bims-mihora 2025-12-21 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–12–21
twenty-six papers selected by
Lisa Patel, Istesso

EVs from Stem Cells Improve Mitochondrial Dysfunction in Neuronal Disorders.
Mitochondria to the rescue: organelle trafficking in renal health and disease.
USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.
The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer.
ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.
Mechano-metabolic dysregulation in osteoarthritis: Piezo1-mediated mitophagy impairment as a novel therapeutic target.
Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.
Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.
A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.
Aagab-driven SHIP2 degradation rescues mitochondrial dysfunction in hypoxic-ischemic encephalopathy.
Multidimensional study on mitochondrial dysfunction in pulmonary hypertension.
Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing.
The impact of cellular senescence on aging skeletal muscle.
Imperfect Repair in Aging: Senescent Cells and the Hepatic Fibrotic Niche.
Bone marrow mesenchymal stem cell-derived exosomes improve pyroptosis and mitochondrial integrity through miR-515-5p-mediated TLR4/NLRP3/GSDMD axis in rheumatoid arthritis.
Extracellular vesicles in osteoimmunomodulation: Orchestrating immune-driven bone regeneration.
Adipocyte Extracellular Vesicle Mitochondrial Cargo is Linked to Cardiomyocyte Dysfunction in Type 2 Diabetes-Related Heart Failure with Preserved Ejection Fraction.
Modulation of mitochondrial voltage dependent anion channel: studies on bilayer electrophysiology.
The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
Revisiting ROS: duality in organ aging progression.
A Tetrahedral DNA Framework-Based Mitochondrial Anchoring System Promotes Diabetic Wound Healing via Mitophagy and Mitostress Regulation.
Mitochondrial RNA cytosolic leakage drives the SASP.
The Role of Mitochondrial Regulation in Macrophage Polarization: Implications for the Pathogenesis of Rheumatoid Arthritis.
3,3'-Diindolylmethane ameliorate obesity-related skeletal muscle atrophy via regulating mitochondrial function.
Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.

Mol Neurobiol. 2025 Dec 19. 63(1): 313

EVs from Stem Cells Improve Mitochondrial Dysfunction in Neuronal Disorders.

Sadaf Jahan, Dipak Kumar, Shaheen Ali, Arif Jamal Siddiqui, Mohammed Alaidarous, Johra Khan, Andleeb Khan.

  Mitochondrial dysfunction is a critical pathological trait of numerous neurodegenerative and inflammatory central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Cellular stressors can directly modulate mitochondrial metabolism and increase the production of reactive oxygen species (ROS), thereby triggering mitochondrial retrograde signaling that alters nuclear gene expression and promotes the release of deleterious signal components into the cytoplasm. These processes contribute to neuronal injury and the progression of disease pathology. Emerging evidence underlines the therapeutic potential of extracellular vesicles (EVs) derived from stem cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in reversing mitochondrial dysfunction. These nanoscale vesicles, which encapsulate transcription factors, nucleic acids, proteins, lipids, and even mitochondria, facilitate intercellular communication and influence the biological behaviour of recipient cells. Notably, stem cell-derived EVs have been shown to enhance mitochondrial function by improving the maximal oxygen consumption rate and spare respiratory capacity in injured neuronal cells. The molecular cargo within EVs, including miR-21, miR-29, and antioxidant enzymes, has been implicated in regulating mitochondrial biogenesis, reducing oxidative stress, and modulating pathways associated with apoptosis, mitophagy, and energy metabolism. Importantly, EVs can cross the blood-brain barrier (BBB), offering a minimally invasive strategy for targeted CNS delivery. In conclusion, stem cell-derived EVs represent a promising, cell-free therapeutic approach to restoring mitochondrial homeostasis and preventing neuronal disorders.

Keywords:  Extracellular vesicles; Mitochondrial dysfunction; Neurodegeneration; Neuronal disorders; Oxidative stress; Stem cells

DOI:  https://doi.org/10.1007/s12035-025-05623-9
Nephron. 2025 Dec 19. 1-18

Mitochondria to the rescue: organelle trafficking in renal health and disease.

Luca Perico, Giuseppe Remuzzi, Ariela Benigni.

BACKGROUND: Mitochondria are central regulators of cellular metabolism, redox signaling, and apoptosis. Their dysfunction plays a pivotal role in the pathogenesis of kidney diseases, including acute kidney injury and diabetic nephropathy.
SUMMARY: Recent advances have unveiled horizontal mitochondrial transfer as a novel intercellular communication by which renal cells exchange mitochondria to promote tissue repair through the modulation of metabolic processes, oxidative stress, apoptosis, and fibrosis.
KEY FINDINGS: Horizontal mitochondrial transfer, mediated by tunneling nanotubes and extracellular vesicles, has emerged as a potential homotypic rescue mechanism between injured tubular and glomerular cells. In addition, heterotypic mitochondrial transfer from mesenchymal stromal cells to renal cells has been described. These findings open new perspectives for exploring therapeutic mitochondrial transplantation in both acute and chronic kidney diseases. Nonetheless, significant challenges remain, including elucidating the poorly characterized biological mechanisms underlying mitochondrial transfer, optimizing delivery strategies, and defining the long-term safety and efficacy of mitochondrial-based therapies.

DOI: https://doi.org/10.1159/000550092
Exp Brain Res. 2025 Dec 16. 244(1): 13

USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.

Xianhai Fang, Yujing Fan, Nan Liu, Shaopeng Huang.

  Deubiquitinating enzymes of the ubiquitin-specific peptidase (USP) family have been increasingly recognized for their roles in modulating neuropathic pain. In this study, bioinformatic analysis identified USP19 as a downregulated gene in trigeminal neuralgia (TN). Using a mouse model of TN induced by foramen lacerum impingement of the trigeminal nerve (FLIT), we demonstrated that adeno-associated virus-mediated overexpression of USP19 in the cerebral cortex significantly alleviated anxiety-like and pain-like behaviors. USP19 overexpression promoted deubiquitination and stabilization of fused in sarcoma (FUS), as confirmed by Western blotting, actinomycin D treatment, and ubiquitination assays. In HT22 and SH-SY5Y cells exposed to lipopolysaccharide to induce mitochondrial dysfunction, USP19 restored mitochondrial membrane potential, reduced mitochondrial reactive oxygen species, suppressed DRP1 phosphorylation, and upregulated CYTB and ND4 levels. These effects were reversed by FUS knockdown, both in vitro and in vivo. Moreover, FUS silencing abolished USP19-mediated improvements in NAD⁺/NADH ratio and mitochondrial function, as well as its analgesic and anxiolytic benefits in TN mice. These findings suggest that USP19 alleviates TN by enhancing FUS deubiquitination and preserving mitochondrial integrity in neurons. This study reveals a novel USP19/FUS signaling axis in the regulation of mitochondrial homeostasis and provides a promising therapeutic target for the treatment of TN.

Keywords:  Fused in sarcoma; Mitochondrial dysfunction; Neuron; Trigeminal neuralgia; Ubiquitin-specific peptidase 19

DOI:  https://doi.org/10.1007/s00221-025-07210-9
Nat Commun. 2025 Dec 14.

The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.

Ina Kirmes, Grace Ching Ching Hung, Anne Hahn, Chuan-Yang Dai, Daniel Campbell, Arnaud Ahier, Rachel Shin Yie Lee, Alexander Palmer, Steven Zuryn.

Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPRmt). Indirectly, miR-71 also reduces the levels of multiple neuro- and insulin-like peptides and their secretion machinery, resulting in decreased cell-non-autonomous signaling of mitochondrial stress from muscle to glia cells. miR-71 therefore beneficially coordinates the suppression of both local and systemic mitochondrial stress pathways during severe organelle dysfunction. These findings open the possibility that metabolic disorders could be ameliorated by limiting the overactivation of mitochondrial stress responses through targeted small RNAs.

DOI: https://doi.org/10.1038/s41467-025-67198-2
Exp Mol Med. 2025 Dec 17.

Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer.

Jiayuan Lin, Huayun Han, Kexin Wu, Xingyu Wu, Juwen Shen, Yiqing Mo, Qiansen Zhang, Huaiyu Yang, Zhihua Yu.

Hyperphosphorylated tau aggregation and neuroinflammation are hallmark pathologies of Alzheimer's disease (AD), with microglia playing a critical role in modulating these processes through maintaining immune homeostasis and clearing pathological tau, both of which depend on mitochondrial health. However, the mechanisms underlying microglial mitochondrial dysfunction in AD remain poorly understood, limiting therapeutic development. Hydrogen voltage-gated channel 1 (Hv1), expressed in microglia within the central nervous system, regulates intracellular pH and reactive oxygen species generation. Here we observe that Hv1 is upregulated in activated microglia in AD mouse models. Remarkably, Hv1 contributes to electron transport chain abnormalities, leading to mitochondrial oxidative stress, loss of mitochondrial membrane potential, impaired ATP production and deficient mitophagy in tau pathology. These deficits impair tau clearance through phagocytosis and autophagy but can be significantly reversed by the Hv1-specific inhibitor YHV98-4. Furthermore, YHV98-4 enhances microglia-to-neuron mitochondrial transfer, promoting the delivery of functional mitochondria to rescue neuronal damage and improve cognitive function. Collectively, our study underscores the pivotal role of Hv1 in microglial mitochondrial dysfunction in AD and identifies YHV98-4 as a promising therapeutic candidate.

DOI: https://doi.org/10.1038/s12276-025-01593-z
Mol Neurobiol. 2025 Dec 16. 63(1): 303

ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.

Jasleen Kaur, Saba Naqvi.

  Parkinson's disease (PD) is a neurodegenerative condition marked by significant motor impairments, resulting from extensive loss of dopaminergic neurons and abnormal protein aggregation. One of the early features of PD is disrupted mitochondrial dynamics, which arises from imbalances in cellular energy regulation. Therapeutic strategies that mitigate the mitochondrial dysfunction and enhance mitochondrial performance offer neuroprotection in PD. To delve into the role of mitochondrial function, we employed the synthetic PGC-1α activator ZLN005 to improve PD outcomes. In cellular PD model, we performed western blotting and immunofluorescence assays to assess disease-specific markers, including tyrosine hydroxylase and proteins related to mitochondrial biogenesis and regulation. Mitochondrial function was further evaluated using MitoTracker and ROS detection. We further investigated ZLN005 in a sub-acute MPTP mouse model. Motor performance was assessed, and subsequently, molecular analyses were conducted. Our findings revealed that ZLN005 significantly reduced MPP+/MPTP-induced neurotoxicity, improved motor deficits, and maintained the expression of PGC-1α, tyrosine hydroxylase, and other key mitochondrial markers involved in DNA replication and mitophagy. Notably, proteins that enhance PGC-1α transcription, including SIRT1, were also upregulated. In addition, the expression of mitochondrial fusion proteins increased, a pattern supported by elevated levels of other transcriptional regulators. Imaging and flow cytometry further confirmed that PGC-1α activation improved mitochondrial integrity and reduced oxidative stress. These results provide preliminary insights into the potential therapeutic role of PGC-1α activator in PD. ZLN005 has a neuroprotective effect in PD, which is elaborated by PGC-1α activator regulating the mitochondrial quality control system.

Keywords:  Mitochondrial biogenesis; Mitophagy; PGC-1α activator; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-025-05612-y
Inflamm Res. 2025 Dec 18. 75(1): 6

Mechano-metabolic dysregulation in osteoarthritis: Piezo1-mediated mitophagy impairment as a novel therapeutic target.

DuJiang Yang, Lin Yang, Wenhhao Yang, Junjie Chen, Shuang Wang, Jiexiang Yang, GuoYou Wang.

The recent study by Yu et al. (2025) elucidates a critical mechanism linking mechanical stress to mitochondrial dysfunction in osteoarthritis (OA), demonstrating that Piezo1 activation is associated with impaired PINK1/Parkin-mediated mitophagy, leading to chondrocyte injury and cartilage degradation. While this work significantly advances our understanding of OA pathogenesis by integrating biomechanical and bioenergetic perspectives, key aspects require further exploration. Specifically, the downstream signaling mechanisms mediated by calcium influx, the potential role of reactive oxygen species (ROS) and inflammasome activation, and alternative therapeutic strategies beyond Piezo1 inhibition warrant deeper investigation. This commentary highlights these avenues for future research and emphasizes the importance of targeting mitochondrial quality control as a promising approach for OA therapy.

DOI: https://doi.org/10.1007/s00011-025-02161-x
Cell Biochem Funct. 2025 Dec;43(12): e70151

Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.

Rodrigo Prieto-Carrasco, Susana Aideé González-Chávez, Eduardo Chaparro-Barrera, Mario Loya-Rivera, Belén Cuevas-López, Fernando E García-Arroyo, Omar Emiliano Aparicio-Trejo, César Pacheco-Tena.

  Joint inflammation and structural damage in spondyloarthritis (SpA) are not fully explained by known immune mechanisms. While mitochondrial dysfunction has been implicated in other rheumatic diseases, such as rheumatoid arthritis and lupus, its role in SpA remains poorly understood. Male DBA/1 mice with spontaneous arthritis (SpAD) and healthy BALB/c mice were compared to assess mitochondrial alterations in joint tissues, isolated mitochondria and cultured fibroblast-like synoviocytes (FLS). Analyses focused on mitochondrial dynamics (fission and fusion) and turnover (biogenesis and mitophagy), bioenergetic function, oxidative stress, and transcriptomic changes associated with mitochondrial function. SpAD induced a coordinated mitochondrial dysfunction in joint tissues characterized by increased fission (Drp1), reduced fusion (Mfn2), and dysregulated turnover processes with elevated mitophagy (PINK1) and biogenesis (PGC-1α). This imbalance led to dysregulation mitochondrial complexes activity, reduced ATP production, and a pronounced increase in oxidative stress. The latter was evidenced by decreased catalase and glutathione peroxidase (Gpx) activity, elevated superoxide dismutase (SOD) activity, and accumulation of 4 hydroxynonenal (4-HNE), highlighting a shift toward a chronic pro-oxidative environment. Similar gene expression changes were observed in cultured FLS. Transcriptomic analysis identified 6,673 differentially expressed genes, including 139 related to mitochondrial function, which reinforces the central role of mitochondrial dysregulation in SpAD pathophysiology. This study is the first to comprehensively characterize mitochondrial dysfunction in a murine model of SpA, identifying it as a potential driver of joint damage. Targeting mitochondrial pathways may offer novel strategies for disease modification in spondyloarthritis.

Keywords:  DBA/1 mice; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial turnover; oxidative stress; spondyloarthritis

DOI:  https://doi.org/10.1002/cbf.70151
Cold Spring Harb Perspect Biol. 2025 Dec 19. pii: a041773. [Epub ahead of print]

Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.

David R Eberhardt, Dipayan Chaudhuri.

Calcium (Ca2+) is vital in hepatocyte metabolism and plays a dual role in liver mitochondrial function: Physiological Ca2+ stimulates respiration and mitochondrial dynamics-processes crucial for proper metabolic functioning. However, Ca2+ overload can be catastrophic, leading to mitochondrial dysfunction and the halt of metabolic processes. This dichotomy plays out in liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic liver disease (ALD), where excess lipid and alcohol, respectively, result in pathological changes in this precarious Ca2+ balance, impairing liver function and contributing to liver failure. In this review, we discuss the complex processes of Ca2+ signaling in hepatic mitochondria and how these processes are altered or fail in liver disease states.

DOI: https://doi.org/10.1101/cshperspect.a041773
Cells Dev. 2025 Dec 11. pii: S2667-2901(25)00070-1. [Epub ahead of print]185 204063

A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.

Xin Tao, Suhong Zhang, Yue Li, Gongbing Tu, Dianfu Zhang, Liping Yin.

  Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.

Keywords:  MEF2A; Mitochondrial biogenesis; Myogenic differentiation; PGC-1α/NRF2; Sarcopenia

DOI:  https://doi.org/10.1016/j.cdev.2025.204063
Mitochondrion. 2025 Dec 16. pii: S1567-7249(25)00106-0. [Epub ahead of print] 102109

Aagab-driven SHIP2 degradation rescues mitochondrial dysfunction in hypoxic-ischemic encephalopathy.

Jinli Han, Lu He, Ling Chen, Bin Wen, Jinglu Ji.

  Neonatal hypoxic-ischemic encephalopathy (HIE), a central nervous system disorder caused by oxygen deprivation and reduced cerebral blood flow, involves complex mechanisms including mitochondrial oxidative stress and neuronal injury. The Rab-like GTPase domain-containing protein Aagab has been linked to neuronal regulation by modulating neural precursor cell expressed, developmentally down-regulated protein 4-1 (NEDD4-1)-mediated ubiquitination and degradation of Src homology 2 domain-containing inositol 5-phosphatase 2 (SHIP2). In this study, we investigated the contribution of the Aagab-NEDD4-1-SHIP2 axis to hypoxic-ischemic encephalopathy (HIE) and its influence on mitochondrial oxidative stress. Multi-omics analyses of publicly available RNA sequencing and proteomic datasets from HIE and control rat brain tissues identified SHIP2 as a significantly upregulated gene strongly associated with oxidative stress pathways. In an oxygen-glucose deprivation (OGD) neuronal model, lentiviral knockdown of SHIP2 enhanced neuronal viability, reduced reactive oxygen species production, and restored mitochondrial membrane potential. In vivo, tail-vein delivery of lentiviral vectors to silence SHIP2 in neonatal rat HIE models led to marked improvements in neurological outcomes, including reduced escape latency in the Morris water maze, increased success rates in the ladder-rung test, and diminished brain lesion area. Mechanistic assays demonstrated that Aagab overexpression increased NEDD4-1 levels, promoted SHIP2 ubiquitination, and accelerated its degradation, whereas NEDD4-1 knockdown reversed these effects. Collectively, these findings indicate that Aagab facilitates NEDD4-1-mediated SHIP2 ubiquitination and degradation, thereby alleviating mitochondrial oxidative stress and mitigating HIE-associated neuronal injury. The Aagab-NEDD4-1-SHIP2 regulatory axis may represent a promising molecular target for therapeutic intervention in HIE.

Keywords:  Aagab; Mitochondrial oxidative stress; NEDD4-1; Neonatal hypoxic-ischemic encephalopathy; SH2-containing inositol 5-phosphatase 2

DOI:  https://doi.org/10.1016/j.mito.2025.102109
Front Med (Lausanne). 2025 ;12 1716485

Multidimensional study on mitochondrial dysfunction in pulmonary hypertension.

Xuntao Yuan, Yutao Zhang, Yuyan Liu, Xiao Guo, Shuying Jia, Xingquan Xiong, Xiuying Sun, Zian Jin.

  Pulmonary hypertension (PH), as a complex clinical syndrome, can be caused by multiple pathophysiological factors. Its characteristics are similar to hemodynamic abnormalities, significant increase of pulmonary artery pressure, contraction and remodeling of blood vessels, which eventually lead to serious complications such as increased pulmonary vascular resistance, hypertrophy of the right ventricle, and heart failure. The etiology of PH is multifaceted and highly variable, with a common pathological basis primarily characterized by mitochondrial dysfunction. Endothelial cell dysfunction, which directly impacts metabolism and function, is closely associated with PH and other lung diseases, making mitochondrial dysfunction the cornerstone of this condition. The therapy for PH primarily focuses on relaxing pulmonary blood vessels. However, existing vasodilation approaches struggle to effectively reverse the observed vascular remodeling process, which limits further therapeutic enhancement. Moreover, mitochondrial dysfunction represents a promising new direction of significant research in the treatment of PH. This review systematically combs the key molecular mechanisms of mitochondrial dysfunction in the pathological process of PH. The study focuses on multi-channel pathogenic mechanisms, including mitochondrial DNA (mtDNA) damage, electron transfer chain (ETC) dysfunction, protein homeostasis imbalance, defects in mitochondrial biogenesis, dynamic abnormality, and autophagy defect. Furthermore, this review summarizes recent research advancements targeting mitochondrial dysfunction as a potential intervention strategy for clinical treatment of PH. By integrating updated findings on molecular mechanisms with insights from existing literature, the study provides a comprehensive understanding of mitochondrial dysfunction's role in PH pathogenesis and offers actionable evidence for developing novel therapeutic approaches.

Keywords:  mitochondrial dysfunction; oxidative stress; pulmonary hypertension; pulmonaryvascular remodeling; research progress

DOI:  https://doi.org/10.3389/fmed.2025.1716485
Chem Biol Interact. 2025 Dec 15. pii: S0009-2797(25)00513-7. [Epub ahead of print] 111883

Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing.

Dinara Afrose, Sofía Alfonso-Sánchez, Ashleigh Philp, Philip M Hansbro, Qian Peter Su, Lana McClements.

  Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D in vitro model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclamptic conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), and inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 hours with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM). Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (mfn1), fission (dnm1l), and autophagy (atg5, map1lc3b). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p<0.0001), increasing circularity (p<0.0001), and decreasing mitochondrial number per cell (p<0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized mfn1 (p=0.04) and atg5 expression (p<0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p<0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration (p=0.03). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.

Keywords:  Autophagy; Mitochondrial dynamics; Mitochondrial dysfunction; Preeclampsia; Trophoblasts

DOI:  https://doi.org/10.1016/j.cbi.2025.111883
Front Cell Dev Biol. 2025 ;13 1719279

The impact of cellular senescence on aging skeletal muscle.

Michael Kamal, Ryan Bevington, Amanda Johnson, Gianni Parise.

  Skeletal muscle is a highly plastic tissue that relies on its resident muscle stem cell population, known as satellite cells (MuSC), for its timely repair and regeneration. During aging, there is a decline in muscle regenerative capacity that is largely attributed to the loss of MuSC content and function. These aberrations are thought to contribute to the aging-related decline in skeletal muscle mass and strength. Cellular senescence, which is characterized by a state of irreversible cell cycle arrest and the presence of a senescence-associated secretory phenotype (SASP), has emerged as a potential factor in the dysfunction of MuSCs with aging. Much effort has recently been made to examine the detrimental effects of senescence on skeletal muscle as well as identify therapeutic approaches to selectively eliminate these cells and improve the aging phenotype. Here, we discuss the current understanding of aging-related MuSC impairments and the underlying mechanisms that link cellular senescence to the decline in muscle regenerative capacity.

Keywords:  SASP; aging; cellular senescence; regeneration; satellite cells; senolytics; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2025.1719279
BMB Rep. 2025 Dec 18. pii: 6700. [Epub ahead of print]

Imperfect Repair in Aging: Senescent Cells and the Hepatic Fibrotic Niche.

Juyeon Kim, Minseong Kim, Chuna Kim.

Aging proceeds in a nonuniform spatiotemporal manner across tissues. While metabolic stress and chronic inflammation are implicated, the underlying mechanisms remain elusive. Here, we propose that imperfect wound healing-a failure of full resolution-creates and sustains pathological niches that drive progressive age-related dysfunction. Using the liver as a model system, we deconstruct this 'imperfect repair'. We posit that it is driven by a pro-fibrotic, non-resolving microenvironment sustained by complex crosstalk between functionally heterogeneous senescent cells and non-senescent scar-associated cell (SAC) populations (including macrophages, endothelial cells (ECs), and hepatic stellate cells (HSCs)). This pathological ecosystem is further shaped by the spatial context of hepatic zonation collapse, and the dysregulation of core signaling hubs, like WNT, Transforming Growth Factor (TGF)-β, and YAP and TAZ (YAP/TAZ). Viewing aging through the lens of imperfect repair provides a unifying framework linking senescence, inflammation, and fibrosis. This perspective shifts the therapeutic paradigm from targeting single senescent cells toward engineering the pathological niche itself, and redirects focus from end-stage disease, to the sub-clinical, spatial origins of tissue vulnerability.
Arthritis Res Ther. 2025 Dec 15. 27(1): 226

Bone marrow mesenchymal stem cell-derived exosomes improve pyroptosis and mitochondrial integrity through miR-515-5p-mediated TLR4/NLRP3/GSDMD axis in rheumatoid arthritis.

Dongfeng Cai, Chao Zhong, Zixiao Yang, Jimo Li, Song Hong.

   BACKGROUND: Bone marrow mesenchymal stem cell (BMSC) therapy can significantly improve the outcomes of rheumatoid arthritis (RA). This study explores the protective role of BMSC-derived exosomes (BMSCs-Exos) in RA through modulation of pyroptosis and mitochondrial integrity via the microRNA (miR)-515-5p/Toll-like receptor 4 (TLR4)/NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) pathway.
METHODS: Exosomes were isolated from rat BMSCs, with or without miR-515-5p transfection. Exosomes were identified and analyzed through transmission electron microscopy, tunable resistive pulse sensing, and protein profiling via Western blot analysis. An in vitro RA model was established by stimulating RA fibroblast-like synoviocytes (RA-FLSs) with interleukin-1β (IL-1β). Co-culture of RA-FLSs with miR-515-5p-enriched BMSCs-Exos was used to evaluate inflammation, extracellular matrix (ECM) adhesion, migration, and invasion. Dual-luciferase reporter and RNA immunoprecipitation assays were performed to validate the targeting relationship between miR-515-5p and TLR4. Pyroptosis, reactive oxygen species (ROS) generation, and mitochondrial function were assessed. In vivo effects were confirmed using the collagen-induced arthritis (CIA) rat model.
RESULTS: In RA-FLSs, BMSCs-Exos suppressed ECM adhesion, migration, and invasion, and attenuated IL-1β-induced inflammation through the TLR4/NLRP3/GSDMD pathway. BMSCs-Exos inhibited pyroptosis and improved mitochondrial function. Inhibition of miR-515-5p reduced cell viability, caused morphological changes, elevated cytosolic calcium (Ca²⁺), and increased mitochondrial ROS, activating caspase-dependent apoptosis and TLR4/NLRP3/GSDMD-mediated pyroptosis. In CIA rats, BMSCs-Exo treatment significantly alleviated joint damage, reduced pro-inflammatory cytokines, and protected against bone erosion.
CONCLUSION: BMSCs-Exos ameliorate RA progression by secreting miR-515-5p, which targets the TLR4/NLRP3/GSDMD pathway, thereby inhibiting pyroptosis and preserving mitochondrial homeostasis in RA-FLSs.

Keywords:  Bone marrow mesenchymal stem cell-derived exosomes; Fibroblast-like synoviocytes; MiR-515-5p; Mitochondria; NLRP3; Pyroptosis; Rheumatoid arthritis

DOI:  https://doi.org/10.1186/s13075-025-03679-5
Int J Biol Macromol. 2025 Dec 12. pii: S0141-8130(25)10171-2. [Epub ahead of print]338(Pt 1): 149614

Extracellular vesicles in osteoimmunomodulation: Orchestrating immune-driven bone regeneration.

Femke Pol, Alessia Longoni, Riccardo Levato, Debby Gawlitta, Kenny Man.

  Large bone fractures pose a substantial challenge to orthopedists and place a significant burden on patients and healthcare systems, necessitating innovative therapeutic strategies. Modulating the interactions between the immune and skeletal systems within the bone microenvironment offers a promising avenue. The immune system plays a role in regulating bone homeostasis and healing, and conversely, skeletal cells influence immune responses. Maintaining a balanced relationship between immune and bone cells is critical for successful fracture repair, as its disruption can lead to excessive inflammation and impaired bone healing. Extracellular vesicles (EVs) are key mediators of the intercellular communication occurring during bone fracture healing, playing a vital role in modulating the immune response. They influence inflammation, regulate immune cell function, and mediate the interactions between immune and bone cells. This review explores the role of immune cells in bone regeneration, with a particular focus on the immunomodulatory function of EVs during fracture repair. Furthermore, it highlights recent advancements in bioengineering approaches aimed at accelerating the translation of EVs for bone repair. Taken together, osteoimmunomodulatory EVs hold immense promise to fundamentally transform regenerative orthopedics, establishing them as the smart, nanotherapeutic frontier capable of turning chronic non-unions into predictable healing outcomes.

Keywords:  Bioengineering; Bone fracture; Exosomes; Extracellular vesicles; Immune response; Osteoimmunomodulation; Regenerative medicine

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149614
Free Radic Biol Med. 2025 Dec 15. pii: S0891-5849(25)01432-7. [Epub ahead of print]

Adipocyte Extracellular Vesicle Mitochondrial Cargo is Linked to Cardiomyocyte Dysfunction in Type 2 Diabetes-Related Heart Failure with Preserved Ejection Fraction.

Haibin Ji, Tian Cao, Zixuan Tan, Rui Zheng, Jinhui Bian, Wenfeng Lin, Chunze Yuan, Yongfeng Shao, Hongyan Li, Junjie Du.

  Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent in type 2 diabetes (T2D), yet disease-modifying therapies remain limited. Here we identify an adipose-cardiac communication axis in which stressed adipocytes export extracellular vesicles (AdEVs) laden with oxidatively damaged mitochondrial proteins that are associated with impaired cardiomyocyte bioenergetics and increased apoptosis. Single-nucleus RNA-seq of human subcutaneous adipose tissue from patients with T2D-HFpEF revealed metabolic stress in adipocytes, characterized by enriched mitochondrial oxidative stress genes and reduced metabolic flux. The severely affected AD3 subpopulation exhibits mitochondrial impairments, potentially accompanied by increased AdEV release. In parallel, circulating AdEVs were elevated and their mitochondrial cargo showed greater oxidative modification; AdEV abundance tracked systemic protein carbonyls and clinical markers of cardiac load. In vitro, lipotoxic adipocytes released AdEVs enriched for mitochondrial components with increased protein carbonylation. When applied to human cardiomyocytes (AC16 and human induced pluripotent stem cell-derived cardiomyocytes), these AdEVs increased reactive oxygen species (ROS), dissipated mitochondrial membrane potential, fragmented mitochondrial networks, reduced oxygen consumption and ATP production, and activated intrinsic apoptosis and heart-failure marker expression. Inhibition of EV biogenesis (GW4869) or scavenging of mitochondrial ROS (Mito-TEMPO) blunted these effects. Collectively, our data support a model in which oxidatively modified mitochondrial cargo within AdEVs links adipose stress to cardiomyocyte dysfunction in T2D-HFpEF and suggest that AdEV release and mitochondrial ROS may represent tractable therapeutic targets.

Keywords:  Heart failure with preserved ejection fraction; adipocyte-derived extracellular vesicles; adipose single-nucleus profiling,cardiomyocytes; apoptosis; intercellular signaling; mitochondrial dysfunction; oxidative stress; type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.016
Front Physiol. 2025 ;16 1666994

Modulation of mitochondrial voltage dependent anion channel: studies on bilayer electrophysiology.

Daniel Tuikhang Koren, Chetan Malik, Shumaila Iqbal Siddiqui, Rajan Shrivastava, Subhendu Ghosh.

  The present paper is a review of the mitochondrial Voltage Dependent Anion Channel (VDAC), popularly known as mitochondrial porin, which is a protein that forms a passive diffusion ion channel across the outer membrane of the mitochondrion. VDAC essentially plays an important role in the transport of metabolites like ATP between the intermembrane space of the mitochondrion and the cytoplasm. However, under certain conditions, it can give rise to cellular dysfunction, e.g., apoptosis. Although VDAC is present in all eukaryotic cells, this review has focused mainly on the animal tissues. Interactions of VDAC with various enzymes, proteins, and small molecules or ligands have been reviewed with a perspective of bilayer electrophysiology. Importantly, the biochemical (post-translational) modifications of the channel protein, namely, phosphorylation (by a series of kinases), acetylation, ubiquitination, oxidative modifications (such as glutathionylation and nitrosylation), etc., and their impact on the electrophysiological properties have been discussed. Finally, the consequences of the above-mentioned experimental findings have been discussed with predictions and hypotheses relevant to living systems.

Keywords:  apoptosis; bilayer electrophysiology; ligand interactions; mitochondrial dysfunction; oxidative stress; post-translational modifications; protein phosphorylation; voltage-dependent anion channel (VDAC)

DOI:  https://doi.org/10.3389/fphys.2025.1666994
Nat Cell Biol. 2025 Dec 19.

The G3BP stress-granule proteins reinforce the integrated stress response translation programme.

Jarrett Smith, David P Bartel.

When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.

DOI: https://doi.org/10.1038/s41556-025-01834-3
Mol Biol Rep. 2025 Dec 15. 53(1): 202

Revisiting ROS: duality in organ aging progression.

Mohan Yu, Shiyi Liu, Chenxin Zhang, Wen Yang.

  The functions of multiple organs decline with the process of aging. Revealing the intrinsic mechanisms governing organ degeneration is a critical pursuit for understanding the aging process and creating interventions for aging-related diseases. Macromolecular damage caused by the generation of reactive oxygen species (ROS) increases with the process of aging. However, excessive ROS generation may only partially account for aging at the individual and organ levels. In contrast, they could serve as important signaling molecules in stress responses. In this review, we focused on the dual role of ROS in the aging processes of several human organ systems. Through this investigation, we aim to reassess the relationship between ROS and aging.

Keywords:  Aging intervention; Aging-related diseases; Organ aging; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1007/s11033-025-11342-0
ACS Appl Mater Interfaces. 2025 Dec 17.

A Tetrahedral DNA Framework-Based Mitochondrial Anchoring System Promotes Diabetic Wound Healing via Mitophagy and Mitostress Regulation.

Yangxue Yao, Tianxu Zhang, Yibo Li, Geru Zhang, Yang Gao, Yunfeng Lin, Shaojingya Gao, Xiaoxiao Cai.

  The dysfunction of mitochondria is a prominent factor of the inflammatory microenvironment that delays diabetic wound healing. However, existing methods have limitations of inadequate regulation of mitochondrial function. Herein, a tetrahedral DNA framework-based mitochondrial anchoring system was constructed to regulate mitophagy and mitostress in diabetic wounds. This system, which is fabricated based on tetrahedral framework nucleic acids (tFNAs), is covalently linked with Rhodamine 19 to further load resveratrol, realizing the mitochondria-targeted delivery of resveratrol and sustained drug release. It can activate superoxide dismutase (SOD) to effectively scavenge mitochondrial ROS and promote mitophagy to eliminate damaged mitochondria, thus rescuing cell viability under oxidative stress, promoting cell migration, and upregulating angiogenesis and extracellular matrix-related proteins. In a diabetic skin defect model, TRh-RSV markedly accelerates wound healing by enhancing the regeneration of connective tissues and skin appendages and upregulating mitophagy. These effects are mediated through the suppression of mitochondrial oxidative stress and the concomitant modulation of mitophagy. This study highlights the potential of this system not only for the treatment of refractory diabetic wounds but also for other diseases associated with mitochondrial dysfunction.

Keywords:  diabetic wound healing; mitochondria; mitophagy; mitostress; resveratrol; tetrahedral framework nucleic acids

DOI:  https://doi.org/10.1021/acsami.5c19661
Nat Commun. 2025 Dec 15. 16(1): 10992

Mitochondrial RNA cytosolic leakage drives the SASP.

Stella Victorelli, Madeline Eppard, Hélène Martini, Seung-Hwa Woo, Stacia P A Everts, Gung Lee, Nicholas Pirius, Nuan Han, Eugene Y Liang, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Eva Nóvoa, Rubén Nogueiras, Patrick L Splinter, Steven P O'Hara, Olivia Morgenthaler, Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas F LaRusso, Petra Hirsova, João F Passos.

Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.

DOI: https://doi.org/10.1038/s41467-025-66159-z
J Inflamm Res. 2025 ;18 17163-17183

The Role of Mitochondrial Regulation in Macrophage Polarization: Implications for the Pathogenesis of Rheumatoid Arthritis.

Pingshun Li, Gang Wang, Zhihui Peng, Lihuan Zhang, Fang Yang, Yong Wei, Meihan Pan, Haohao Zang, Mengru Zhou.

  Rheumatoid arthritis (RA) is an autoimmune arthropathy closely associated with chronic inflammation, whose pathogenesis involves macrophages, particularly M1 macrophage-induced inflammatory responses. Mitochondria, as key organelles governing macrophage metabolism and function, regulate M1/M2 macrophage polarization through multiple pathways and signaling molecules, thereby inducing immune and inflammatory responses that contribute to RA development. Therefore, this paper delves into the intricate mechanisms by which mitochondria regulate macrophage-specific polarization. These pathways encompass metabolic processes, signaling molecules, mitochondrial dynamics, mitochondrial-associated molecules, mitochondrial autophagy, ion homeostasis, and mitochondrial translocation. The study underscores the pivotal role of mitochondria in macrophage-specific polarization and highlights the potential for basic research to intervene in RA by modulating Mitochondrial metabolism, mitochondrial dynamics, mitochondrial autophagy, and mitochondrial translocation to promote M1-to-M2 macrophage conversion and suppress RA inflammatory responses. This holds significant implications for repairing RA-induced bone destruction and advancing clinical treatment.

Keywords:  M1/M2 polarization; inflammatory response; macrophages; pathogenesis; rheumatoid arthritis

DOI:  https://doi.org/10.2147/JIR.S560635
J Nutr Biochem. 2025 Dec 15. pii: S0955-2863(25)00385-7. [Epub ahead of print] 110223

3,3'-Diindolylmethane ameliorate obesity-related skeletal muscle atrophy via regulating mitochondrial function.

Yuquan Zhong, Siyuan Chen, Jingyun Pan, Ruomei Niu, Junqiang Du, Qiuxia Dong, Yanxi Liu, Yilu Yao, Yunfeng Lin, Heng Fang, Jiewen Su, Xudong Li, Yan Zhang, Guangyu Yang, Jinyin Wu, Juntao Li, Weiwen Liu, Bing Huang, Jie Tang, Wei Zhu.

  Skeletal muscle is the primary storage and metabolic site for amino acids and proteins in the body, and its mass and function are affected by various pathological factors. Studies have shown that mitochondrial dysfunction is associated with skeletal muscle atrophy. Indole-3-carbinol (I3C) and its active metabolite 3,3'-Diindolylmethane (DIM) have bioactivities such as inhibiting fat formation, but it is unclear whether they can affect skeletal muscle atrophy in obesity by improving mitochondrial function. Our research found that high-fat factors can induce obesity-related skeletal muscle atrophy, characterized by decreased muscle mass and function, reduced mitochondrial number, and impaired function in muscle cells. DIM can improve obesity-related skeletal muscle atrophy caused by a high-fat diet, and the mechanism may be related to the regulation of AMPK/SIRT1/PGC-1α pathway protein expression and improved mitochondrial function in muscle cells.

Keywords:  3,3′-Diindolylmethane; High-fat diet; Mitochondrial dysfunction; Muscle atrophy; Obesity

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110223
Aging Dis. 2025 Dec 14.

Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.

Sen Huang, Ang Li, Yixia Ling, Xinyu Yang, Jiayu Wang, Jing Yuan, Dajiang Qin, Xiaoli Yao.

Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1G93A, TDP43A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.

DOI: https://doi.org/10.14336/AD.2025.1224