bims-mitmed 2026-07-05 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–07–05
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
Functional characterization of a biallelic MIPEP variant associated with global developmental delay, infantile epileptic spasms syndrome, and hypotonia.
DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
Dysregulation of sphingolipid-metabolizing enzymes in Friedreich's ataxia: In vitro and in vivo insights into therapeutic targeting.
When mitochondria lose their fold: matrix proteostasis and stress signaling.
Programmable aging function-related mitochondrial DNA 5-methylcytosine (m5C) modification with a TALE-directed methyltransferase.
Mitochondrial encephalomyopathy caused by a novel ACAD9 mutation: a case report.
Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.
Transcriptomic and epigenetic characterization of paraventricular thalamic nucleus neurons in Polg1 mutant mice.
Mitochondrial quality control in human ageing and longevity.
Advances in Gene and Cellular Therapy in Friedreich Ataxia.
Tau protein as a regulator of mitochondrial function and dynamics.
Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.
UC-MSCs prevent cigarette smoke-induced early cellular senescence like phenotype in bronchial epithelial cells via the SIRT1/PGC-1α pathway.
Gravitational and mechanical forces shape mitochondrial translation.
Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.

Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00080-2. [Epub ahead of print]91 102190

A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.

Shane Thomas Bell, Rebeca Acín-Pérez, Iffath Ghouri, Jon Meyrick, Robert Lightowlers, Oliver Russell.

  Large-scale mitochondrial DNA (mtDNA) deletions can result in deficiency of oxidative phosphorylation and subsequent mitochondrial dysfunction, ultimately leading to mitochondrial disease. To investigate effective treatments, we report a characterised heteroplasmic iPSC-derived neuronal model with a single, large scale ∼6 kb mtDNA deletion. While mtDNA heteroplasmy remains stable during iNGN2-induced neuronal differentiation from iPSCs, the presence of this mtDNA deletion results in an upregulation of mtDNA copy number and compensatory adaptation of oxidative phosphorylation (OXPHOS) machinery. Despite this increase, mitochondrial dysfunction and reduced oxygen consumption is prevalent. Furthermore, as differentiated neurons mature over time, mitochondrial supercomplexes and isolated complex II diminish, suggesting an increase of severity of the mitochondrial dysfunction. In summary, this study provides insight into a novel compensatory mechanism during iPSC differentiation to bypass mitochondrial dysfunction, and how this response exacerbates dysfunction during culture of mature neurons.

Keywords:  Complex II; Copy number; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Mitochondrial supercomplexes; iPSC-derived neurons

DOI:  https://doi.org/10.1016/j.mito.2026.102190
Mol Genet Metab Rep. 2026 Sep;48 101335

Functional characterization of a biallelic MIPEP variant associated with global developmental delay, infantile epileptic spasms syndrome, and hypotonia.

Benedetta Ruzzenente, Pierre-Hadrien Becker, Elissa Afram, Pauline Gaignard, Agnes Rötig, Denis M Nyaga, Cynthia Sharpe, Lynette G Sadleir, Bryony Ryder, Metodi D Metodiev.

  The mitochondrial intermediate peptidase (MIP) catalyzes the post-import removal of an N-terminal octapeptide from a subset of nuclear-encoded mitochondrial proteins. While the mechanistic role of this processing remains unclear, biallelic MIPEP variants have been linked to respiratory chain dysfunction and mitochondrial disease. Patients expressing these variants most often presented with cardiomyopathy, variable neurological defects, and early mortality. Here, we report the identification and functional characterization of a homozygous MIPEP variant in a patient presenting with a comparatively milder clinical phenotype involving global developmental delay, infantile epileptic spasms syndrome, and hypotonia. Analyses of patient-derived fibroblasts revealed reduced MIP abundance and impaired processing of established MIP substrates MRPL12, NDUFV2, and ATP5F1. Expression of wild-type MIPEP restored these defects, confirming the pathogenic nature of the variant. Thus, our findings expand the genetic and phenotypic spectrum of MIPEP-linked disease.

Keywords:  COXPD31; MIP; MIPEP; Mitochondrial disease; Mitochondrial intermediate peptidase; Mitochondrial proteostasis; OXPHOS assembly defect

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101335
Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00075-9. [Epub ahead of print]91 102185

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Melissa Geng, Dahai Wang, Sam Kavoosi, Brett A Kaufman, Neal Sondheimer.

  Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Keywords:  Autophagy; Guanine quadruplex; Heteroplasmy shifting; Mitochondrial fission; Mitochondrial heteroplasmy

DOI:  https://doi.org/10.1016/j.mito.2026.102185
iScience. 2026 Jul 17. 29(7): 116479

Dysregulation of sphingolipid-metabolizing enzymes in Friedreich's ataxia: In vitro and in vivo insights into therapeutic targeting.

Zenouska Ramchunder, Ester Kalef-Ezra, Saqlain Suleman, Fred Jonathan Edzeamey, Sandor Szunyogh, Owen Gittins, Natalia Castro Mena, Richard Wade-Martins, Adamo Valle, Charareh Pourzand, Sara Anjomani Virmouni.

  Friedreich's ataxia (FRDA) is an inherited neurodegenerative disorder caused by a GAA repeat expansion within the FXN gene, leading to reduced frataxin levels. This deficiency results in mitochondrial dysregulation, oxidative stress, and progressive cell death. Currently, only one approved treatment exists for FRDA in the United States, Canada, and the European Union, which improves neurological outcomes but has not been fully evaluated for broader disease symptoms. Therefore, identifying new therapeutic targets remains essential. Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA.

Keywords:  Cell biology; Genetics; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2026.116479
Front Physiol. 2026 ;17 1873221

When mitochondria lose their fold: matrix proteostasis and stress signaling.

Nils Bertram, Dejana Mokranjac.

  A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.

Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis

DOI:  https://doi.org/10.3389/fphys.2026.1873221
Cell Commun Signal. 2026 Jun 27.

Programmable aging function-related mitochondrial DNA 5-methylcytosine (m5C) modification with a TALE-directed methyltransferase.

Guo Li, Xinzhi Zhou, Guanglin Zhu, Yaxian Cheng, Yingjia Pan, Xiaomeng Guo, Guoya Liao, Xiangyang Li, Xiaoxiang Hu, Yuan Yao, Zhimin Gu, Wen Jiang.

  Mitochondrial epigenetic editing offers a potential strategy for modulating disease-causing mitochondrial genes while leaving the underlying DNA sequence unchanged. In this study, we present MEE, a mitochondrial epigenetic editor consisting of mitochondrion-targeted TALE modules fused to Dnmt3A and Dnmt3L methyltransferases. MEE efficiently directed site-specific 5mC methylation within cellular mitochondrial DNA with low detectable off-target activity under the tested conditions. MEE-mediated methylation at the C12191 (H) site exceeded 53% and was associated with an approximately 95% reduction in steady-state MT-ND5 mRNA levels in human cells. Notably, MEE increased methylation at the aging-associated C11168 (H) site by 11.76% in vivo, leading to reduced MT-ND4 expression in the targeted brain region and altered plasma levels of t-Tau and NFL in mice. These findings demonstrate that MEE provides a tool for precise epigenetic engineering of mitochondrial DNA, enabling experimental interrogation of specific 5mC modifications and exploration of the functional roles of mitochondrial DNA methylation in aging-associated diseases.

Keywords:  5mC methylation; Aging-related diseases; Mitoepigenetic editor; mtDNA

DOI:  https://doi.org/10.1186/s12964-026-03030-8
Front Hum Neurosci. 2026 ;20 1828023

Mitochondrial encephalomyopathy caused by a novel ACAD9 mutation: a case report.

Shuo Li, Yijun Li, Yonghua Chen.

  Background A 27-year-old male with perinatal hypoxia presented with global developmental delay, progressive hearing loss, ataxia, dysarthria, and intellectual disability. Whole-exome sequencing revealed compound heterozygous ACAD9 variants: c.456del (p.Ile153Serfs*46) and c.869G > A (p.Gly290Glu). Brain MRI showed bilateral cerebellar atrophy and a prominent cisterna magna. OCT confirmed optic atrophy. The diagnosis of mitochondrial encephalomyopathy (complex I deficiency type 20) was established. This report expands the known genetic spectrum associated with mitochondrial encephalomyopathy and underscores the critical role of genomic sequencing in diagnosing atypical, slowly progressive multisystem disorders.

Keywords:  ACAD9; ataxia; case report; complex I deficiency; encephalomyopathy; mitochondrial disease

DOI:  https://doi.org/10.3389/fnhum.2026.1828023
EMBO J. 2026 Jul 03.

Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.

Rebeca Acin-Perez, Essam A Assali, Michaela Veliova, Jennifer Ngo, Alexandra J Brownstein, Francisco Villalobos, Anton Petcherski, Pablo Hernansanz-Agustin, Doyeon Kim-Vasquez, Shili Xu, Mikayla Tamboline, Raquel Maria Silva, Alexander Upcher, Cynthia Shu, Daniel E Ferriss, Marc Liesa, Jose Antonio Enriquez, Israel Sekler, Orian S Shirihai.

Adrenergic stimulation of brown adipocytes induces a robust detachment of mitochondria from lipid droplets (LD), which is followed by lipolysis and lipid catabolism. However, the signals inducing mitochondria attachment or detachment, and their role in lipid metabolism, remain unknown. Here, we reconstituted mitochondria-LD interaction in brown adipocyte tissue (BAT) ex vivo. We find that removal of mitochondria from lipid droplets permits higher lipolytic activity of recombinant lipases. Testing the effect of thermogenic secondary messengers and metabolites on attachment and detachment identified elevated mitochondrial matrix calcium as a potent inducer of detachment. Further, deletion of the mitochondrial sodium/calcium exchanger, NCLX, resulted in reduced attachment and increased detachment, while activation of NCLX increased attachment. We find that elevated matrix calcium causes detachment by inducing architectural transformation of peridroplet mitochondria (PDM) from their typical LD-surface-bound crescent shape into a round shape. PDE2A inhibition activates NCLX and increases PDM content in BAT in vitro and in vivo. We conclude that a surge in mitochondrial matrix calcium ions serves as a potent signal to induce mitochondrial detachment from lipid droplets, thereby facilitating lipolysis.

DOI: https://doi.org/10.1038/s44318-026-00827-8
Neurosci Res. 2026 Jul 03. pii: S0168-0102(26)00076-3. [Epub ahead of print] 105089

Transcriptomic and epigenetic characterization of paraventricular thalamic nucleus neurons in Polg1 mutant mice.

Emilie Kristine Bagge, Mie Kubota-Sakashita, Noriko Fujimori-Tonou, Takaoki Kasahara, Tadafumi Kato.

  How damaged mitochondrial DNA (mtDNA) affects gene expression in mtDNA-related diseases is not well understood. Here, we investigated the changes in the transcriptome and chromatin modifications associated with the accumulation of mtDNA mutations in a proof-reading-deficient mitochondrial DNA polymerase transgenic mouse (Polg1 mutant mice), which accumulate mtDNA mutations preferentially in the paraventricular thalamic nucleus (PVT) and exhibit depressive-like episodes. We examined PVT neurons that were positive or negative for cytochrome oxidase (COX) in the mutant mice in depressive-like or euthymic states. The genes that were upregulated in the COX-negative PVT neurons during the depressive-like state were enriched for mitophagy or interferon signalling pathways. We observed no differentially accessible regions between WT and Polg1 mutant mice by ATAC (Assay for Transposase-Accessible Chromatin), but the loss of H3K27Ac signal in Polg1 mutant mice was associated with a higher number of ATAC tags. The change in H3K27Ac signal was seen only in brain regions that accumulate mtDNA mutations. In addition, we found that mtDNA, especially partially deleted mtDNA, was released from mitochondria upon opening of the mitochondrial permeability transition pore. These findings altogether suggest that mutated mtDNA molecules are released from mitochondria, which may contribute to the depression-specific transcriptomic alterations in the PVT neurons of the mood disorder animal model. (186 words).

Keywords:  chromatin; cytochrome oxidase; gene expression; histone acetylation; mitochondrial DNA; mitochondrial permeability transition pore; paraventricular nucleus of the thalamus

DOI:  https://doi.org/10.1016/j.neures.2026.105089
Nat Metab. 2026 Jun 29.

Mitochondrial quality control in human ageing and longevity.

Anna Picca, Luigi Ferrucci.

Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.

DOI: https://doi.org/10.1038/s42255-026-01563-3
Mol Diagn Ther. 2026 Jun 29.

Advances in Gene and Cellular Therapy in Friedreich Ataxia.

Michael P Lazaropoulos, David R Lynch.

Friedreich ataxia is a rare, autosomal recessive neurogenerative disorder caused by mutations to the frataxin (FXN) gene resulting in loss of functional FXN protein. Applications of cutting-edge genetic and cellular therapies expand therapeutic options for patients with rare, genetic diseases including Friedreich ataxia. Multiple investigational techniques and strategies seek to permanently alter the disease course in patients with Friedreich ataxia, although no product has established definitive benefit. This review catalogs both the history and ongoing efforts of genetic and cellular therapies applied to Friedreich ataxia and its disease models, including therapeutic efficacy and adverse effects. We list the key limitations and cautions of such therapies, chiefly those of potential FXN overexpression toxicity, critical therapeutic windows, and adverse effects of these therapies applicable to any disease target. As gene and cellular therapy continue to diversify in design and strategy, Friedreich ataxia patients will likely have multiple therapeutic options in the future from both investigational therapies described here and future ones yet to be optimized.

DOI: https://doi.org/10.1007/s40291-026-00854-5
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2521642123

Tau protein as a regulator of mitochondrial function and dynamics.

Eleni Tsakiri, Carlos Campos-Marques, Christina Ploumi, Kalliopi Skourti, Antonis Roussos, Eirini Mytilinaiou, Anastasia Vamvaka Iakovou, Ildete Luísa Ferreira, Chrysoula Dioli, Despoina D Gianniou, Martina Samiotaki, Jonas Campos, Clarissa Waites, Nuno Sousa, Ioannis P Trougakos, Joana M Silva, A Cristina Rego, Ioannis Sotiropoulos, Konstantinos Palikaras.

  Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans. Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.

Keywords:  Tau; mitochondria; mitochondrial dynamics; neurodegeneration; neuron

DOI:  https://doi.org/10.1073/pnas.2521642123
Mol Syndromol. 2026 Apr 29.

Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.

Ibrahim Bingol, Ozge Umur, Sare Guntulu Sık, Tonguc Utku Yilmaz, Remzi Emiroglu, Agop Citak.

   Introduction: Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma (POLG) gene, especially those associated with Alpers-Huttenlocher syndrome, significantly increase susceptibility to VPA hepatotoxicity.
Case Presentation: We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3(POLG):c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate.
Conclusion: This case is notable for its late adolescent onset, homozygous POLG c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of POLG-related VPA-ALF. These findings underscore the importance of POLG testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.

Keywords:  Acute liver failure; Liver transplantation; Mitochondrial disease; POLG mutation; Valproic acid

DOI:  https://doi.org/10.1159/000552241
Sci Rep. 2026 Jun 30.

UC-MSCs prevent cigarette smoke-induced early cellular senescence like phenotype in bronchial epithelial cells via the SIRT1/PGC-1α pathway.

Lingli Zhao, Yixuan Chen, Yixin Wang, Shuang Zhou, Meihong Liu, Xiangrui Li, Liang Wang, YanXia Li.

  Chronic obstructive pulmonary disease (COPD) is an age-related chronic disease, and most of the patients are elderly. Smoking is the main pathogenic factor, and the course of disease continues to develop. Cigarette smoke exposure leads to mitochondrial dysfunction and activation of cellular senescence. Umbilical cord mesenchymal stem cells (UC-MSCs) play a significant role in mitochondrial protection, airway repair and tissue regeneration.SIRT1/PGC-1α is a key regulator of mitochondrial function and cellular senescence. Therefore, this study aims to explore whether UC-MSCs can improve cigarette smoke extract (CSE)-induced mitochondrial dysfunction and cellular senescence in bronchial epithelial cells by activating the SIRT1/PGC-1α pathway. In vitro results show that: (1) CSE induced mitochondrial dynamic imbalance, leading to mitochondrial dysfunction and ROS accumulation, which induced cellular senescence. (2) UC-MSCs activate the SIRT1/PGC-1α pathway and significantly reduce the expression of markers related to cellular senescence and improving mitochondrial function after CSE induction. (3) The SIRT1 inhibitor EX527 reversed the protective effect of UC-MSCs. This study, for the first time, reveals that UC-MSCs can improve CSE-induced mitochondrial dysfunction and cellular senescence in bronchial epithelial cells by activating the SIRT1/PGC-1α pathway. It provides a new target for COPD treatment and a strategy for slowing the progression of the disease.

Keywords:  COPD; Cellular senescence; Mitochondrial; PGC-1α; SIRT1; UC-MSCs

DOI:  https://doi.org/10.1038/s41598-026-60236-z
Nat Commun. 2026 Jun 30. pii: 5552. [Epub ahead of print]17(1):

Gravitational and mechanical forces shape mitochondrial translation.

Taisei Wakigawa, Yusuke Kimura, Mari Mito, Toshiya Tsubaki, Muhoon Lee, Koki Nakamura, Abdul Haseeb Khan, Hironori Saito, Tohru Yamamori, Tomokazu Yamazaki, Akira Higashibata, Tatsuhisa Tsuboi, Yusuke Hirabayashi, Nono Takeuchi-Tomita, Taku Saito, Atsushi Higashitani, Yuichi Shichino, Shintaro Iwasaki.

Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin-integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.

DOI: https://doi.org/10.1038/s41467-026-74493-z
FASEB J. 2026 Jul 15. 40(13): e72089

Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.

Julien Goldstick, Diego Compte, Chun-Ling Sun, Alison E Ritter, C Michael Crowder.

Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measured the effect of hypoxia on mitochondrial morphology in a Caenorhabditis elegans Raptor mutant resistant to hypoxic death and in mutants with disrupted mitochondrial fission and fusion. The Raptor loss-of-function mutant reduced hypoxia-induced mitochondrial fragmentation and death. However, forcing mitochondrial fragmentation prior to hypoxia by combining the Raptor mutation with a loss-of-function mutation in mitofusin did not increase hypoxic death. A loss-of-function mutation in drp-1, which is required for mitochondrial fission, did not block hypoxia-induced mitochondrial fragmentation nor enhance Raptor hypoxia resistance; rather, drp-1(lf) was surprisingly mildly hypoxia resistant and partially suppressed the high-level hypoxia resistance of the Raptor mutant. Likewise, loss of DRP-1 function interacted synthetically with the Raptor(lf) mutant to produce tangled mitochondria, demonstrating a role of Raptor in maintenance of the mitochondrial network. Vitamin B12 supplementation and feeding with a bacterial strain replete in vitamin B12 mitigated hypoxia-induced mitochondrial fragmentation. Our results demonstrate that fragmented mitochondria do not necessarily promote hypoxic cell death, and hypoxia-induced mitochondrial fragmentation is mechanistically distinct from physiological mitochondrial fission.

DOI: https://doi.org/10.1096/fj.202601561R