bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–09–27
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. The predicted interactome of the human mitochondrial proteome.
  2. Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
  3. Phosphodiesterase-5 inhibition as an off-label therapy in mitochondrial disease.
  4. Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
  5. Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
  6. Astrocyte Senescence Disrupts the Extracellular Mitochondrial Compartment and Compromises Bioenergetic Support to Human Neurons.
  7. A De Novo Gain-of-Function Variant of DNM1L Causes Developmental Encephalopathy.
  8. Metabolic regulation of oocyte maturation and early embryo development in mammals.
  9. β-hydroxy-β-methylbutyrate improves fast-twitch muscle function, histopathology and mitochondrial respiration in the D2.mdx dystrophic mouse.
  10. Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
  11. Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.
  12. Recent advances in mitochondrial fission and fusion in diabetic cardiomyopathy.
  13. Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
  14. Additive protection of transcranial direct current stimulation and mitochondrial transplantation on ischemic stroke via inducing A2 astrocytes.
  15. Curating the Fetal Genome: Experience of the ClinGen Prenatal Gene Curation Expert Panel (GCEP).
  16. Genetic dissection of one-carbon metabolism: Roles in pluripotency and embryonic development.
  1. Nat Commun. 2026 Aug 25. pii: 10162. [Epub ahead of print]17(1):
    The predicted interactome of the human mitochondrial proteome.
    Abhinav B Swaminathan, Mohammad Zulkifli, Rachel M Guerra, Sofia M Calabrese, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Despite the fundamental importance of mitochondria in cellular metabolism, the molecular function(s) of many mitochondrial proteins remain unknown. Since protein function can be inferred from their interacting partners, we repurpose the protein structure prediction algorithm AlphaFold Multimer (AFM) as a classification model to predict protein-protein interactions of the entire human mitochondrial proteome. By screening 630,003 protein pairs, we create a compendium of 2,895 previously known and newly observed interactions, which include the interacting partner(s) of 85 uncharacterized mitochondrial proteins, thereby linking them to a known biochemical pathway. Extending the AFM-based analysis to 11 diverse eukaryotes identifies evolutionarily conserved interactions among human hits, including regulators of core bioenergetic pathways. Our experiments, guided by these predictions, nominate protein interactions that form the coenzyme Q metabolon and define the mitochondrial copper delivery pathway to cytochrome c oxidase. Our compendium represents a powerful resource for the systematic, structure-based functionalization of the human mitochondrial proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77112-z
  2. Int J Mol Sci. 2026 Sep 17. pii: 8270. [Epub ahead of print]27(18):
    Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
    Chung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Huang-Ying Huang, Hsiang-Yu Lin, Shuan-Pei Lin.
      Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
    Keywords:  Barth syndrome; Friedreich ataxia; cardiolipin; elamipretide; gene therapy; mitochondrial cardiomyopathy; mitochondrial quality control; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms27188270
  3. Mol Genet Metab. 2026 Sep 16. pii: S1096-7192(26)00544-5. [Epub ahead of print]149(3): 110261
    Phosphodiesterase-5 inhibition as an off-label therapy in mitochondrial disease.
    Ibrahim Elsharkawi, Graeme Preston, Tamas Kozicz, Eva Morava.
      
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110261
  4. Mol Neurobiol. 2026 Sep 21. pii: 912. [Epub ahead of print]63(1):
    Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
    Xing Wei, Fuxian Liu, Jingxi Yao, Peng Feng, Fuchun Xue, Zhenggang Shi.
      Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.
    Keywords:  Bioenergetics; Intercellular mitochondrial transfer; Mitochondrial extracellular vesicles; Neuroimmune interactions; Neuroinflammation; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/s12035-026-06224-w
  5. Aging Cell. 2026 Oct;25(10): e70720
    Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
    Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.
      Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.
    Keywords:  HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux
    DOI:  https://doi.org/10.1111/acel.70720
  6. Antioxidants (Basel). 2026 Sep 06. pii: 1127. [Epub ahead of print]15(9):
    Astrocyte Senescence Disrupts the Extracellular Mitochondrial Compartment and Compromises Bioenergetic Support to Human Neurons.
    Pedro Amorim, Lívia de Sá Hayashide, Vitor Emanuel Leocadio, Mariana Marques, Isabelle Navarra, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Rafael Serafim Pinto, Luan Pereira Diniz.
      Astrocyte senescence is a recognized feature of brain aging, but its impact on neuronal mitochondrial homeostasis remains poorly defined, particularly in human cells. Here we show that doxorubicin-induced senescence disrupts mitochondrial function in primary human astrocytes and compromises their capacity to sustain neuronal bioenergetics. Senescent astrocytes accumulated a denser population of smaller, ultrastructurally damaged mitochondria together with increased levels of fission, fusion and biogenesis-associated proteins. Despite this apparent expansion of the mitochondrial compartment, these cells displayed reduced mitochondrial membrane potential, intracellular ATP and cellular metabolic activity, indicating accumulation of a functionally impaired mitochondrial population. Senescence also remodeled the extracellular mitochondrial compartment: conditioned medium from senescent astrocytes contained fewer mitochondrial particles with lower membrane potential and reduced ATP. Functionally, conditioned medium from control astrocytes increased TOMM20 and PGC-1α levels in human postmitotic neurons, whereas medium from senescent astrocytes failed to elicit this response and instead promoted hydrogen peroxide accumulation, ATP depletion and reduced cellular metabolic activity in the absence of overt cytotoxicity. Neurons acquired an astrocyte-derived MitoTracker signal from both conditions. Our data indicate that factors released by senescent human astrocytes are sufficient to induce neuronal mitochondrial and redox dysfunction.
    Keywords:  astrocyte senescence; astrocyte–neuron communication; brain aging; doxorubicin; extracellular mitochondria; human astrocytes; mitochondrial dysfunction; neuronal bioenergetics; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15091127
  7. Eur J Med Genet. 2026 Sep 23. pii: S1769-7212(26)00040-6. [Epub ahead of print] 105106
    A De Novo Gain-of-Function Variant of DNM1L Causes Developmental Encephalopathy.
    Shangsheng Dong, Yanjuan Chen, Mengfang Yan, Xiaoli Huang, Qiannan Deng, Jianxiang Liao, Ke Zhang.
       BACKGROUND: Variants in the dynamin 1-like (DNM1L) gene, which encodes dynamin-related protein 1 (Drp1), can cause encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1) and optic atrophy 5 (OPA5), two neurodevelopmental disorders with distinct symptoms. Given the critical role of Drp1 in mitochondrial fission, it is believed that disrupted mitochondrial fission is key to EMPF1 and OPA5 pathogenesis. However, it is unclear whether other cellular defects also contribute to pathogenesis.
    RESULTS: Here, we report a novel DNM1L variant (c.1994+3T>G) in an EMPF1 patient with delayed psychomotor development, microcephaly, and hypotonia but without epilepsy. This de novo, heterozygous, and intronic variant causes the retention of a DNM1L intron, leading to an aberrant Drp1 protein with a gain of toxicity. Mechanistic studies suggested that the mutant Drp1 forms aggregates and disrupts mitochondrial morphology in cultured cells. Compared to expressing the mutant protein alone, co-expressing both wild-type and mutant Drp1 causes defects at a similar level, suggesting that the mutant Drp1 can confer toxicity to wild-type proteins.
    CONCLUSIONS: Combined, our findings broadened the spectrum of pathogenic DNM1L variants and suggested protein aggregation as a potentially novel pathogenic contributor.
    Keywords:  DNM1L; mitochondria; neurodevelopmental disorders; protein aggregate
    DOI:  https://doi.org/10.1016/j.ejmg.2026.105106
  8. Life Metab. 2026 Dec;5(6): loag024
    Metabolic regulation of oocyte maturation and early embryo development in mammals.
    Sifan Rong, Yixuan Fu, Yan Li, Yingxin Celia Jiang, Lanruo Chen, Yue Zhao, Wencheng Zhu, Liangshan Mu.
      Metabolism plays a central role in coordinating mammalian oocyte maturation and early embryonic development. The metabolic changes that occur during these stages are essential for the acquisition of developmental competence and successful reproduction. This review summarizes metabolic regulation from oocyte growth and maturation through fertilization and preimplantation development, with particular emphasis on glucose, lipid, and amino acid metabolism, as well as mitochondrial function. We also discuss how metabolic disturbances associated with maternal obesity, ovarian aging, and polyendocrine metabolic ovarian syndrome (formerly termed polycystic ovary syndrome) impair oocyte quality and embryonic developmental potential. By integrating recent insights from multi-omics, live-cell imaging, and genetic studies, we propose a framework for understanding how metabolism not only supports but also actively governs developmental decisions. We further discuss mechanism-based strategies to restore metabolic balance and improve reproductive outcomes.
    Keywords:  embryo metabolism; metabolic regulation; oocyte metabolism
    DOI:  https://doi.org/10.1093/lifemeta/loag024
  9. J Physiol. 2026 Sep 19.
    β-hydroxy-β-methylbutyrate improves fast-twitch muscle function, histopathology and mitochondrial respiration in the D2.mdx dystrophic mouse.
    Nicholas Giourmas, Hannah Lalunio, Memphis Calzoni, Ryan Bagaric, Craig A Goodman, Alan Hayes.
      Duchenne muscular dystrophy (DMD) is a severe inherited muscle disorder caused by mutations that eliminate the protein, dystrophin, resulting in disrupted protein homeostasis, mitochondrial dysfunction, chronic inflammation and progressive muscle degeneration. The leucine metabolite, β-hydroxy-β-methylbutyrate (HMB), has shown therapeutic potential in dystrophic muscle. We previously reported that HMB supplementation improves fast-twitch muscle histopathology and function in juvenile mdx mice during their peak damage phase (3-6 weeks). However, the mdx model exhibits a relatively mild pathology compared to human DMD, limiting clinical relevance. Here, we investigated 8 weeks of HMB supplementation (1 mg g-1 day-1 via drinking water) in the more severe D2.mdx mouse model at 3 and 6 months of age, representing skeletal muscle pathologies consistent with chronic inflammation and advanced muscle fibrosis, respectively. HMB-treated D2.mdx mice had improved grip strength compared to controls, whereas isolated fast-twitch extensor digitorum longus (EDL) muscles displayed increased fibre size, reduced tissue infiltrate and enhanced force production ex vivo. Mechanistically, HMB increased the phospho-to-total ratio of direct downstream mammalian target of rapamycin complex 1 (mTORC1) targets p70S6K1 and 4EBP1, consistent with enhanced anabolic signalling. Mitochondria assessed from treated flexor digitorum brevis muscles exhibited improved respiration and ATP production, with functional improvements aligning with elevated complex II succinate dehydrogenase activity in HMB-treated EDL muscles. By contrast, no significant HMB-induced effects were observed in the slow-twitch soleus muscle. This study is the first to demonstrate that HMB enhances in vivo and ex vivo muscle function, downstream mTORC1 signalling, and mitochondrial performance in the severe D2.mdx model, supporting its potential as a therapeutic strategy for DMD. KEY POINTS: β-Hydroxy-β-methylbutyrate (HMB) supplementation improves skeletal muscle function in the D2.mdx mouse model of Duchenne muscular dystrophy. HMB treatment increased voluntary grip strength and enhanced force production in isolated extensor digitorum longus extensor digitorum longus muscles in 3- and 6-month-old D2.mdx mice. Functional improvements were accompanied by reduced tissue infiltrate, increased mean muscle fibre size, and elevated succinate dehydrogenase activity. Τηεδδ adaptations coincided with increased markers of mammalian target of rapamycin complex 1 signalling, mitochondrial respiration and ATP production, suggesting improved metabolic capacity in dystrophic muscle.
    Keywords:  Duchenne muscular dystrophy; extensor digitorum longus; histopathology; mitochondria; β‐hydroxy‐β‐methylbutyrate
    DOI:  https://doi.org/10.1113/JP291639
  10. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2607452123
    Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
    Qing Li, Tong Shu, Chen Liu, Min Zheng, Yuanpei Li, Lei Zhang, Gao Fan, Wenbin Lu, Huiwen Zhang, Pingping Liu, Xiaoniu He, Hong Zheng, Wen Liu, Jing Ye, Zhenyu Yin, Xianming Deng, Chensong Zhang, Canhua Huang, Han You.
      PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD+ pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.
    Keywords:  PARPi resistance; de novo mitochondrial dTMP biosynthesis; mitochondrial NAD+ metabolism
    DOI:  https://doi.org/10.1073/pnas.2607452123
  11. Aging Cell. 2026 Oct;25(10): e70729
    Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.
    Yuyao Yin, Zijian Li.
      Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerotic cardio-cerebrovascular disease. The role of impaired mitochondrial dynamics in the pathophysiological process of aging-related diseases is being actively researched. We discovered that targeting proteins related to mitochondrial dynamics, especially those involved in fission and fusion, may offer new treatment strategies for these diseases. Various approaches, including aerobic interval and treadmill training and the use of drugs such as the antidiabetic agents metformin and dapagliflozin, the antihypertensive agent irbesartan, and certain traditional Chinese medicine components, have shown potential in alleviating imbalances in mitochondrial dynamics in aging-related cardio-cerebrovascular diseases. In this review, we systematically summarize recent research on alterations in mitochondrial dynamics in age-related cardio-cerebral diseases and explore therapeutic strategies targeting these alterations, which may offer new directions for improving cardiac and brain health and guiding clinical practice.
    Keywords:  age‐related disease; cardiovascular disease; fission and fusion; mitochondrial dynamics; neurodegenerative disease
    DOI:  https://doi.org/10.1111/acel.70729
  12. Front Cardiovasc Med. 2026 ;13 1897303
    Recent advances in mitochondrial fission and fusion in diabetic cardiomyopathy.
    Jinjin Hao, Xiaochen Zhang, Xueying Tian, Jingying Su.
      Diabetic cardiomyopathy (dCM) is characterized by myocardial dysfunction in diabetes and reflects interacting metabolic, redox, calcium, inflammatory, fibrotic, and microvascular disturbances. Mitochondrial fission and fusion are not merely morphological endpoints; when uncoupled from mitophagic clearance and cristae maintenance, they contribute to energetic failure and cell-specific cardiac injury. This review synthesizes evidence from human diabetic myocardium and dCM-specific experimental models, while distinguishing direct fission-fusion evidence from broader mitochondrial quality-control findings. We summarize how glucolipotoxicity, impaired energy sensing, calcium entry, mechanosensing, innate immunity, epitranscriptomic regulation, and ubiquitin editing converge on dynamin-related protein 1 (DRP1)/ fission 1 (FIS1)/ mitochondrial fission factor (MFF) and mitofusin 1 (MFN1)/ mitofusin 2 (MFN2)/ optic atrophy 1 (OPA1) pathways. We further compare consequences in cardiomyocytes, cardiac fibroblasts, and coronary microvascular endothelial cells, including ATP depletion, oxidative stress, regulated cell death, fibrosis, and perfusion injury. Candidate interventions are organized according to whether they restrain pathological fission, restore MFN/OPA1-dependent fusion, or normalize mitophagic flux. Despite strong cellular and rodent evidence, direct clinical validation and pharmacodynamic biomarkers remain limited. Future progress will require human myocardial phenotyping, single-cell and spatial analyses, in vivo measurement of mitochondrial dynamics, cell-selective delivery, and standardized flux-based endpoints. The therapeutic goal should be restoration of adaptive mitochondrial dynamics rather than indiscriminate inhibition of fission or promotion of fusion.
    Keywords:  diabetic cardiomyopathy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.3389/fcvm.2026.1897303
  13. Front Cell Dev Biol. 2026 ;14 1963467
    Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
    Xiaoqian Fu, Qianyi Huang, Huimei Wu, Lidan Liu.
      Mitochondrial Ca2+ homeostasis is a critical interface connecting ovarian cell signaling, energy metabolism, redox balance, and reproductive competence. Transient Ca2+ uptake into the mitochondrial matrix activates Ca2+-sensitive dehydrogenases, enhances reducing-equivalent generation, and supports oxidative phosphorylation. By contrast, sustained Ca2+ accumulation promotes reactive oxygen species production, membrane-potential collapse, mitochondrial permeability transition, and cell death. The identification of the mitochondrial calcium uniporter together with its regulators MICU1, MICU2, and EMRE, has established a molecular framework for mitochondrial Ca2+ influx. NCLX and its interacting protein TMEM65 contribute to Ca2+ efflux and determine recovery after individual Ca2+ transients. In ovarian cells and oocytes, endoplasmic reticulum (endoplasmic reticulum)-mitochondria contact sites, including the IP3R1-GRP75-VDAC1 axis, couple cytosolic Ca2+ signals to mitochondrial metabolism. Evidence from mouse, porcine, avian, zebrafish, Xenopus, and sea-urchin models implicates mitochondrial Ca2+ in follicular-cell survival, oocyte meiotic maturation, fertilization-associated Ca2+ oscillations, the oocyte-to-embryo transition, and early embryonic development. Obesity, aging, cryopreservation, heavy metals, environmental chemicals, and oxidative stress can disturb this system. However, mitochondrial Ca2+ dysregulation is not always readily separable from broader mitochondrial or ER dysfunction. Major limitations of the current literature include reliance on non-selective pharmacological agents, incomplete calibration of organelle-targeted indicators, insufficient temporal resolution, interspecies differences, and limited direct evidence from human oocytes. Future studies should integrate cell-type-specific genetic perturbation, quantitative multi-organelle Ca2+ imaging, mitochondrial bioenergetics, and long-term developmental assessment. Mitochondrial Ca2+ is a promising mechanistic node and candidate biomarker, but it is not yet a validated clinical target in reproductive medicine.
    Keywords:  ER-mitochondria contact; MCU; MICU1; NCLX; embryo development; fertilization; mitochondrial Ca2+; oocyte competence
    DOI:  https://doi.org/10.3389/fcell.2026.1963467
  14. Front Mol Neurosci. 2026 ;19 1855078
    Additive protection of transcranial direct current stimulation and mitochondrial transplantation on ischemic stroke via inducing A2 astrocytes.
    Yaomin Guo, En-Ming Kang, Min Li, Taozhi Wang, Zhongqing Sun, Yazhou Wang, Wen Jiang, Jiang Li.
       Introduction: Therapeutic options for the acute phase of ischemic stroke remain limited. Transcranial direct current stimulation (tDCS) and mitochondrial transplantation have emerged as promising neuroprotective approaches, but their individual efficacy is variable. We hypothesized that combining these two therapies would produce additive benefits for post-stroke recovery.
    Methods: Focal cortical ischemia was induced in mice using photothrombotic technique. Mice were randomly assigned to receive sham treatment, tDCS, mitochondrial transplantation, or combined treatment. Grid-walking, cylinder tests and 2,3,5-triphenyltetrazolium chloride staining were used to assess motor recovery and infarct volume, respectively. Immunofluorescence staining, and western blotting were performed to determine mitochondrial internalization and polarization of astrocytes in vivo and in vitro.
    Results: Combining tDCS with mitochondrial transplantation resulted in a significantly greater reduction in infarct volume and improvement in locomotor function compared to either treatment alone. Interestingly, tDCS specifically enhanced the uptake of exogenous mitochondria by astrocytes. This was associated with a significant increase in beneficial A2 astrocytes and decrease in detrimental A1 astrocytes. Mechanistically, the combined treatment led to a marked upregulation of CD38 in astrocytes, suggesting their involvement in the tDCS-facilitated mitochondrial endocytosis. Suppression of CD38 expression by short interfering RNA attenuated astrocyte mitochondrial endocytosis and A2 phenotype induced by tDCS.
    Conclusion: Our findings demonstrate that combining tDCS with mitochondrial transplantation conferred superior neuroprotection against ischemic brain damage than either treatment alone, and may represent a promising strategy for ischemic stroke treatment.
    Keywords:  astrocytes; endocytosis; ischemic stroke; mitochondria; tDCS; transplantation
    DOI:  https://doi.org/10.3389/fnmol.2026.1855078
  15. Prenat Diagn. 2026 Sep 23.
    Curating the Fetal Genome: Experience of the ClinGen Prenatal Gene Curation Expert Panel (GCEP).
    Prenatal GCEP Panel members
       OBJECTIVE: Expert prenatal focused gene-disease curation is necessary to accurately inform clinical care in the setting of rapidly expanding prenatal genomic sequencing.
    METHODS: An international Prenatal Gene Curation Expert Panel assembled and systematically reviewed genes asserted to be associated with prenatal hydrops, stillbirth, or severe anomalies using the ClinGen framework.
    RESULTS: The ClinGen Prenatal GCEP published evidence summaries for 63 disease relationships involving 61 genes with unique and clinically severe prenatally observed fetal phenotypes.
    CONCLUSION: The ClinGen Prenatal GCEP work addresses a gap in genomic medicine by deepening our understanding of lethal and severe prenatal phenotypes, while supporting accurate diagnosis, counseling, and future treatment strategies in prenatal care.
    DOI:  https://doi.org/10.1002/pd.70246
  16. Dev Biol. 2026 Sep 21. pii: S0012-1606(26)00203-4. [Epub ahead of print]540 83-93
    Genetic dissection of one-carbon metabolism: Roles in pluripotency and embryonic development.
    Hilda Lomelí.
      One-carbon (1C) metabolism is a central metabolic network that integrates nutrient availability with biosynthetic and epigenetic processes essential for embryonic and placental development. By transferring carbon units derived from amino acids and folate metabolism, this pathway generates nucleotides, methyl donors, and other intermediates required for cell proliferation and differentiation. The pathway is compartmentalized between mitochondria and cytosol, with mitochondrial reactions frequently supplying formate and other 1C units to sustain cytosolic biosynthesis in rapidly dividing cells. Pluripotent stem cells illustrate the strong dependence of cell identity on 1C metabolism. Mouse embryonic stem cells rely on threonine catabolism to produce glycine, acetyl-CoA, and S-adenosylmethionine (SAM), which supports chromatin methylation and self-renewal. In contrast, human ESCs lack a functional threonine catabolic pathway and instead depend on high methionine metabolism and glycine cleavage to maintain SAM levels and pluripotency. Genetic and metabolomic studies in diverse animal models have revealed stage-specific roles for 1C metabolism in processes including zygotic genome activation, DNA replication, epigenetic reprogramming, cell-cycle progression, organogenesis, cell migration, and longevity. Importantly, disruption of individual enzymes often produces defined developmental defects rather than general metabolic failure. Beyond early development, 1C metabolism also contributes to transgenerational epigenetic inheritance through its effects on germline DNA and histone methylation which are sensitive to perturbations in the folate and methionine pathways. Together, these findings show that 1C-metabolism links cellular metabolism with epigenetic regulation and developmental processes.
    Keywords:  Embryonic development; Epigenetic regulation; Folate cycle; Loss-of-function; Methionine cycle; Neural tube closure; One-carbon metabolism; Pluripotency
    DOI:  https://doi.org/10.1016/j.ydbio.2026.09.008
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