bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–10–18
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.
  2. Fetal Ganglionic Eminence Cysts as an Early Neuroimaging Finding for Mitochondrial Dysfunction Caused by a Novel TMEM70 Variant.
  3. RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
  4. Age, metabolites, and diagnostic discrimination in mitochondrial disease.
  5. After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
  6. NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
  7. Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
  8. Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.
  9. Tailored Amino Acid Treatment for Pediatric Patients With Mitochondrial Aminoacyl-tRNA Synthetase Deficiencies.
  10. Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.
  11. Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia.
  12. Sex-Specific Adaptations in Placental Mitochondrial Biogenesis and Function in babies Born with Critical Congenital Heart Disease.
  13. The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
  14. Perfluorooctanoic acid alters mitochondrial bioenergetics and redox status in isolated mouse liver mitochondria.
  15. A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
  16. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
  17. ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
  18. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  19. Metabolic homeostasis and women's reproductive health.
  20. Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis.
  21. Autophagy Defects and Mitochondrial Retention in Erythroid Diseases.
  22. Mitochondrial Quality Control in Degenerative Musculoskeletal Diseases: Signaling Networks and Therapeutic Landscapes.
  1. J Clin Invest. 2026 Oct 15. pii: e209546. [Epub ahead of print]136(20):
    Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.
    Anusha Sivakumar, Alexis N Corl, Keneth Jordan Muñoz, Subhashini Arumugam, Betul B Gunes, Angelyn B Solis, Rishika Murthy, Lilas Rony El-Hachem, Donald P Pizzo, Ian A Blair, Teerapat Rojsajjakul, Clementina Mesaros, Xinlong Wan, Joseph N Rainaldi, Rafael A Badell-Grau, Veenita Khare, Kevin Eric Thai, Kavya Biederman, Stephanie Cherqui.
      Friedreich's ataxia (FRDA) is a multisystemic neurodegenerative disorder caused by GAA repeat expansion in intron 1 of frataxin (FXN), resulting in FXN deficiency and mitochondrial dysfunction. Current therapies do not correct the underlying genetic defect. Here, we demonstrate that ex vivo CRISPR/Cas9 excision of the GAA expansion in hematopoietic stem and progenitor cells (HSPCs) provides durable, systemic therapy for FRDA. A single infusion of gene-edited Sca1+ HSPCs, mPPL-001, into myeloablative, humanized YG8JR mice resulted in long-term engraftment of donor-derived cells across hematopoietic and FRDA-affected tissues. mPPL-001 increased FXN expression and corrected multiple key pathogenic drivers of FRDA, including mitochondrial stress, microglial and macrophage activation, and inflammatory signaling. These coordinated effects improved motor functions, preserved cerebellar architecture, mitigated cardiac pathology, and promoted survival of insulin-producing β cells in the pancreatic islets of Langerhans. Collectively, these findings establish FXN-edited autologous HSPCs as a one-time, disease-modifying therapy for FRDA and support advancement toward a first-in-human trial.
    Keywords:  Bone marrow transplantation; Cell biology; Genetic diseases; Hematopoietic stem cells; Inflammation; Neuroscience
    DOI:  https://doi.org/10.1172/JCI209546
  2. Prenat Diagn. 2026 Oct 10.
    Fetal Ganglionic Eminence Cysts as an Early Neuroimaging Finding for Mitochondrial Dysfunction Caused by a Novel TMEM70 Variant.
    Sergio Gómez-Limón, Inés Tamarit, Óscar Toldos, Carmina Bermejo, Irene Gómez-Manjón, Francisco Javier Fernández-Martínez, David Coca, Alberto Galindo, Ignacio Herraiz.
      
    DOI:  https://doi.org/10.1002/pd.70270
  3. EMBO Mol Med. 2026 Oct 14.
    RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
    Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii.
      Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s44321-026-00534-1
  4. Mol Genet Metab. 2026 Oct 05. pii: S1096-7192(26)00571-8. [Epub ahead of print]149(3): 110288
    Age, metabolites, and diagnostic discrimination in mitochondrial disease.
    Didem Tatar, Ercan Yılmaz, Nezihe Köker Özer.
      
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110288
  5. Clin Transl Med. 2026 Oct;16(10): e70857
    After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
    Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.
       BACKGROUND: Mitochondrial transplantation is built on a simple idea: failing cells might be rescued by healthy mitochondria. The approach has entered early clinical testing, and encapsulation and cell-type targeting have improved uptake in selected systems. Better delivery, however, does not explain the therapy.
    MAIN BODY: Internalised donor mitochondria encounter an established network, quality-control machinery and sensors for mitochondrial material. Donor material may remain in the endolysosomal system or reach the cytosol. Cytosolic fates include network integration, clearance and a candidate functional contribution without fusion. Intracellular processing may also generate bioactive cargo. These fates imply different mechanisms and evidence requirements. This Review examines how recipient cells shape the contribution of internalised mitochondria, while recognising extracellular routes to benefit. We distinguish direct transplantation evidence from mechanistic support drawn from endogenous mitochondrial biology and natural intercellular transfer. The required donor fate and duration depend on the therapeutic task. Transient rescue may rely on short-term donor function or productive processing in specific models; sustained support may depend on continued donor function, recipient adaptation or redosing. Durable mitochondrial DNA (mtDNA) correction requires donor-mtDNA retention and replication.
    CONCLUSIONS: Linking these tasks to product design, safety assessment and clinical endpoints shifts the question from how many mitochondria enter cells to what they accomplish after arrival.
    KEY POINTS: Recipient-cell handling shapes what transplanted mitochondria do after uptake. Uptake, structural integration and donor mitochondrial DNA retention require distinct evidence. Transient rescue, sustained support and durable mitochondrial DNA correction impose different requirements. Therapeutic goals should guide donor selection, product testing and clinical endpoints.
    Keywords:  endosomal escape; heteroplasmy; innate immunity; mitochondrial fusion; mitochondrial transplantation; mitophagy; translational medicine
    DOI:  https://doi.org/10.1002/ctm2.70857
  6. Front Neurol. 2026 ;17 1943801
    NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
    Tianbao Wang, Xue Zhou, Xinhua Chen.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α-synuclein (α-syn), mitochondrial dysfunction, and neuroinflammation. Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in cellular energy metabolism, DNA repair, and epigenetic regulation, declines with aging and is markedly reduced in the brains of patients with PD. Emerging evidence suggests that supplementation with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), exerts neuroprotective effects through multiple mechanisms, such as activation of the mitochondrial unfolded protein response (UPR∧mt), enhancement of autophagy, and suppression of excessive poly(ADP-ribose) polymerase 1 (PARP1) activation. This review summarizes the central role of NAD+ dysregulation in the pathogenesis of PD, with particular emphasis on the interplay between NAD+ depletion, mitochondrial quality control, proteostasis, and neuroinflammation. Furthermore, we discuss recent advances in NAD+-boosting strategies in PD models and clinical studies, highlighting their potential therapeutic implications for PD intervention.
    Keywords:  NAD+; Parkinson's disease; mitochondrial quality control; neuroprotection; nicotinamide riboside
    DOI:  https://doi.org/10.3389/fneur.2026.1943801
  7. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2602028123
    Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
    Kiyoshi Miyagawa, Noriko Hosoya.
      Each human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) copies, only a small fraction of which replicates independently of the cell cycle. An asynchronous replication of the leading and lagging strands has been proposed to represent a major replication mode in mitochondria, complicating the investigation of mechanisms that regulate mtDNA replication. Using single-DNA-molecule analysis that distinguishes the origins and timing of replication of each strand, we show that the mitochondrial DNA replication machinery responds to the transition from quiescence to proliferation by dynamically dissociating strand-specific replication rates and modulating the physiological requirements for factors involved in replication and transcription. During this response, the requirement for mitochondrial RNA polymerase (POLRMT) in replication initiation increases, whereas that for primase-polymerase (PrimPol), which is thought to function in DNA repriming at DNA lesions, eventually decreases. Thus, precise quantification of mtDNA replication rates at the single-strand level reveals the temporally dynamic nature of the mtDNA replication machinery during the transition from quiescence to proliferation.
    Keywords:  asynchronous replication; mitochondrial DNA; quiescence
    DOI:  https://doi.org/10.1073/pnas.2602028123
  8. Methods Mol Biol. 2026 ;3057 189-200
    Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.
    Fasih A Rahman, Joe Quadrilatero.
      Mitophagy is the selective degradation of mitochondria via autophagy and is essential for maintaining mitochondrial quality and cellular homeostasis as well as being required for skeletal muscle differentiation and myogenesis. While traditional techniques such as immunoblotting, electron microscopy, and live-cell imaging provide valuable insights, they often offer only static or indirect measurements of mitophagy. Mitophagy flux assays capture dynamic turnover events and are, therefore, more informative. In this chapter, we present a streamlined method for monitoring and measuring mitophagic flux in C2C12 myoblasts during differentiation. Further, this approach allows for simultaneous quantification of mitochondrial morphology, providing a powerful platform for studying mitochondrial quality control in vitro.
    Keywords:  Adenovirus; Fluorescence mitophagy reporter; Mitochondrial network analysis; Mitochondrial quality control; Mitochondrial remodeling; Mitophagic flux; Mitophagy; Myogenesis
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_15
  9. J Inherit Metab Dis. 2026 Nov;49(6): e70254
    Tailored Amino Acid Treatment for Pediatric Patients With Mitochondrial Aminoacyl-tRNA Synthetase Deficiencies.
    I J J Muffels, G Kok, Z Tang, L S Medeiros, F O Poswar, W P Vermeij, R Rodenburg, K Smit, S K Sukumaran, S B Wortmann, L Averdunk, J Munch, J Pak-Lam Ho, A M K Kwok, E E S Nieuwenhuis, P M van Hasselt, I V D Schwartz, C M A Lubout, A M Bosch, K Koop, E M M Hoytema van Konijnenburg, S A Fuchs.
      Aminoacyl-tRNA synthetases (ARSs) facilitate the loading of transfer RNAs with their cognate amino acids in the cytosol (ARS1), mitochondria (ARS2), or both (dual ARS). ARS deficiencies are clinically heterogeneous and can cause severe, occasionally fatal disease. Supplementation with cognate amino acids to prevent local amino acid depletion has shown promise in ARS1 deficiencies, but its potential in ARS2 deficiencies remains largely unexplored. We investigated the effects of cognate amino acid depletion on mitochondrial function in fibroblasts from seven patients with ARS2 deficiencies using Seahorse respirometry and imaging flow cytometry. During amino acid depletion, patient fibroblasts showed decreased mitochondrial membrane potential and reduced basal and maximal respiratory capacity. We additionally evaluated oral cognate amino acid supplementation in nine patients with SARS2, EARS2, LARS2, WARS2, FARS2, or VARS2 deficiencies. Supplementation was well tolerated, with no adverse effects observed. Several patients showed clinical improvements during treatment, including improved development, increased growth, and/or improved cardiac function. In two patients, treatment discontinuation coincided with severe neurological regression. Together, these findings demonstrate that assessing mitochondrial function during cognate amino acid depletion provides a novel functional assay for ARS2 deficiencies that may aid variant interpretation and supports a biological rationale for cognate amino acid supplementation. Clinical supplementation was well tolerated and showed preliminary beneficial effects. These findings support further investigation of cognate amino acid supplementation as a potential supportive treatment strategy for patients with ARS2 deficiencies.
    Keywords:  amino acid supplementation; aminoacyl‐tRNA synthetase deficiency; genetic disease; metabolic disorder; mitochondrial disease; seahorse
    DOI:  https://doi.org/10.1002/jimd.70254
  10. Front Cell Dev Biol. 2026 ;14 1935788
    Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.
    Bo Pang, Xin Li, Yunlong Sun, Lin Ding.
      Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but how impaired mitochondrial homeostasis drives the selective death of dopaminergic neurons is still poorly understood. At the center of this problem lies the mitochondrial protein import machinery-the TOM and TIM23 translocases-which doubles as a stress-sensing hub that coordinates two distinct quality control pathways. When import is compromised, the kinase PINK1 accumulates on the mitochondrial surface, recruits Parkin to ubiquitinate outer membrane proteins, and triggers mitophagy. Meanwhile, the stress sensor DELE1 is cleaved and released to the cytosol, where it activates the HRI kinase to phosphorylate eIF2α and engage the integrated stress response (ISR). These two pathways are not independent. Recent work shows they engage in antagonistic crosstalk: the DELE1-HRI-ISR axis suppresses PINK1/Parkin-dependent mitophagy by preserving mitochondrial import efficiency, acting as a molecular brake on organelle clearance. The balance between these pathways is governed by the SIFI E3 ubiquitin ligase complex, which targets both DELE1 and HRI for degradation. Disruption of SIFI causes progressive neurodegeneration in humans. Here we synthesize the structural, biochemical, and genetic evidence that defines the TOM/TIM-PINK1/Parkin-DELE1/HRI signaling axis, examine how its dysregulation contributes to dopaminergic neuron vulnerability, and evaluate therapeutic strategies targeting mitochondrial import stress in PD.
    Keywords:  DELE1; HRI; PINK1; Parkinson’s disease; integrated stress response; mitochondrial protein import; mitophagy; parkin
    DOI:  https://doi.org/10.3389/fcell.2026.1935788
  11. Redox Biol. 2026 Oct 13. pii: S2213-2317(26)00436-2. [Epub ahead of print]98 104437
    Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia.
    Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Israel Manjarres-Raza, Maria Pazos-Gil, Fabien Delaspre, Jordi Tamarit, Juan P Bolaños, Joaquim Ros, Elisa Cabiscol.
      Friedreich's ataxia (FA) is a rare autosomal recessive neurodegenerative disorder caused by reduced expression of frataxin, a mitochondrial protein important for iron-sulfur cluster assembly and mitochondrial homeostasis. Although FA has traditionally been attributed to neuronal dysfunction, increasing evidence suggests that glial cells play a critical role in disease progression, although their contribution remains poorly defined. Using the FXNI151F mouse model, we investigated cell-type-specific metabolic and redox alterations in neurons and glial populations from the cerebrum, cerebellum, and dorsal root ganglia (DRG). Neuronal and glial-enriched fractions were isolated by immunomagnetic separation and analyzed for mitochondrial function, iron metabolism and reactive oxygen species (ROS). The analyses identified the DRG as the most severely affected region, exhibiting early and progressive mitochondrial respiratory deficits, increased ROS, mitochondrial iron accumulation, lipid peroxidation, and reduced levels of glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 in both neuronal and non-neuronal cells, ultimately resulting in significant neuronal loss. These results highlight the vulnerability of sensory neurons and their supporting satellite glial cells. In contrast, in the cerebrum and cerebellum, astrocytes displayed earlier and more severe alterations than neurons, including impaired respiratory chain efficiency, disrupted complex I-III supercomplex interaction, elevated ROS, and hallmarks consistent with ferroptosis. Neuronal abnormalities emerged later, suggesting that glial dysfunction precedes and may contribute to neuronal pathology. Overall, these findings reveal pronounced region and cell-type-specific vulnerabilities in FA and support the importance of targeting glial mechanisms-particularly iron dysregulation, oxidative stress, and ferroptosis-associated alterations- as targets for potential therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.redox.2026.104437
  12. Clin Sci (Lond). 2026 Oct 16. pii: CS20260162. [Epub ahead of print]
    Sex-Specific Adaptations in Placental Mitochondrial Biogenesis and Function in babies Born with Critical Congenital Heart Disease.
    Marie Demonceaux, Alban-Elouen Baruteau, Chloé Cloteau, Mathilde Gourdel, Bénédicte Romefort, Nadir Benbrik, Morgane Vincke, Garance Devarenne, Norbert Winer, Veronique Ferchaud-Roucher.
      Congenital heart disease (CHD) is the leading cause of birth defects; most critical (c)CHD newborns will develop neurodevelopmental disorders. Abnormal placental development may be involved, as genetics explains only 30% of sporadic CHD cases. Growing evidence suggests that placental dysfunction may result in heart and brain defects, as it shares a common early development. We hypothesized that newborns with critical CHD exhibit sex-specific alterations in placental mitochondrial biogenesis and function which may affect the fetal growth trajectory. Term placenta and paired umbilical cord (UC) blood were collected at birth from cCHD (n=16) and matched control (n=20) neonates. Mitochondrial lipid complex (phosphatidic acid (PA), phosphatidylglycerol (PG), cardiolipin (CL)), acylcarnitine metabolites and organic acids were determined in placenta by LC-MS/MS. Gene expressions of enzymes involved in mitochondrial biogenesis, dynamics and lipid pathway were measured in placenta by RT-qPCR. Placental protein expressions of β-oxidation and OXPHOS were determined by Western Blot. Mitochondrial dynamics were reduced in cCHD placentas, particularly in male infants. Long-chain acylcarnitine (LC-acar) metabolites decreased in female cCHD placentas and increased in males, while they increased in both sexes in UC plasma. Malonate levels increased in cCHD placentas, affecting the TCA cycle. CL de novo synthesis was dysregulated in the cCHD placentas, though CL concentrations were similar in both groups. The cCHD placenta may compensate for cardiac defect in a potential sex-dependent manner, leading to an accumulation of LC-acylcarnitine in the UC plasma. Placental mitochondrial adaptation to metabolic needs may have a cardioprotective and neuroprotective effects.
    Keywords:  Perinatal period; congenital heart defect; fetal sex; placental mitochondrial function; pregnancy
    DOI:  https://doi.org/10.1042/CS20260162
  13. J Biol Chem. 2026 Oct 14. pii: S0021-9258(26)02520-2. [Epub ahead of print] 113648
    The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
    Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J Wolfgang.
      Acsf3, a mitochondrial malonyl-CoA synthetase, is mutated in the human inborn error Combined Malonic and Methylmalonic Aciduria. To clarify its role in mammalian metabolism, we generated Acsf3 knockout mice. We show that the loss of Acsf3 results in high concentrations of malonate and methylmalonate and exhibit expected defects in mitochondrial metabolism, but the KO mice are largely healthy similar to the human inborn error. Acsf3 KO mice exhibit redundancy in malonyl-CoA synthetase activity suggesting a genetic modifier of disease severity. Malonate and methylmalonate are metabolic poisons generated as a by-product of biotin dependent carboxylation that require metabolic editing. Indeed, the liver-specific loss of the biotin ligase, Holocarboxylase Synthetase (hlcs), inhibits all biotin dependent carboxylation and results in broad changes in liver mRNA, protein, posttranslational and metabolic regulation. Loss of Hlcs suppresses the metabolic deficits in Acsf3KO liver due to the inhibition of malonate and methylmalonate generation. Mice with a double knockout of Acsf3 and Hlcs maintained mitochondrial lipoylation demonstrating the highly redundant generation of mitochondrial malonyl-CoA. These data define the role of Acsf3 in metabolic editing of malonate and methylmalonate to maintain mitochondrial metabolism in the face of endogenously produced anti-metabolites.
    Keywords:  biotin; metabolic disease; metabolomics; mitochondrial metabolism; proteomics; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jbc.2026.113648
  14. Toxicology. 2026 Oct 15. pii: S0300-483X(26)00222-2. [Epub ahead of print] 154615
    Perfluorooctanoic acid alters mitochondrial bioenergetics and redox status in isolated mouse liver mitochondria.
    Dongshin Yang, Jaeyeong Shin, Joo Young Huh, Sooim Shin.
      Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant linked to metabolic diseases, wherein mitochondrial dysfunction plays a critical role. This study investigated the direct effects of PFOA on isolated liver mitochondria from male and female mice exposed to 50-1,000μM PFOA for 10min. We assessed mitochondrial respiratory complex (CI-CIV) activities, ATP production, oxidative stress markers, and mitochondrial membrane potential (MMP). PFOA selectively altered CII and CIV activities, while CI and CIII remained largely unaffected. Notably, CIV activity increased at higher concentrations, while ATP production decreased at 1mM and MMP showed a decreasing trend at 500μM and 1mM, consistent with impaired mitochondrial energy coupling. Furthermore, ROS/RNS levels showed an increasing trend with increasing PFOA concentrations. Male- and female-derived mitochondria showed different response patterns across several endpoints. GSH levels showed no consistent concentration-dependent pattern, SOD activity showed no statistically significant changes, and cytochrome c levels showed no statistically significant changes under the present experimental conditions. These findings suggest that PFOA directly alters mitochondrial bioenergetic and redox-related processes, consistent with impaired energy coupling and altered redox status.
    Keywords:  Electron transport chain; Mitochondrial dysfunction; Mitochondrial energy coupling; Oxidative phosphorylation; Oxidative stress; Perfluorooctanoic acid
    DOI:  https://doi.org/10.1016/j.tox.2026.154615
  15. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2619615123
    A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
    Kentaro Hirose, Xiaoxin Chen, Chakrapani Kalyanaraman, Mark T Waddingham, Makoto Nakamura, Feng Zhang, Christina Chen, Shun Yao, Steven Chang, Hongyao Yu, Jiajia Wang, Emanuele Barca, Haruko Nakano, Austin Hsu, Sheamin Khyeam, Sara Gonzalez Ortega, Kazuki Tajima, Takeshi Yoneshiro, Hao Zhang, Arun Padmanabhan, Shingo Kajimura, Saptarsi Haldar, Atsushi Nakano, Masatoshi Murai, Yoshitaka Fujihara, Kinya Otsu, Catarina M Quinzii, Matthew P Jacobson, Guang Hu, James T Pearson, Guo N Huang.
      Increased mitochondrial biogenesis and aerobic respiration in postnatal mammalian organs are essential for adaptation to extrauterine life, yet the functions of many tissue-enriched, developmentally regulated mitochondrial proteins remain poorly defined. By integrating mitochondrial proteome annotations with mouse and human transcriptomic datasets, we identified Coenzyme Q10a (Coq10a), a striated muscle-enriched mitochondrial protein, as a regulator of postnatal cardiac growth. Coq10a, the mammalian homolog of the yeast ubiquinone-binding protein Coq10p, is highly induced in the heart after birth through thyroid hormone-, Nkx2.5-, and Tbx5-dependent regulation. To define its physiological function, we generated three independent Coq10a-deficient mouse models. Both global and cardiomyocyte-specific loss of Coq10a promoted postnatal cardiac hypertrophy without impairing basal cardiac function or mitochondrial respiration. Instead, Coq10a deficiency altered intracellular ubiquinone partitioning, resulting in increased ubiquinone accumulation in a microsomal membrane fraction. Transcriptomic analyses revealed enrichment of PPAR-associated metabolic gene sets and induction of established PPAR-responsive genes in Coq10a-deficient hearts. Pharmacological inhibition of PPARα and PPARγ, but not PPARδ, attenuated the hypertrophic phenotype. Molecular dynamics simulations, docking analyses, and mutagenesis identified PPARα residues that contribute to differential responsiveness to ubiquinone. Although Coq10a-deficient hearts maintained near-normal function under basal conditions, they exhibited increased susceptibility to pressure-overload stress. Together, these findings establish Coq10a as a regulator of intracellular ubiquinone partitioning and support a model linking altered mitochondrial lipid distribution and PPAR-associated signaling to postnatal cardiac growth. More broadly, they demonstrate how tissue-enriched mitochondrial proteins can mediate organ-specific physiological functions beyond energy production.
    Keywords:  Coq10a; PPAR signaling; cardiac hypertrophy; mitochondria; ubiquinone
    DOI:  https://doi.org/10.1073/pnas.2619615123
  16. J Cell Sci. 2026 Oct 01. pii: jcs265172. [Epub ahead of print]139(19):
    Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
    Marina R Hanna, James Costanzo, Madison Yarbrough, Melanie Gil, Matthew Murrow, Vivian Gama.
      Myeloid cell leukemia 1 (MCL-1) is a canonical anti-apoptotic protein crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to a swollen network with disorganized cristae and destabilized OPA1-MICOS machinery that fails to maintain inner mitochondrial membrane architecture. These structural defects are accompanied by displacement of ACSL1 from the outer mitochondrial membrane, impaired fatty acid oxidation, lipid droplet accumulation and reduced mitochondrial oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner mitochondrial membrane and retaining ACSL1 at the outer mitochondrial membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS and ACSL1, and identify it as a critical coordinator of cristae organization, lipid metabolism and neural progenitor fate. This establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights non-canonical MCL-1 functions as critical regulators of human brain development.
    Keywords:  ACSL1; Cristae; Intermediate progenitors; MCL-1; MICOS; Mitochondria; Neural progenitor cells; OPA1
    DOI:  https://doi.org/10.1242/jcs.265172
  17. Nat Commun. 2026 09 10. pii: 10690. [Epub ahead of print]17(1):
    ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
    Shiqi Xu, Yi Peng, Hengda Zhou, Xuecong Ren, Xin Wang, Zhenguang Ying, Meijiao Li, Yujie Sun, Bing Yang, Mao Zhang, Chonglin Yang, Weirui Ma, Suhong Xu.
      Mitochondrial Ca2+ uptake couples cellular Ca2+ signals to mitochondrial metabolism and stress responses and is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we identify an ATAD-3-dependent mechanism that promotes mitochondrial Ca2+ uptake following plasma membrane injury in C. elegans. Living imaging reveals robust, albeit delayed, mitochondrial Ca2+ influx following injury in mcu-1 mutants, indicating the existence of a compensatory Ca2+ uptake mechanism. RNAi screen identifies the conserved AAA+ ATPase ATAD-3 as an essential regulator of this pathway, whereas MICU-3 acts as a negative regulator. Wounding induces ATAD-3 oligomerization and mitochondrial enrichment, which are enhanced in mcu-1 mutants. Disrupting ATAD-3 oligomerization or expression of disease-associated ATAD-3 variants abolishes wounding-induced mitochondrial Ca2+ uptake. Structure modeling predicts that oligomeric ATAD-3 adopts a channel-like architecture. These findings uncover ATAD-3 as a context-dependent regulator of mitochondrial Ca2+ homeostasis during cellular stress and provide insight into how this process may be disrupted in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77690-y
  18. Cell Rep. 2026 Oct 16. pii: S2211-1247(26)01258-1. [Epub ahead of print]45(10): 118179
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.118179
  19. Nat Metab. 2026 Oct 15.
    Metabolic homeostasis and women's reproductive health.
    Xiao Liu, Lili Yang, Jingjing Jiang, Hsun-Ming Chang, Liangshan Mu.
      Metabolic homeostasis and female reproductive health are governed by tightly coupled regulatory systems, yet their reciprocal interactions have often been investigated in isolation. In this Review, we synthesize current epidemiological, mechanistic and clinical evidence to propose an integrated framework in which dynamic, bidirectional crosstalk between key metabolic organs and endocrine mediators constitutes a central determinant of female reproductive function across the life course. We delineate how disruption of this integrated network underpins a broad spectrum of reproductive dysfunction, particularly in polyendocrine metabolic ovarian syndrome and reproductive ageing, as well as cardiometabolic risk, highlighting the bidirectional nature of these associations. Finally, we critically evaluate current metabolism-targeted strategies, including lifestyle interventions, metabolic surgery and pharmacological therapies, and discuss emerging opportunities for precision approaches. By integrating mechanistic insights with clinical evidence, this Review reframes female reproductive disorders from a systemic metabolic perspective and outlines future directions for metabolism-focused strategies to improve reproductive health outcomes.
    DOI:  https://doi.org/10.1038/s42255-026-01646-1
  20. PLoS Biol. 2026 Oct 14. 24(10): e3004061
    Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis.
    Xiao Peng Liu, Xiao Zhang, Chun Xia Cai, Miao Miao Qin, Xiang Kai Leng, Jia Hao Chen, Yi Fan Han, Jun Ying Xiao, Jia He Huang, Jiang Wei Wu.
      Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, yet its underlying mechanism remains elusive. Here, we show that growth differentiation factor 15 (GDF15) levels are significantly reduced in the placenta and fetal circulation in mouse and pig FGR models and correlate positively with fetal weight. Placenta-specific GDF15 deficiency causes FGR, while placenta-specific Gdf15 mRNA delivery through targeted lipid nanoparticle (LNP) effectively alleviates FGR. Mechanistically, placental GDF15 is a major contributor to the fetal circulating GDF15 pool and enters the fetal compartment, where it activates the hepatic STAT3 signaling pathway to stimulate IGF2 production during pregnancy. Placental GDF15 deficiency decreases hepatic STAT3 phosphorylation and IGF2 levels in fetuses. Inhibition of STAT3 in primary mouse fetal hepatocytes blocks GDF15-induced IGF2 upregulation. Placenta-specific Gdf15 mRNA-LNP administration rescues the decreased hepatic p-STAT3 and IGF2 levels in FGR fetuses. Collectively, our findings identify a placenta-fetal liver metabolic axis where placental GDF15 promotes fetal growth by activating the fetal hepatic STAT3-IGF2 pathway, revealing a potential therapeutic target for FGR.
    DOI:  https://doi.org/10.1371/journal.pbio.3004061
  21. Int J Mol Sci. 2026 Sep 23. pii: 8467. [Epub ahead of print]27(19):
    Autophagy Defects and Mitochondrial Retention in Erythroid Diseases.
    Claudio M Fader, Julieta Jacob, Santiago Castro Perez, Cécile Deleschaux, Alice Dussouchaud, Gaël Nicolas, Betiana N Salassa, Sophie D Lefevre, Mariano A Ostuni.
      Erythropoiesis requires extensive cellular remodeling, culminating in enucleation and organelle clearance to generate mature red blood cells (RBCs). Over the past 15 years, accumulating evidence has established that macroautophagy-particularly ULK1-, NIX-, and PINK1-dependent mitophagy-plays a central role in erythroid maturation. Defective autophagy can lead to mitochondrial retention, increased reactive oxygen species (ROS) production, membrane alterations, and ineffective erythropoiesis. Such abnormalities have now been documented in several hematological disorders, including myelodysplastic syndromes, Fanconi anemia, Diamond-Blackfan anemia, sickle cell disease, and β-thalassemia. This review summarizes current knowledge of autophagy regulation during erythropoiesis, the molecular mechanisms governing mitochondrial clearance, and the pathological consequences of impaired autophagy in red blood cell disorders. Finally, we discuss emerging therapeutic strategies targeting autophagy pathways.
    Keywords:  anemia; autophagy; erythropoiesis; hemoglobinopathies; mitophagy
    DOI:  https://doi.org/10.3390/ijms27198467
  22. Adv Sci (Weinh). 2026 Oct 14. e78309
    Mitochondrial Quality Control in Degenerative Musculoskeletal Diseases: Signaling Networks and Therapeutic Landscapes.
    Haiyang Gao, Zhangrong Cheng, Xianglong Chen, Wenbo Wu, Wang Wu, Zimu Yu, Cao Yang, Yukun Zhang.
      Degenerative musculoskeletal disorders, including osteoarthritis (OA), intervertebral disc degeneration (IVDD), and osteoporosis (OP), are increasingly viewed as disorders of mitochondrial quality control (MQC) rather than passive mechanical wear. The MQC network, comprising mitochondrial dynamics, mitophagy-biogenesis coupling, and inter-organelle communication, organizes the aging-inflammation-metabolism axis. Its collapse releases mtDNA fragments that act as damage-associated molecular patterns (DAMPs) activating innate immunity via cGAS-STING, and metabolic intermediates that remodel the epigenome through histone lactylation, potentially locking acute stress into a "metabolic memory", although the mtDNA-methylation component remains hypothesis-level. Multi-omics and cell-free mtDNA liquid biopsy underpin a proposed subtyping into bioenergetic failure, immuno-inflammatory activation, and senescent cell accumulation, still a within-OA hypothesis pending independent and cross-disease validation. Therapy is shifting from symptom management toward organelle medicine, including cardiolipin stabilizers, PROTAC-mediated protein degradation, mitochondrial base editing, and engineered mitochondrial transplantation. Metformin has randomized trial evidence in knee OA pending confirmation, NAD+ precursors are in early clinical testing, and SS-31 holds accelerated approval only for Barth syndrome; other strategies remain preclinical. Delivery barriers and disease heterogeneity require precision stratification, biomimetic models, and AI-driven decision-making. This review delineates the shared molecular logic of the three diseases and proposes a prototype subtyping-to-treatment roadmap pending validation.
    Keywords:  degenerative musculoskeletal diseases; epigenetics; mitochondrial quality control; molecular subtyping; targeted therapy
    DOI:  https://doi.org/10.1002/advs.78309
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒18 at 7:08.