bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–12–07
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
  2. Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
  3. Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
  4. Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.
  5. Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
  6. Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
  7. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  8. Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.
  9. Slirp2 modulates oogenesis via regulating mitochondrial protein translation.
  10. Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
  11. Mitochondrial Disease Diagnosed Following Preterm Birth at 29 Weeks of Gestation and Postpartum Heart Failure: A Case Report and Literature Review.
  12. Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
  13. Precision rewriting of muscle genetics: therapeutic horizons of base and prime editing in skeletal muscle disorders.
  14. Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
  15. Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
  16. Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
  17. The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.
  18. A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.
  19. Critical role of mitochondrial aconitase in skeletal muscle maturation.
  20. Blockade of mitochondrial components release by exosome pathway promotes the pathogenesis of Fuchs endothelial corneal dystrophy.
  1. J Clin Invest. 2025 Dec 01. pii: e187571. [Epub ahead of print]135(23):
    Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
    Laura Sánchez-Benito, Melania González-Torres, Irene Fernández-González, Laura Cutando, María Royo, Joan Compte, Miquel Vila, Sandra Jurado, Elisenda Sanz, Albert Quintana.
      Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.
    Keywords:  Epilepsy; Inflammation; Mitochondria; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/JCI187571
  2. Nat Commun. 2025 Nov 29.
    Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
    Carla Pernaci, Avalon Johnson, Sydney Gillette, Anna S Warden, Chad McCormick, Sammy Weiser-Novak, Gabriela Ramirez, Emily H Broersma, Priyanka Mishra, Anusha Sivakumar, Stephanie Cherqui, Nicole G Coufal.
      Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.
    DOI:  https://doi.org/10.1038/s41467-025-66710-y
  3. Mol Cell Biochem. 2025 Dec 01.
    Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
    Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.
      The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.
    Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s11010-025-05441-6
  4. Nat Commun. 2025 Dec 04. 16(1): 10891
    Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.
    Yi Wang, Min Zhao, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Lu-Xin Qie, Na-Hui Liu, Jia-Qi Chen, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu-Lin Jiang.
      Mutations in mitochondrial DNA (mtDNA) lead to various mitochondrial diseases for which no cure is currently available. Despite the promising potential of mtDNA correction to treat these disorders, the double mitochondrial membranes have proven to be a tough barrier to overcome. Here, we develop fluorinated lipid nanoparticles with a mitochondrial targeting sequence (F-M-LNP) to overcome the mitochondrial barrier by virtue of their high affinity for mitochondrial membranes, thereby effectively introducing gene into mitochondria. Through the rational design of ionizable lipid structures, we synthesize 16 lipid nanoparticles (LNPs) with varying degrees of fluorination and investigate the key structural features required for efficient mitochondria-targeted gene delivery. As fluorinated ionizable lipid-mediated mitochondrial transport is independent of mitochondrial membrane potential (MMP), F-M-LNPs deliver gene to mitochondria under pathological conditions where MMP is impaired, resulting in a 3.8-fold increase in functional protein expression compared to non-fluorinated LNPs. In a male mouse model of genetically induced mitochondrial disease, F-M-LNP demonstrate functional complementation of mutant mtDNA, alleviating disease symptoms. Together, our results show that modifying vectors with fluorinated groups offers valuable tools for correcting mitochondrial genome defects.
    DOI:  https://doi.org/10.1038/s41467-025-65874-x
  5. Nat Commun. 2025 Dec 01. 16(1): 10817
    Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
    Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
      Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1038/s41467-025-66900-8
  6. PLoS Genet. 2025 Dec 03. 21(12): e1011562
    Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
    Qin Xie, Haibo Wu, Jiaxin Qiu, Junbo Liu, Xueyi Jiang, Huihui Wu, Qifeng Lyu, Hui Long, Wenzhi Li, Shuo Zhang, Yuxiao Zhou, Yining Gao, Aaron J W Hsueh, Yanping Kuang, Lun Suo.
      Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that purifying selection acts against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G > A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed a transgenerational reduction of the mutant mtDNA. Utilizing a mouse follicle culture system in which pathogenic mtDNA mutations were introduced in vitro, followed by mtDNA sequencing and digital PCR, we found that the germline heteroplasmy shift during early folliculogenesis was driven by a decrease in mutant mtDNA along with compensatory replication of wild-type mtDNA. In contrast, synonymous mtDNA mutations did not affect mtDNA dynamics. These findings demonstrate that mice can eliminate certain pathogenic mtDNA mutations in the germline during early folliculogenesis, thus advancing our understanding of mtDNA purifying selection during oogenesis. Furthermore, our use of mtDNA editing in in vitro-cultured follicles provides a novel approach to create and monitor mitochondrial DNA mutations.
    DOI:  https://doi.org/10.1371/journal.pgen.1011562
  7. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
  8. Eur J Pharmacol. 2025 Dec 03. pii: S0014-2999(25)01187-2. [Epub ahead of print] 178433
    Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.
    Xihang Piao, Xiaolei Tang, Li Li, Ying Zhang, Haiyan Li.
      Stroke remains a leading cause of death and long-term disability worldwide. Although revascularization therapies have transformed acute care, effective neuroprotective strategies are still lacking. Intercellular mitochondrial transfer has recently gained attention as a promising endogenous repair mechanism. Through tunneling nanotubes, extracellular vesicles, or cell fusion, healthy mitochondria can be transferred from donor to recipient cells, helping restore bioenergetic homeostasis in injured neurons. This phenomenon, functionally comparable to organelle-level metabolic rescue, offers several advantages. It avoids the ethical concerns associated with genetic manipulation, leverages intrinsic intercellular communication for targeted delivery, and provides mitochondrial DNA complementation to correct metabolic defects. Here, we integrate current evidence on the cellular sources, transfer routes, and regulatory mechanisms underlying poststroke mitochondrial exchange; delineate the coordinated contributions of astrocytes, mesenchymal stem cells, microglia, and endothelial cells to this process; and critically evaluate its translational promise alongside the key barriers that must be addressed for successful clinical application.
    Keywords:  Mitochondrial transfer; multicellular cooperation; stroke; therapeutic strategies; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178433
  9. J Mol Cell Biol. 2025 Dec 02. pii: mjaf047. [Epub ahead of print]
    Slirp2 modulates oogenesis via regulating mitochondrial protein translation.
    Jinguo Cao, Jiting Zhang, Zhaoqi Wu, Wei Luan, Yue Zhou, Huihui Huang, Lingling Li, Wen Hu.
      Mitochondria are essential organelles responsible for generating ATP through oxidative phosphorylation (OXPHOS). Despite having their own genome, mitochondria rely on a complex interplay with nuclear-encoded proteins to maintain their function, as mutations in these proteins can lead to mitochondrial dysfunction and associated diseases. Mutations in the SLIRP (stem-loop interacting RNA-binding protein) gene are known to cause severe human mitochondrial diseases, and loss of SLIRP function can impair mitochondrial mRNA stability and translation. However, in vivo roles of the SLIRP protein remain inadequately understood. Drosophila melanogaster serves as a powerful model for studying mitochondrial function, particularly in the context of reproductive system development and gametogenesis. In this study, we focus on the role of the fly Slirp2 in oogenesis. Loss of Slirp2 impairs mitochondrial protein synthesis, leading to reduced OXPHOS efficiency, diminished ATP production, and disrupted insulin/mTOR signaling. These defects ultimately promote reactive oxygen species-induced programmed cell death, resulting in infertility. Our findings provide novel insights into the mechanistic role of Slirp2 in mitochondrial function and reproductive biology in vivo. We demonstrate that Slirp2 exhibits species-specific regulation of mitochondrial translation, revealing its complex, context-dependent function. These results have broader implications for understanding mitochondrial diseases, suggesting that the effects of Slirp2 mutations may vary across different organisms and tissue types.
    Keywords:  SLIRP; Slirp2; mitochondrial diseases; oogenesis
    DOI:  https://doi.org/10.1093/jmcb/mjaf047
  10. Nat Commun. 2025 Dec 01. 16(1): 10426
    Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
    Su Bin Lee, Bui Thanh Thu, Tae Wook Nam, Yaechan Song, Jae Hoon Lee, Yangsik Jeong, Han-Woong Lee.
      Brown adipocytes facilitate non-shivering thermogenesis, which is critical for maintaining energy balance and heat production in response to environmental stimuli. Here, we delineate the physiological and biochemical role of etoposide-induced 2.4 (Ei24) in adenosine triphosphate (ATP) production and thermogenesis in brown adipocytes. We generated Ei24 adipocyte-specific knockout (EiaKO) mice that exhibited brown adipose tissue hypertrophy, lipid accumulation, and various mitochondrial abnormalities. Despite mitochondrial defects, uncoupling protein 1 (UCP1) expression and activity remained unchanged. However, those impairments caused lethal hypothermia in mice subjected to cold challenge, underscoring the key role of Ei24 in mitochondrial functions. Mechanistically, Ei24 deficiency disrupted cristae structure, dissipated mitochondrial membrane potential, and reduced matrix pH, leading to severe ATP depletion. We further identify the C-terminal region of Ei24 as essential for supporting ATP synthase function. Those bioenergetic defects not only destabilized the mitochondrial environment necessary for efficient UCP1-mediated thermogenesis, but also impaired ATP-dependent futile cycles such as SERCA-mediated calcium cycling and creatine substrate cycling. Together, our findings indicate that Ei24 functions as a thermogenic regulator that ensures mitochondrial ATP synthesis and structural integrity, enabling both coupled and uncoupled respiration in brown adipose tissue.
    DOI:  https://doi.org/10.1038/s41467-025-66460-x
  11. Clin Case Rep. 2025 Dec;13(12): e71532
    Mitochondrial Disease Diagnosed Following Preterm Birth at 29 Weeks of Gestation and Postpartum Heart Failure: A Case Report and Literature Review.
    Tomoyuki Watanabe, Gen Ishikawa, Tsutomu Tabata.
      In some cases, mitochondrial disease can remain undiagnosed until pregnancy reveals systemic symptoms. Clinicians should therefore consider this diagnosis in young patients presenting with diabetes, kidney disease, and hearing loss. Early diagnosis can improve maternal and fetal outcomes, particularly in high-risk pregnancies complicated by unexplained preterm birth or cardiomyopathy.
    Keywords:  diabetes mellitus; mitochondrial DNA; mitochondrial diseases; pregnancy; premature birth
    DOI:  https://doi.org/10.1002/ccr3.71532
  12. Nat Metab. 2025 Dec 03.
    Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
    Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
    DOI:  https://doi.org/10.1038/s42255-025-01412-9
  13. Gene Ther. 2025 Dec 04.
    Precision rewriting of muscle genetics: therapeutic horizons of base and prime editing in skeletal muscle disorders.
    Selin Saydam, Pervin Dinçer.
      Base Editing (BE) and Prime Editing (PE), novel precision tools of the CRISPR/Cas toolbox, have emerged as transformative technologies that enable highly specific genetic modifications. Their compatibility with post-mitotic cell types makes them invaluable for treating genetic skeletal muscle disorders. Despite their severity and progressive nature, monogenic muscle diseases remain without definitive treatments. They are caused by diverse mutations in critical muscle proteins, for which gene editing offers a promising therapeutic avenue. However, traditional CRISPR/Cas9 applications face challenges such as genotoxicity and inefficiency in post-mitotic tissues. BE and PE technologies overcome these limitations by enabling safe and efficient modifications without causing double-strand breaks or requiring homology-directed repair. Their therapeutic potential comes from two key features: their ability to work in non-dividing cells such as myotubes and cardiomyocytes, and their capacity to target a broad range of mutations found in genetic muscle diseases. In this review, we explore mechanisms of BE and PE and summarize their current applications in monogenic skeletal muscle disorders. We discuss the challenges of in vivo application in skeletal muscle and highlight innovations to bypass them. Collectively, both systems offer flexible precision solutions with immense potential for mutation-specific and personalized gene therapy approaches for monogenic skeletal muscle disorders.
    DOI:  https://doi.org/10.1038/s41434-025-00574-1
  14. Nat Commun. 2025 Dec 04. 16(1): 10898
    Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
    Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.
      T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.
    DOI:  https://doi.org/10.1038/s41467-025-65910-w
  15. Nat Commun. 2025 Dec 02.
    Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group
      We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
    DOI:  https://doi.org/10.1038/s41467-025-65845-2
  16. Mol Metab. 2025 Nov 29. pii: S2212-8778(25)00201-7. [Epub ahead of print] 102294
    Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
    Dipsikha Biswas, Ever Espino-Gonzalez, Danial Ahwazi, Jordana B Freemantle, Amy M Ehrlich, Charline Jomard, Jonas Brorson, Agnete N Schou, Jean Farup, Julien Gondin, Jesper Just, Marc Foretz, Jonas T Treebak, Marianne Agerholm, Kei Sakamoto.
       OBJECTIVE: Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
    METHODS: Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1-/-/γ3-/-) and single knockout (imγ1-/- and imγ3-/-) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
    RESULTS: snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1-/-/γ3-/- muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3-/-, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1-/- mice.
    CONCLUSIONS: While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
    Keywords:  AICAR; AMP-activated protein kinase; MK-8722; Single nucleus RNA sequencing; glucose uptake
    DOI:  https://doi.org/10.1016/j.molmet.2025.102294
  17. Front Endocrinol (Lausanne). 2025 ;16 1645711
    The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.
    Huiyi Zhao, Ying Wang, Han Han, Yue Jiang, Xiang Ji, Yuehui Zhang.
      Mitophagy is a catabolic mechanism that selectively degrades damaged mitochondria and precisely modulates mitochondrial content, thereby maintaining intracellular homeostasis under stress conditions. To date, most reviews on mitophagy have predominantly focused on neurodegenerative diseases, cardiovascular disorders, cancer, metabolic syndromes, and inflammation- or immune-related diseases. In recent years, accumulating evidence has highlighted the critical involvement of mitophagy in various physiological and pathological processes associated with female reproduction. This review systematically synthesizes existing evidence to elucidate the regulatory roles of mitophagy during the occurrence and development of follicles, oocyte fertilization, and embryo implantation, as well as its essential contributions to the pathogenesis of endometriosis, polycystic ovary syndrome, primary ovarian insufficiency, and ovarian aging. Furthermore, we outline current therapeutic strategies targeting mitophagy while emphasizing the potential value of traditional Chinese medicine. Our aim is to provide novel insights into the regulatory network and specific targets of mitophagy in female reproduction, facilitate clinical translation, and offer innovative approaches for managing female reproductive health.
    Keywords:  female reproductive; female reproductive dysfunction; mitochondrial function; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3389/fendo.2025.1645711
  18. Nat Commun. 2025 Dec 02.
    A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.
    Yingying Zhang, Brianna Watson, Ajitanuj Rattan, Tyrone Lee, Smriti Chawla, Ludwig Geistlinger, Yilin Guan, Finley B Lord, Minghe Ma, Takashi Miwa, Madhu Golla, Barbara J Caldarone, Wen-Chao Song, Jeffrey R Moffitt, Michael C Carroll.
      Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from late embryonic stage to adulthood. Here we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency alters molecular structure of the brain and causes working spatial memory defects, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity.
    DOI:  https://doi.org/10.1038/s41467-025-66048-5
  19. Sci Rep. 2025 Dec 02. 15(1): 42957
    Critical role of mitochondrial aconitase in skeletal muscle maturation.
    Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Md Mizanur Rahman, Anayt Ulla, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi, Takeshi Nikawa.
      Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.
    Keywords:  Aconitase 2-knockout mice; Apoptosis; Mitochondrial dysfunction; Sarcomere disruption; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-025-25560-w
  20. Cell Death Discov. 2025 Dec 02.
    Blockade of mitochondrial components release by exosome pathway promotes the pathogenesis of Fuchs endothelial corneal dystrophy.
    Can Zhao, Qun Wang, Qingjun Zhou, Zhiqing Wang, Shuangqing Yao, Tian Sang, Haoyun Duan, Jingyi Wu, Xiaowei Zhong, Xin Sui, Weiyun Shi, Ting Wang.
      Fuchs endothelial corneal dystrophy (FECD) is the leading indication of corneal transplantation worldwide and the focus of pathogenesis has been on the corneal endothelium. Instead of cellular analysis, we aimed to identify the protein changes of aqueous humor (AH) in patients with FECD and investigate in more detail the relationship between AH and corneal endothelium. We collected 13 AH samples of 7 early/middle stage FECD patients and 6 control patients during routine cataract surgery. The proteomes of AH were profiled with the 4D label-free quantitative tandem mass spectrometry. Among 1613 identified proteins, 44 proteins exhibited above two-fold upregulation in the AH of FECD patients than control patients. Gene ontology (GO) analysis showed the enrichment of mitochondrial components, which were further validated by ELISA of mitochondrial proteins SLC25A3, PC, and PARK7. Moreover, immunofluorescence staining and ultrastructural observation were conducted in clinical specimens, mouse corneal endothelium and cultured human corneal endothelial cells (HCECs). The mitochondrial protein TOM20 was reduced in the FECD corneal endothelium, accompanied by damaged mitochondrial ejection. We next isolated extracellular vesicles by ultracentrifugation from HCECs and revealed that the mitochondria copy numbers were significantly increased in UVA-irradiated cells. Inhibition of exosome biogenesis aggravated cell death and mitochondrial membrane potential impairment in FECD endothelial cells. Taken together, our results provided novel insights into the proteome characterization of the AH from FECD patients and offered new perspective to deepen the impaired mitochondrial quality control in the pathogenesis of FECD.
    DOI:  https://doi.org/10.1038/s41420-025-02881-3
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