness. Thus, it is imperative to understand how these viruses antagonize host responses and cause lethal disease. We show here that the betacoronavirus non-structural protein (nsp)1 promotes shutdown of host protein synthesis while preserving viral protein synthesis and, in addition, promotes degradation of host mRNAs. However, SARS-CoV-2 and MERS-CoV differ in their ability to manipulate the host integrated stress response, indicating that it is important to understand detailed coronavirus-host interactions and how they differ even between lethal coronaviruses. Such insights will inform the development of antiviral therapeutics to treat and prevent current and future coronavirus outbreaks.

DOI: https://doi.org/10.64898/2025.12.28.696697
Cells. 2026 Jan 05. pii: 88. [Epub ahead of print]15(1):

Photobiomodulation Activates Coordinated Signaling Networks to Modulate Inflammation, Adaptive Stress, and Tissue Healing via Redox-Mediated NFκB-TGF-β1-ATF-4 Axis.

Sasikumar Ponnusamy, Mahmud Amin, Amruta Bhat, Sarah Garczynski, Saeed Ur Rahman, Sailee Rasam, Sharaschandra Reddy Govindool, Imran Khan, Praveen Arany.

  Photobiomodulation (PBM) therapy has been effectively used to relieve pain and inflammation and promote tissue healing and regeneration in a broad range of ailments. Prior work has focused on intracellular mitochondrial cytochrome c oxidase, while extracellular latent TGF-β1 activation had been noted. This work investigated the role of PBM-generated redox signaling and integration in normal oral keratinocytes, using Western blots and pathway-specific small molecule inhibitors. We observed that PBM primarily generates ROS intracellularly within mitochondria, which then diffuse extracellularly to activate latent TGF-β1. This activation triggers ATF-4 expression through both canonical (Smad3) and non-canonical (p38, ERK) TGF-β signaling pathways. We observed a critical role for NFκB as an essential integrator, coordinating these responses as evidenced by the loss of ATF-4 expression following NFκB inhibition (BAY II) after both PBM and TGF-β1 treatments. Proteomic pathway analysis revealed that PBM downregulates inflammatory and apoptotic pathways while activating stress-adaptive responses in the NFκB pathway. A core set of PBM-induced redox, NFκB, and TGF-β signaling targets was identified. These findings suggest that optimal PBM treatment responses require a coordinated action of multiple signaling pathways that optimize cellular adaptation to stress and promote tissue repair rather than protracted inflammation and cell death.

Keywords:  ATF-4; LLLT; NFκB; ROS; TGF-β1; photobiomodulation

DOI:  https://doi.org/10.3390/cells15010088
Sci Rep. 2026 Jan 06.

Uncovering the role of integrated stress in Alzheimer's disease through single-cell and transcriptomic analysis.

Ning Sheng, Hong-Yan Wang, Kun Song, Yong Zheng, Zi-Ying Zong, Jin-Wen Ge, Da-Hua Wu, Ya-Han Wang.

  Alzheimer's disease (AD) is a common neurodegenerative disorder; however, its molecular complexity remains poorly understood. Single-cell analysis can reveal the molecular changes in AD in different types of brain cells. In this study, we integrated single-cell sequencing and transcriptome data to explore the molecular mechanism of integrated stress response (ISR) in AD. Analysis of the GSE264648 (49 cases) and GSE48350 (253 cases) datasets showed that the integrated stress response (ISR) activity of endothelial cells in patients with AD was significantly increased compared with normal control group. Six key genes (BTG1, EPB41L4A, HERPUD1, SLC3A2, SLC7A11, and SLC7A5) were screened by combining the Least Absolute Shrinkage and Selection Operator (LASSO) regression and the random forest algorithm. Urine test for β-amyloid protein, Clinical Dementia Rating, modified Hachinski Ischemia Scale, Hamilton Depression Scale, Hamilton Anxiety Scale and head magnetic resonance imaging were used to screen cilinical subjects, and then verified the six key genes in their blood samples. These key genes are enriched in inflammatory pathways such as NF-κB and TNF, and are closely related to immune cell infiltration (e.g., M2 macrophages and neutrophils). This research also revealed the association between key and core genes of AD (e.g., APOE) and their clinical predictive value, providing new clues for mechanistic research and targeted therapy of AD.

Keywords:  Alzheimer’s disease; Clinical validation; Integrated stress response; Key genes; Single-cell sequencing

DOI:  https://doi.org/10.1038/s41598-026-34997-6
bioRxiv. 2025 Dec 23. pii: 2025.12.21.695844. [Epub ahead of print]

Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response.

Subhaan M Mian, Sera I Nakisli, Brodie J Woodall, Pooja J Patel, Aariz Nackvi, Noura Elhamadany, Kree Goss, Nwasinachi Adriana Ezeji, Muhammad Saad Yousuf.

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a noncanonical cap binding protein implicated in selective mRNA translation under stress conditions. Here, we investigate the contribution of eIF3d to pain processing using a heterozygous eIF3d knockout (eIF3d +/- ) mouse model. We first validated this model, confirming substantial reductions in eIF3d mRNA and protein levels in dorsal root ganglia. Baseline assessments revealed no differences in mechanical, thermal, cold, or spontaneous pain behaviors between eIF3d +/- (HET) and eIF3d +/+ (WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behavior in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming was comparable between HET and WT mice following IL-6 exposure. Experimental autoimmune encephalomyelitis (EAE) induced mice were unaffected by eIF3d reduction. These findings demonstrate that eIF3d selectively modulates nociceptive plasticity under defined stress conditions and suggests a context dependent role in the regulation of inflammatory and central pain sensitization.
Highlights: Baseline mechanical, thermal, cold and spontaneous pain are intact in eIF3d +/- mice Methylglyoxal-evoked ISR activation and mechanical pain is blunted in eIF3d +/- mice IL-6-evoked mechanical and cold pain are reduced without altered priming Mechanical hypersensitivity is reduced in eIF3d +/- mice with paw incision EAE pain is unaltered but increased pain in phase II formalin pain in eIF3d +/- mice.

DOI: https://doi.org/10.64898/2025.12.21.695844
iScience. 2026 Jan 16. 29(1): 114279

Mitochondrial integrity modulates mTOR signaling and podocyte function.

Cem Özel, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, David Unnersjö-Jess, Martin Höhne, Wilhelm Bloch, Henning Hagmann, Richard J M Coward, Sebastian Brähler, Bernhard Schermer, Thomas Benzing, Philipp Antczak, Paul T Brinkkötter.

  Mitochondrial dysfunction has emerged as a key contributor to the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and genetic focal-segmental glomerulosclerosis (FSGS). This study explores the role of mitochondrial integrity in podocyte biology, focusing on the impact of OMA1, a critical regulator of mitochondrial morphology. Using a model of disrupted mitochondrial homeostasis, we show that mitochondrial dysfunction sensitizes podocytes to insulin, triggering the overactivation of mTOR signaling. Disruption of OMA1 function was achieved through the deletion of Oma1 or a podocyte-specific knockout of its regulator Phb2. Remarkably, simultaneous Oma1 deletion extended the lifespan of severely affected Phb2 pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in Phb2 pko , Oma1 del , and Phb2/Oma1 double-knockout mice. Our findings highlight the critical role of mitochondrial integrity in podocyte function and disease mitigation, providing potential therapeutic insights for mitochondrial dysfunction-associated nephropathies.

Keywords:  cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114279
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2423340122

Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.

Abhijnya Kanugovi, Paola Aguiari, Rachel Choi, Soochi Kim, Di Wu, Antoine De Morree, Summer Bui, Richard Lam, Stefano Biressi, Ling Liu, Thomas A Rando.

  Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibro-adipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in the muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration.

Keywords:  aging; complement, C1q; fibro-adipogenic progenitors; fibrosis; muscular dystrophy

DOI:  https://doi.org/10.1073/pnas.2423340122