bims-mihora 2026-03-22 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–03–22
23 papers selected by
Lisa Patel, Istesso

Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.
Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
Hypoxic-inflammatory preconditioning endows BMSC-derived appoptotic extracellular vesicles with potent efficacy against IVDD via cell activation and mitochondrial homeostasis regulation.
Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.
Single-cell sequencing combined with transcriptome sequencing to reveal the molecular mechanisms related to integrated stress responses in atherosclerosis.
Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
Nanomaterials regulate cellular functions and influence cell fate through mitophagy.
Ginsenoside Rg1 alleviates MASH by targeting GLS2 to enhance PINK1/Parkin-mediated mitophagy and improve mitochondrial function.
Mitochondrial Precursor Overaccumulation Stress.
Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.
The stress responsive transcription factor ATF4: from molecular structure to disease mechanisms.
Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.
PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.
METTL14 mitigates osteoporosis progression by promoting osteogenic differentiation of BMMSCs through improving mitochondrial dysfunction.
Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.
Mitochondrial DNA: Bridging cellular senescence and chronic inflammation in aging and beyond.
ZEB1 maintains mitochondrial fission and macrophage efferocytosis by restraining MFN2, thereby limiting inflammation and improving tendon‑bone healing.
IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration.
Balancing inflammation and regeneration: immune cell dynamics in nerve repair: a comprehensive review.
Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
27-Hydroxycholesterol inhibits muscle cell viability via mitochondrial dysfunction: Protective role of ROS-induced HIF-1α.
m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria.

Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00038-3. [Epub ahead of print] 102148

Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.

Merlin Jeejo, Mrudula Mathew, Kochupurackal P Mohanakumar, Usha Rajamma.

  Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunction, manifested through disruptions in ATP synthesis, mitochondrial DNA (mtDNA) mutations, and heightened oxidative stress, as a significant contributor to the pathophysiology of ASD. Notably, individuals with ASD demonstrate a higher prevalence of mitochondrial disorders compared to the general population, suggesting a potential pathogenic link. However, the relationship between mitochondrial dysfunction and ASD is heterogeneous and varies among individuals, reflecting the disorder's intrinsic complexity. Recent interest in the Mitochondrial Unfolded Protein Response (UPRmt), which is activated in response to mitochondrial stress and misfolded proteins, underscores its critical role in maintaining mitochondrial integrity. Yet, its specific implications in ASD have been insufficiently investigated. This review aims to consolidate the current literature on UPRmt-related biomarkers in the context of ASD, elucidating how disruptions in this pathway may exacerbate mitochondrial dysfunction and contribute to ASD pathogenesis. In this narrative review, based on our literature search from academic databases such as PubMed, Scopus, Web of Science, and Google Scholar, and also grey literature, we present a conceptual framework to enhance our understanding of ASD pathophysiology that integrates mitochondrial stress, UPRmt activation, and neurodevelopmental outcomes. This review aims to expand the existing knowledge of mitochondrial contributions to ASD and identify new research dimensions to explore the mechanisms underlying UPRmt deregulation in ASD pathophysiology, thereby highlighting the potential therapeutic directions for targeting mitochondria-mediated UPRmt dysfunction in ASD.

Keywords:  Autism spectrum disorders; Gut-brain axis; Mitochondrial dysfunction; Mitochondrial unfolded protein response; Mitokine

DOI:  https://doi.org/10.1016/j.mito.2026.102148
J Diabetes Res. 2026 ;2026(1): e1498605

Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.

Tianlei Chen, Min Yang.

  Diabetic nephropathy (DN), a predominant cause of end-stage renal disease (ESRD), is primarily driven bfigolic disturbances and mitochondrial dysfunction. Apolipoprotein M (ApoM), a protein associated with high-density lipoprotein (HDL), is notably downregulated in DN and is correlated with a decline in renal function. Recent studies have identified a protective bidirectional axis between ApoM and mitophagy, the selective autophagy of mitochondria. ApoM, chiefly through its role as a carrier for sphingosine-1-phosphate (S1P), enhances mitophagy by activating the silent information regulator 1 (SIRT1) and parkin induced kinase 1 (PINK1)/Parkin pathways, thereby improving mitochondrial quality control. Conversely, mitophagy facilitates ApoM synthesis by supplying sufficient adenosine triphosphate (ATP) for its production and the assembly of HDL. In the context of DN, hyperglycemia disrupts this reciprocal relationship, leading to a detrimental cycle of impaired mitophagy and reduced ApoM, which exacerbates renal injury. Targeting the ApoM-mitophagy axis through ApoM enhancement or mitophagy activation emerges as a promising therapeutic approach for personalized renal protection in DN. This review synthesizes the mechanistic interplay between lipid metabolism and mitochondrial quality control, emphasizing its translational potential and the necessity for further investigation.

Keywords:  apolipoprotein m; diabetic nephropathy; lipid metabolism; mitophagy; sphingosine-1-phosphate

DOI:  https://doi.org/10.1155/jdr/1498605
J Nanobiotechnology. 2026 Mar 15.

Hypoxic-inflammatory preconditioning endows BMSC-derived appoptotic extracellular vesicles with potent efficacy against IVDD via cell activation and mitochondrial homeostasis regulation.

Weiqi Zhang, Tianhao Guo, Dazhuang Miao, Xiaowei Ma, Wei Chen, Zhiyong Hou, Yingze Zhang, Xianda Gao, Di Zhang.

  Intervertebral disc degeneration (IVDD) is the primary cause of chronic low back pain, with the senescence of nucleus pulposus cells (NPCs) as its core driving mechanism. Mitochondrial homeostasis acts as a critical mediator linking cellular stress responses to the senescence program of nucleus pulposus cells. Recent studies have indicated that the transplantation of apoptotic extracellular vesicles (ApoEVs) derived from the apoptotic mesenchymal stem cells (MSCs) represents a novel direction for tissue regeneration therapy. Given that the pathological microenvironment of IVDD exhibits hypoxic-inflammatory characteristics, the functional regulatory effects of ApoEVs pretreated under such conditions remain unclear. Here, we aimed to assess whether modulation of the MSCs culture microenvironment (hypoxia alone versus hypoxic-inflammatory conditions) generates ApoEVs (specifically I-ApoEVs) with enhanced therapeutic efficacy in the context of IVDD repair. A secondary focus of this study was to clarify the underlying mechanism through which such therapeutic effects are mediated by the regulation of mitochondrial homeostasis. Notably, the results demonstrated that I-ApoEVs were significantly superior to enhance the viability of NPCs and improve mitochondrial function. These findings suggest that the combined hypoxic-inflammatory pretreatment can more efficiently enhance the capacity of MSCs-derived ApoEVs to regulate mitochondrial homeostasis, thereby providing experimental evidence for optimizing ApoEV-based therapeutic strategies for IVDD.

Keywords:  Apoptotic extracellular vesicles; Hypoxia; Intervertebral disc degeneration; Mesenchymal stem cells; Mitochondrial homeostasis

DOI:  https://doi.org/10.1186/s12951-026-04289-2
Transl Res. 2026 Mar 14. pii: S1931-5244(26)00062-9. [Epub ahead of print]

Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.

Arpit Sharma, Shruti S Raut, Alok Shukla, Amit Singh, Abha Mishra.

  Mitochondria are fundamental organelles that regulate cellular homeostasis through energy production, metabolic integration, and signaling cascades. Beyond their bioenergetic role, mitochondrial dysfunction is increasingly recognized as a pivotal instigator of PANoptosis, a novel, coordinated inflammatory cell death pathway that amalgamates key features of pyroptosis, apoptosis, and necroptosis. This integrated cell death is executed by multiprotein complexes termed PANoptosomes, which are nucleated by specific sensors like ZBP1, AIM2, and NLRC5. Central to this process is the release of mitochondrial danger signals, including reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as potent upstream triggers. For instance, ROS can directly oxidize and activate necroptotic mediators like RIPK1, while cytosolic mtDNA engages innate immune sensors such as cGAS-STING and inflammasomes, thereby initiating PANoptosome assembly. Concurrently, defects in core mitochondrial processes including impaired oxidative phosphorylation, disrupted dynamics (fission/fusion), and faulty mitophagy exacerbate these inflammatory signals, creating a permissive environment for PANoptosis. This mitochondrial-PANoptosis axis is implicated in the pathogenesis of a broad spectrum of diseases. Consequently, therapeutic strategies targeting mitochondrial integrity or specific PANoptotic components hold significant promise for mitigating pathological inflammation and cell loss. This review focuses on the molecular mechanisms linking mitochondrial dysfunction to PANoptosis and explores the translational potential of this interplay to reshape therapeutic approaches in diseases.

Keywords:  & Mitochondrial dysfunction; Cell death; Immune; PANoptosis; Therapeutics

DOI:  https://doi.org/10.1016/j.trsl.2026.03.004
J Cardiothorac Surg. 2026 Mar 17.

Single-cell sequencing combined with transcriptome sequencing to reveal the molecular mechanisms related to integrated stress responses in atherosclerosis.

Teng Li, Xiaobao Gu, Xiangyang Yin, Pengbo Zhai, Zixun Wang, Yang Li, Bing Wang.



Keywords:  Atherosclerosis; Biomarkers; Integrated stress response; Machine learning; Single-cell sequencing

DOI:  https://doi.org/10.1186/s13019-026-03862-y
FEBS J. 2026 Mar 19.

Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.

Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.1111/febs.70497
J Control Release. 2026 Mar 12. pii: S0168-3659(26)00218-X. [Epub ahead of print]393 114816

Nanomaterials regulate cellular functions and influence cell fate through mitophagy.

Yan Wang, Dan Li, Zhen Ai, YuJia Tian, Chao Zhang.

  Mitophagy plays a crucial role in maintaining mitochondrial quality control, energy metabolism, redox homeostasis, and cell fate regulation. Its dysregulation is considered a key mechanism underlying the onset and progression of various metabolic disorder- and cell fate abnormality-associated diseases. In recent years, nanomaterials have emerged as ideal tools for modulating mitophagy owing to their designability, targeting capability, and multidimensional regulatory potential. Moreover, moderate activation of mitophagy helps to remove damaged mitochondria, alleviate oxidative stress, and restore metabolic balance, whereas excess or impaired mitophagy may trigger energy crises and lead to cellular injury. However, the bidirectional mechanisms and biosafety issues associated with nanomaterial-mediated mitophagy regulation remain poorly understood. This review highlights recent advances in how nanomaterials regulate cellular functions through mitophagy, focusing on their roles in energy metabolism, oxidative stress, senescence, programmed cell death, and diverse disease models, and summarizes the major signaling pathways involved. This study aimed to provide a theoretical framework for understanding the biological basis of nanomaterial-mediated mitophagy modulation and offer guidance for future nanomedicine design, disease intervention, and safety evaluation.

Keywords:  Cell fate regulation; Mitophagy; Nanomaterial-based therapy; Nanomaterials; Redox balance

DOI:  https://doi.org/10.1016/j.jconrel.2026.114816
Biochem Pharmacol. 2026 Mar 13. pii: S0006-2952(26)00224-8. [Epub ahead of print]249 117891

Ginsenoside Rg1 alleviates MASH by targeting GLS2 to enhance PINK1/Parkin-mediated mitophagy and improve mitochondrial function.

Zhijian Wang, Yinuo Wang, Peiyun Peng, Huating Luo, Liuling Xiao, Wenxiang Huang.

  Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by profound metabolic dysregulation and hepatic inflammation and represents a major global health burden with limited effective therapeutic options. Increasing evidence suggests that improving mitochondrial function and enhancing mitophagy may offer promising strategies for MASH treatment. Ginsenoside Rg1 (G-Rg1) has been reported to exert potent anti-inflammatory and antioxidant effects; however, its precise molecular mechanisms and targets in MASH remain unclear. In this study, we investigated whether G-Rg1 ameliorates diet-induced MASH by promoting mitophagy and sought to identify its direct molecular target. Mice treated with G-Rg1 were evaluated using histological, biochemical, and indirect calorimetric analyses to assess hepatic steatosis, fibrosis, inflammation, and energy metabolism. Transcriptomic profiling and transmission electron microscopy revealed enhanced mitophagy and improved mitochondrial ultrastructure following G-Rg1 treatment. Virtual screening and molecular docking identified glutaminase 2 (GLS2) as a potential target of G-Rg1, which was subsequently confirmed by drug affinity-responsive target stability, cellular thermal shift, and binding assays. Mechanistically, G-Rg1 activated the GLS2/PINK1/Parkin pathway, leading to increased mitophagy, reduced hepatocellular lipid accumulation, restoration of mitochondrial function, and attenuation of oxidative stress. Notably, GLS2 overexpression recapitulated the protective effects of G-Rg1 both in vitro and in vivo. Collectively, these findings demonstrate that G-Rg1 alleviates MASH by targeting GLS2 to activate PINK1/Parkin-mediated mitophagy, highlighting GLS2-regulated mitophagy as a potential therapeutic target for MASH.

Keywords:  GLS2; Gene therapy; Ginsenoside Rg1; MASH; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.bcp.2026.117891
Annu Rev Biochem. 2026 Mar 20.

Mitochondrial Precursor Overaccumulation Stress.

Liam P Coyne, Xin Jie Chen.

Damage to mitochondria imparts multifaceted cellular stress that extends beyond bioenergetic deficit. One newly emerged example is mitochondrial precursor overaccumulation stress (mPOS). mPOS is marked by impaired mitochondrial protein import, causing the toxic accumulation and aggregation of unimported mitochondrial precursor proteins in the cytosol. Analogous to the well-studied endoplasmic reticulum stress, which blocks proteins from leaving the cell, mPOS can impose a drastic proteostatic burden in the cytosol and closely interconnects with cell signaling pathways. Here, we review how researchers discovered mPOS and discuss its central importance in several major mitochondria-induced stress signaling pathways. We then focus on the emerging field of mPOS in cell demise and human disease, and we present recent evidence that mPOS can affect cell fitness and survival independent of bioenergetics. Looking forward, mPOS may provide a complementary or alternative pathogenic mechanism to bioenergetic deficit for classic mitochondriopathy and many aging-associated degenerative diseases involving mitochondrial stress.

DOI: https://doi.org/10.1146/annurev-biochem-051424-061016
Biogerontology. 2026 Mar 15. pii: 71. [Epub ahead of print]27(2):

Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.

Jyothi Priyanka Ghantasala, Timothy Wai, Writoban Basu Ball, Manjunatha Thondamal.

  Mitochondria provide energy and maintain homeostasis, and their dysfunction relates to aging. Disrupted structure and function of mitochondria are linked to age-related diseases, but the roles of many mitochondrial proteins in mitochondrial dynamics and aging remain unclear. We studied the role of the mitochondrial fission protein MTP-18 in mitochondrial dynamics and aging in C. elegans. Our data show that loss of mtp-18 increases longevity and stress resistance, alongside changes in key physiological processes. We tested whether mtp-18-mediated longevity is linked to the PI3K-dependent insulin/IGF-1 signaling (IIS) pathway. mtp-18-mediated longevity requires the Forkhead transcription factor DAF-16, a primary effector of the IIS pathway, but is not mediated by the canonical IIS cascade. We also observed unique interactions between mtp-18 and genes encoding components of the mobile electron carrier system in mitochondria, such as coenzyme Q and cytochrome c. Our study reveals that mtp-18 is an evolutionarily conserved, key aging regulator that maintains mitochondrial morphology. What sets this study apart from previous research is the identification of a novel mechanism by which MTP-18 affects these processes independently of the canonical IIS pathway, particularly through unique interactions with genes encoding components of the electron transport chain.

Keywords:   C. elegans ; Electron transport chain; Insulin signlling pathway; Longevity; Mitochondrial fission; ROS

DOI:  https://doi.org/10.1007/s10522-026-10415-2
J Gerontol A Biol Sci Med Sci. 2026 Mar 15. pii: glag065. [Epub ahead of print]

ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.

Jingcheng Fan, Xin Wen, Xuemei Duan, Xue Zhang, Tan Zhang.

  Although exercise is well-established in alleviating aging-associated skeletal muscle atrophy, the underlying mechanism is not fully understood. Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) has been shown to be a crucial adaptor for inflammation and mitochondrial function, however, little is known about the action of ECSIT in skeletal muscle atrophy. Firstly, the young and middle-aged mice were performed with exercise training, skeletal muscle atrophy, mitochondrial quality control, and mitochondrial complex in skeletal muscle were detected. Then, we analyzed the Gene Expression Omnibus (GEO) database and performed in vivo experiments to determine the effect of exercise on ECSIT expression. Furthermore, ECSIT was knockdown in myoblasts to examine its effects on muscle atrophy, mitochondrial quality control and mitochondrial complex. Compared with young mice, middle-aged mice exhibited significant reductions in relative weights of skeletal muscles, grip strength, hang time, and exhaustion exercise performance, while exercise restored these deficits dramatically. Consistently, exercise promoted protein synthesis and inhibited protein degradation in the gastrocnemius of middle-aged mice. Therefore, exercise significantly mitigated skeletal muscle atrophy in middle-aged mice. Concomitantly, exercise alleviated the impaired mitophagy in the gastrocnemius of middle-aged mice. ECSIT expression was elevated in the gastrocnemius of middle-aged mice but was reversed by exercise intervention. Mechanistically, ECSIT knockdown impaired myoblast differentiation, mitochondrial complex and mitochondrial quality control in myoblasts. Collectively, this study reveals, for the first time, that ECSIT is important for myogenesis by maintaining mitochondrial quality control, thereby facilitating exercise-induced amelioration of skeletal muscle atrophy during aging.

Keywords:  ECSIT; anti-aging; exercise; mitochondria

DOI:  https://doi.org/10.1093/gerona/glag065
J Adv Res. 2026 Mar 12. pii: S2090-1232(26)00236-5. [Epub ahead of print]

The stress responsive transcription factor ATF4: from molecular structure to disease mechanisms.

Jian-Rong Yuan, Jie Tang, Rui Sheng.

   BACKGROUND: Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, regulates cell survival and death via governing the expression of genes involved in integrated stress response, endoplasmic reticulum stress, autophagy, and metabolism. ATF4's protein level is tightly controlled by translational regulation (via eIF2α phosphorylation), epigenetic modifications, and post-translational modifications (PTMs) under stress, which are linked to cancer, cardiovascular, neurodegenerative, and metabolic diseases.
AIM: This review aims to summarize recent advances in epigenetic- and PTM-mediated regulation of ATF4 stability and function, and to clarify its multifaceted roles in relevant pathological processes.
KEY SCIENTIFIC CONCEPTS: Emerging evidence highlights that epigenetic modifications and PTMs are critical for fine-tuning ATF4 activity. These regulatory mechanisms not only modulate ATF4-dependent stress responses but also contribute to disease progression, providing potential therapeutic targets for ATF4-associated disorders.

Keywords:  ATF4; Autophagy; Epigenetic modification; Integrated stress response; Oxidative stress; Post-translational modification

DOI:  https://doi.org/10.1016/j.jare.2026.03.017
J Orthop Translat. 2026 Jan;56 101036

Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.

Chang Yang, Jin Ke, Qiongdong Xu, Wei Dong, Wenqian Yu, Yan Wang, Jiawei Wang.

   Objective: Emerging evidence has shown that inflammatory synovial macrophage and anabolism-impaired chondrocytes play essential roles in osteoarthritis (OA). The present work aims at uncovering the pathogenic mechanism of how the damage-associated molecular patterns (DAMPs) released from inflammatory synovial macrophage promote extracellular matrix (ECM) degradation of chondrocytes and developing feasible strategies to counter its detrimental effects.
Methods: We identified pyroptosis of synovial macrophages in the synovium of OA human and mouse. The effect and mechanism of mitochondrial DNA (mtDNA) released from pyroptotic synovial macrophage in ECM degradation of chondrocytes and cartilage degeneration was further explored in cellular and animal models. Finally, the ameliorative effect of folic acid-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles in OA was elucidated by in vivo experiments.
Results: Mitochondrial dysfunction in synovial macrophages leads to the release of mtDNA into the cytoplasm, which promotes macrophage pyroptosis, thereby facilitating extracellular release of mtDNA and creating an inflammatory microenvironment unfavorable to cartilage in OA. DDIT3 deficiency inhibits mtROS production by enhancing PINK1/Parkin-dependent mitophagy, which constraining the mtDNA release into the cytoplasm. The decreased cytosolic mtDNA, in turn, dampens macrophage pyroptosis. In vivo, DDIT3 deficiency significantly alleviates synovial inflammation and cartilage degeneration in OA progression, and targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles mimics the protective effects of DDIT3 deficiency against OA progression.
Conclusions: Our findings identified the pathological role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA, and demonstrated the efficacy of using folic acid-modified PLGA nanoparticles as a delivery for OA treatment.
The translational potential of this article: This study highlights the pivotal role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA. Targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles might serve as a potential therapeutic target for alleviating cartilage degeneration in OA.

Keywords:  Cartilage degeneration; DDIT3; Osteoarthritis; Pyroptotic macrophages; mtDNA release

DOI:  https://doi.org/10.1016/j.jot.2025.101036
Biochem Biophys Res Commun. 2026 Mar 09. pii: S0006-291X(26)00356-6. [Epub ahead of print]812 153592

PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.

Chengyao Ni, Peng Hu, Yiming Ni.

  Heart failure (HF) is associated with mitochondrial quality control, a key process in quality control. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) regulates mitophagy, but its role in HF remains unclear. This study investigates the role of PGC-1α in HF and its mechanism in mitophagy. Myocardial injury was induced in AC16 cells using pentobarbital, followed by PGC-1α overexpression and treatment with apoptosis inhibitor HY-19696 and mitophagy inhibitor Mdivi-1. A rat HF model was established via aortic constriction, with PGC-1α overexpressed through lentiviral injection. In the cell model, PGC-1α overexpression increased Creatine kinase isoenzyme MB (CK-MB), cardiac troponin T (cTnT), lactate dehydrogenase (LDH) levels, reduced cell viability and mitochondrial membrane potential, enhanced apoptosis and ROS production. These effects were attenuated by apoptosis inhibitor HY-19696. PGC 1α also promoted mitophagy related changes, including an increased LC3 II to LC3 I ratio, and this response was suppressed by Mdivi 1. In the rat model, PGC-1α overexpression aggravated myocardial injury, apoptosis, and damage markers, whereas pharmacological inhibition of apoptosis or mitophagy alleviated these effects. PGC-1α exacerbates HF by promoting apoptosis and enhancing mitophagy through the Hypoxia-inducible factor-1 (HIF-1)/BCL2 interacting protein 3 (BNIP3) pathway. Therefore, PGC-1α changed mitochondrial dynamic homeostasis and promoted HIF-1α/BNIP3-dependent mitophagy in HF.

Keywords:  Apoptosis; BNIP3; HIF-1α; Heart failure; Mitophagy; PGC-1α

DOI:  https://doi.org/10.1016/j.bbrc.2026.153592
J Mol Histol. 2026 Mar 17. pii: 117. [Epub ahead of print]57(2):

METTL14 mitigates osteoporosis progression by promoting osteogenic differentiation of BMMSCs through improving mitochondrial dysfunction.

Biao-Lin Wan, Zi-Hua Chen, Hong-Sheng Zeng.

  Osteoporosis, a prevalent metabolic bone disorder characterized by diminished bone mass and microarchitectural deterioration, poses a significant global health burden. Bone marrow mesenchymal stem cells (BMMSCs) are crucial for bone homeostasis, and their declined osteogenic potential is a key pathogenic factor in osteoporosis. This study investigates the role of METTL14 in BMMSCs, hypothesizing that it attenuates osteoporosis progression by enhancing their osteogenic differentiation. Osteogenic and adipogenic differentiation were assessed by Alizarin Red and Oil Red O staining, respectively. Cell proliferation was evaluated using the CCK-8 assay, and protein expression was analyzed by Western blot. An ovariectomized (OVX) rat model of osteoporosis was established, with bone changes examined through histopathology and immunohistochemistry. Mitochondrial function was assessed via JC-1 staining, ROS/ATP assays, and respiratory chain protein expression analysis. METTL14 upregulation enhanced BMMSC proliferation, promoted osteogenic differentiation, and increased osteogenesis-related protein expression, whereas its suppression had opposing effects. In OVX rats, METTL14 elevation improved bone repair and improved mitochondrial function by recovering membrane potential, reducing mitochondrial ROS, increasing ATP production, and normalizing respiratory chain protein expression. METTL14 mitigates osteoporosis progression by promoting osteogenic differentiation of BMMSCs through improving mitochondrial dysfunction. Our research provides a foundation for targeting METTL14 in osteoporosis treatment.

Keywords:  BMMSCs; METTL14; Mitochondrial dysfunction; Osteoporosis

DOI:  https://doi.org/10.1007/s10735-026-10735-0
Front Neurol. 2026 ;17 1772036

Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.

Xiaohua Xiao, Xueqin Yan, Chunhua Liang, Yunzhu Yang.

  Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.

Keywords:  Alzheimer's disease; brain energy metabolism; emerging interventions; insulin resistance; metabolic dysfunction; mitochondrial failure; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3389/fneur.2026.1772036
Mutat Res Rev Mutat Res. 2026 Mar 17. pii: S1383-5742(26)00003-7. [Epub ahead of print]797 108587

Mitochondrial DNA: Bridging cellular senescence and chronic inflammation in aging and beyond.

Shimeng Wang, Fanglong Wu, Hongmei Zhou.

  Aging is a progressive and irreversible physiological process driven by a complex network of interrelated molecular and cellular mechanisms. Among these, cellular senescence and chronic inflammation, as two core hallmarks of aging, are interlinked and jointly promote the development and progression of aging. However, the precise molecular crosstalk between these two processes remains unclarified. Mitochondrial DNA (mtDNA), as the only cytoplasmic DNA, has recently emerged as a pivotal "bridge" linking cellular senescence and chronic inflammation through various mechanisms. Anchored on the unique characteristics of mtDNA, this review systematically elucidates its central roles in mitochondrial dysfunction and oxidative stress, with a particular emphasis on the dynamic changes of mtDNA within the cytosol and extracellular space that construct and amplify the cellular "inflammation-senescence" coupling network. Furthermore, we propose a conceptual framework linking mtDNA mutation/damage to the cellular senescence and the propagation of chronic inflammation. Finally, we discuss the therapeutic potential of targeting mtDNA dynamics and highlight key challenges and future directions in this emerging field, offering novel insights for mitigating aging and age-related diseases.

Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Mitochondrial DNA; Therapeutic intervention

DOI:  https://doi.org/10.1016/j.mrrev.2026.108587
Int J Mol Med. 2026 May;pii: 134. [Epub ahead of print]57(5):

ZEB1 maintains mitochondrial fission and macrophage efferocytosis by restraining MFN2, thereby limiting inflammation and improving tendon‑bone healing.

Yan Zhao, Yuankai Zhang, Tian Lei, Shangqing Zhang, Kai Nan, Xin Zhang, Li-Hong Fan.

  Excessive inflammation and scar formation at the tendon‑bone interface (TBI) hinder effective healing. Macrophage efferocytosis is critical for resolving inflammation, yet its regulatory mechanisms in TBI healing remain unclear. The present study investigated the role of zinc finger E‑box binding homeobox 1 (ZEB1) in macrophage efferocytosis and rotator cuff repair. Zeb1 knockdown in rats was achieved using short hairpin RNA (shRNA). Bone marrow‑derived macrophages co‑cultured with apoptotic Jurkat cells were used to evaluate efferocytosis efficiency. Mechanistically, ZEB1 was demonstrated to function as a critical regulator of mitochondrial dynamics by transcriptionally repressing Mitofusin‑2 (MFN2), thereby maintaining the mitochondrial fission necessary for efficient efferocytosis. ZEB1‑knockdown relieved MFN2 suppression, leading to excessive mitochondrial fusion and a subsequent decrease in apoptotic cell clearance. In vivo, ZEB1 deficiency resulted in the accumulation of secondary necrotic cells, aggravated the inflammatory microenvironment (increased M1/decreased M2 polarization), and impaired histological and biomechanical healing of the tendon‑bone interface. These findings indicate a novel ZEB1/MFN2/mitochondrial fission axis that governs macrophage efferocytosis. Targeting this axis to restore the immune microenvironment offers a potential therapeutic strategy for improving tendon‑bone healing.

Keywords:  ZEB1; efferocytosis; inflammatory microenvironment; rotator cuff injury; tendon and bone healing

DOI:  https://doi.org/10.3892/ijmm.2026.5805
J Hepatol. 2026 Mar 18. pii: S0168-8278(26)00137-6. [Epub ahead of print]

IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration.

Taofei Zeng, Yabin Huang, Hao He, Jiuxiang Chang, Shengwei Tao, Zihao Liu, Rick Francis Thorne, Weiqiao Chen, Kejia Liu, Xuedan Sun, Lianxin Liu, Dalong Yin.

   BACKGROUND & AIMS: Liver regeneration is a tightly regulated process requiring coordinated interactions between hepatocytes and non-parenchymal cells; however, its molecular mechanisms remain incompletely defined. Here, we aimed to investigate the role of interferon-related developmental regulator 1 (IFRD1) in regulating metabolic-immune crosstalk during liver regeneration.
METHODS: We integrated public transcriptomic datasets, human liver disease samples, and multiple in-house-generated experimental models to characterize the dynamic expression of IFRD1 during liver regeneration. Genetic loss-of-function approaches, including global and cell type-specific knockout mice, together with adeno-associated virus-mediated gain-of-function strategies, were combined with single-nucleus RNA-seq, ATAC-seq, metabolic and biochemical assays, protein interaction analyses, and in vivo rescue experiments to elucidate the underlying mechanisms and clinical relevance.
RESULTS: Hepatocyte IFRD1 was rapidly induced during the early phase of liver regeneration in mice but markedly diminished in human chronic liver disease. Hepatocyte-specific loss of IFRD1 impaired liver repair and regeneration, whereas IFRD1 overexpression enhanced regenerative responses across multiple models, including partial hepatectomy, toxic liver injury, and hepatic ischemia-reperfusion injury. Mechanistically, IFRD1 was required to sustain hepatocyte β-oxidation and mitochondrial ATP production by stabilizing SLC25A5 through competition with the E3 ubiquitin ligase TRIM21. This ATP boost enables chromatin remodeling in hepatocytes, promoting CCL/CXC chemokine expression to recruit CCR2+ monocytes and expand the regenerative GPNMB+ macrophage pool. Notably, IFRD1 overexpression restored liver regenerative capacity after partial hepatectomy in mice with metabolic dysfunction-associated steatohepatitis or DEN-induced liver fibrosis.
CONCLUSIONS: Our findings define IFRD1 as a key immunometabolic regulator of liver regeneration, mediating hepatocyte metabolic control to macrophage-driven regenerative responses, and support the therapeutic potential of targeting IFRD1 to enhance regenerative capacity in liver disease.
IMPACT AND IMPLICATIONS: Liver regeneration is essential for recovery from surgical resection and acute injury, yet therapeutic options to enhance this process remain limited. Our study identifies the IFRD1-SLC25A5-ATP axis as a critical regulator that coordinates hepatocyte energy metabolism with expansion of pro-regenerative macrophage pool. This previously unrecognized regulatory node provides a scientific rationale for developing therapeutic strategies that enhance IFRD1 function to accelerate liver repair. Although limitations remain, such as undefined upstream regulators of IFRD1, these findings provide a foundation for developing improved therapies for patients with compromised regenerative capacity.

Keywords:  APAP; GPNMB; Hepatectomy; Hepatic ischemia–reperfusion injury; Hepatocytes; IFRD1; Lipid associated macrophages; Liver injury; Liver regeneration; Metabolism; Monocyte-Derived Macrophages

DOI:  https://doi.org/10.1016/j.jhep.2026.03.012
Inflamm Res. 2026 Mar 21. pii: 66. [Epub ahead of print]75(1):

Balancing inflammation and regeneration: immune cell dynamics in nerve repair: a comprehensive review.

Anam Anjum, Yogeswaran Lokanathan.

   BACKGROUND: Nerve injuries initiate a complex immune response that is crucial for triggering repairprocesses but can also exacerbate tissue damage if dysregulated. A tightly regulated balancebetween pro-inflammatory and anti-inflammatory signals is essential for optimal nerveregeneration, as excessive or prolonged inflammation can impede repair, while insufficientimmune activation may delay debris clearance and regeneration.
PURPOSE: This review aims to examine the roles of key immune cells, including macrophages,neutrophils, T cells, and B cells exert diverse roles in this process, orchestrating the inflammatoryenvironment and promoting tissue remodeling. Central to their function is metabolicreprogramming, which dictates immune cell activation, phenotype, and regenerative capacity.
METHOD: Relevant literature on immune responses and metabolic regulation in nerve injury wasanalyzed to explore how shifts between glycolysis, oxidative phosphorylation, and fatty acidoxidation govern the balance between inflammatory and reparative states. Macrophages displayremarkable functional plasticity, transitioning from pro-inflammatory (M1-like) to proregenerative(M2-like) phenotypes in response to metabolic and microenvironmental cues.Emerging therapeutic strategies aim to harness this immune-metabolic plasticity to improveoutcomes after nerve injury.
RESULTS: Evidence suggests that metabolic reprogramming is a critical determinant of immune cellbehavior in nerve repair. Interventions such as small-molecule modulators, metabolicglycoengineering, and targeted delivery systems are being explored to fine-tune immune cellmetabolism and restore inflammatory balance. However, challenges remain in achieving cell-typespecificity, managing the intricacies of the immune milieu, and ensuring safe and effective clinicaltranslation. This review examines the cellular and metabolic mechanisms underlying immunemediatednerve repair, highlights the critical importance of inflammatory balance in determiningregenerative outcomes, and discusses promising metabolic targets and therapeutic approaches.
CONCLUSION: Understanding the interplay between immune responses and cellular metabolismoffers promising opportunities to enhance nerve regeneration. Advances in immunometabolismmay facilitate the development of precision therapeutic strategies aimed at optimizinginflammatory balance and improving functional recovery following nerve injury.

Keywords:  Immune cells; and metabolic glycoengineering; glucose metabolism; inflammation; macrophage polarization; nerve regeneration; neurodegeneration; tissue repair

DOI:  https://doi.org/10.1007/s00011-026-02207-8
Genome Biol Evol. 2026 Mar 16. pii: evag067. [Epub ahead of print]

Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.

Jess E Sterling, Kendra D Zwonitzer, Justin C Havird.

  Why do some species live for mere months, while others persist for centuries? A leading explanation implicates mitochondria. The mitochondrial theory of aging predicts that mitochondrial efficiency diminishes with age due to the accumulation of mutations within mitochondrial DNA (mtDNA). While experimental evidence for this theory is mixed, evolutionary analyses offer an ideal opportunity to determine if mitochondrial substitution rates are linked to longevity. Here, we explored the relationship between mtDNA evolution and species' lifespans across four clades-Aves, Actinopterygii, Bivalvia, and Sebastidae-using five normalization strategies. Across most methods, long-lived vertebrates showed reduced synonymous and nonsynonymous substitution rates, suggesting lower mtDNA mutation. However, we found that the strength and direction of these relationships varied drastically depending on the normalization approach used (i.e., correcting for divergence, generation time, and phylogeny). We also analyzed mtDNA mutation spectra and found similar patterns in long- and short-lived species, suggesting decreased rates of mtDNA mutations in long-lived species are not due to suppression of specific mutation processes, as predicted from the free-radical theory of aging. We also find little evidence for a relationship between selection on mitochondrial protein-coding genes and lifespan. Our results align with the idea that decreased mutation rates may help preserve mitochondrial integrity in long-lived vertebrate species, but that these species have not been selected to have particularly efficient OXPHOS or protection against a specific mitochondrial mutation process. Together, these findings underscore the critical link between mitochondrial stability and lifespan, and highlight the power of natural systems in this field.

Keywords:  Mitochondrial DNA; comparative genomics; generation time; longevity; phylogenetic comparative methods; substitution rates

DOI:  https://doi.org/10.1093/gbe/evag067
Free Radic Biol Med. 2026 Mar 13. pii: S0891-5849(26)00234-0. [Epub ahead of print]249 393-408

27-Hydroxycholesterol inhibits muscle cell viability via mitochondrial dysfunction: Protective role of ROS-induced HIF-1α.

Bakhovuddin Azamov, Wan-Seog Shim, Chanhee Lee, Yeowon Kang, Yuna Jo, Vinoth Kumar Rethineswaran, Shakhnoza Muradillaeva, Seonghwan Hwang, Seungjin Ryu, Sun Sik Bae, Jae Ho Kim, Hyo Youl Moon, Chihong Song, Jin-Hong Shin, Changwan Hong, Kwang Min Lee, Parkyong Song.

  The oxysterol 27-hydroxycholesterol (27OHC), which is widely distributed in various tissues and circulation, plays a notable role in pathological processes, such as including breast cancer, atherosclerosis, and neurodegenerative diseases. Although these processes are closely linked to muscle pathophysiology, the effects of 27OHC on metabolic changes associated with muscular atrophy and sarcopenia remain poorly understood. In this study, we demonstrated that 27OHC decreased skeletal muscle viability by activating pro-apoptotic signaling pathways. RNA sequencing revealed that 767 and 989 genes were upregulated and downregulated, respectively, in 27OHC-treated myoblasts. Upregulated genes were associated with hypoxia-inducible factor 1-alpha response, whereas downregulated genes were commonly involved in the phosphoinositide 3-kinase pathway and muscle differentiation process. Myoblast cell death induced by 27OHC was mediated by generation of reactive oxygen species followed by mitochondrial morphological impairments and disruption of mitochondrial membrane potential (ΔΨm). Moreover, 27OHC reduced mitochondrial gene expression via glycogen synthase kinase-3 beta activation, ultimately leading to increased mitochondrial ROS. Concurrently, hypoxia-inducible factor 1-alpha induction upon 27OHC exposure activated cellular defense mechanisms to mitigate oxidative damage. In addition, a significant reduction was observed in the expression of genes involved in myotube differentiation and fusion index following 27OHC treatment, and hypoxia-inducible factor 1-alpha knockdown further aggravated the impairment of tube formation. Furthermore, mice treated with 27OHC exhibited reduced exercise endurance, decreased muscle cross-sectional area, and impaired muscle recovery following barium chloride-induced injury. As plasma levels of 27OHC are increased in elderly individuals, our findings suggest that pharmacological inhibition of 27OHC generation could be a therapeutic strategy to treat age-related muscle atrophy.

Keywords:  27-Hydroxycholesterol; Exercise performance; Mitochondrial abnormality; Muscle atrophy; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.043
J Clin Invest. 2026 Mar 17. pii: e197183. [Epub ahead of print]

m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria.

Sun Liu, Qihuan Ren, Guiling Mo, Zengguang Li, Huili Huang, Yuhao Zhou, Ziteng Miao, Xin Cao, Bilian Wu, Zhuoyu Xiao, Shihui Yu, Guangjin Wu, Linjian Xia, Jinru Cui, Junyuan Mo, Yuan Li, Laixin Xia, Juan Shen, Shan Xiao.

  Despite substantial progress in understanding the molecular pathology of Parkinson's disease (PD), the underlying drivers of PD in many cases remain unknown. Here we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from PD patients. We find preferential m6A deposition on transcripts of PD risk genes and a previously unreported heterozygous METTL3 p.K480R mutation in PD patients. Mettl3K480R/+ mice exhibit progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupts mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impairs m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop and alleviates parkinsonism in mouse models. Our findings reveal m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.

Keywords:  Genetics; Mitochondria; Neuroscience; Parkinson disease; RNA processing

DOI:  https://doi.org/10.1172/JCI197183