bims-mitmed 2026-05-03 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–05–03
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics.
Fetal Expression of Pontocerebellar Hypoplasia Linked to Pathogenic COASY Variants.
Hepatic gene replacement improves energy metabolism and extends survival in a mouse model of neonatal mitochondrial disease GRACILE syndrome.
Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.
Quality control of protein import into mammalian mitochondria.
Expanding the Clinical Spectrum of LYRM7-Associated Mitochondrial Complex III Deficiency: Insights from New Cases and Literature Review.
Mild-cerebellar ataxia due to impaired mitochondrial function caused by the MSTO1 variations.
Specific elimination of m.8993T>G mitochondrial haplotype in NARP cybrid cells by CRISPR-Cas9 system.
Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.
A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.
RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.
Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
Correction of Hypoxemia and Hypoglycemia Restores Muscle Mitochondrial Respiration and Remodels Mitochondrial Proteome in Growth-Restricted Sheep Fetuses.
Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.
Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.
Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

JIMD Rep. 2026 May;67 e70092

Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics.

MitoMDT Diagnostic Network for Genomics and Omics

  MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.

Keywords:  MRPS22; corpus callosum; genomic autopsy; hydrops fetalis; mitochondrial disease; mitoribosome; proteomics

DOI:  https://doi.org/10.1002/jmd2.70092
Pediatr Dev Pathol. 2026 Apr 26. 10935266261434714

Fetal Expression of Pontocerebellar Hypoplasia Linked to Pathogenic COASY Variants.

Cassandre Garnier, Charles Mégier, Grégoire Dumery, Ferechté Encha-Razavi, Jelena Martinovic.

   INTRODUCTION: Pontocerebellar hypoplasia (PCH) comprises a group of rare, perinatal-onset neurodegenerative genetic disorders characterized by reduced cerebellar and brainstem volume. Among the 17 recognized subtypes listed in the OMIM database, PCH12 is notable for its severe presentation. This subtype results from biallelic pathogenic variants in the COASY gene, leading to loss of function and impair coenzyme A (CoA) biosynthesis.
CASE REPORT: We report 2 fetal cases from a consanguineous Pakistani couple, referred to a fetal medicine center for PCH associated with a homozygous COASY c.1486-3C>G pathogenic variant. The couple's first pregnancy was uneventful. However, the second and third pregnancies revealed severe cerebellar hypoplasia and additional brain anomalies on ultrasound and fetal MRI. Both pregnancies were terminated following prenatal findings, and post-fetopathological molecular testing confirmed the COASY variant.
DISCUSSION: These cases highlight the severe fetal phenotype of PCH12, characterized by cerebellar and brainstem hypoplasia, microcephaly, and neurodegeneration. The recurrence of this lethal condition in a consanguineous family underscores the importance of molecular diagnosis for early detection and genetic counseling. Preimplantation genetic testing for future pregnancies and cascade testing of extended family members are essential in such populations. Our antenatal report emphasizes the need for a multidisciplinary approach to the diagnosis and management of PCH12.

Keywords:  COASY gene; pontocerebellar hypoplasia; pregnancy termination; prenatal diagnosis

DOI:  https://doi.org/10.1177/10935266261434714
Mol Ther. 2026 Apr 24. pii: S1525-0016(26)00309-6. [Epub ahead of print]

Hepatic gene replacement improves energy metabolism and extends survival in a mouse model of neonatal mitochondrial disease GRACILE syndrome.

Rishi Banerjee, Janne Purhonen, Nasrin Sultana, Oliver Ros, Anni I Nieminen, Christa Kietz, Vineta Fellman, Jukka Kallijärvi.

Preclinical gene therapy studies of mitochondrial diseases remain limited due to the typically multiorgan manifestations and the scarcity of physiologically relevant animal models. Mutations in BCS1L, a nuclear gene encoding an assembly factor for mitochondrial complex III (CIII), are the most common cause of CIII deficiency. The most severe phenotype, GRACILE syndrome, is caused by a homozygous Finnish founder mutation (c.A232G, p.S78G). The corresponding Bcs1lp.S78G knock-in mouse model recapitulates the human disease, with juvenile-onset hepatopathy, tubulopathy, growth restriction, segmental progeria, and short survival. Here, we performed liver-targeted recombinant adeno-associated virus (rAAV)-mediated gene replacement in this model. A single intraperitoneal injection of rAAVs encoding wild-type Bcs1l restored CIII assembly and activity in the liver, preventing hepatopathy. Hepatocyte-specific correction was sufficient to alleviate hypoglycemia, improve growth, normalize systemic metabolism, and extend survival by nearly two-fold, despite persistent CIII deficiency in other tissues. Remarkably, restoring CIII activity in the liver robustly corrected the skeletal muscle transcriptomic changes, particularly those linked to altered energy substrate utilization. These results underscore the central role of the liver in systemic energy homeostasis and growth regulation in multiorgan mitochondrial diseases and demonstrate the therapeutic potential of hepatocyte-directed gene replacement in phenotypes with prominent hepatopathy.

DOI: https://doi.org/10.1016/j.ymthe.2026.04.044
Mol Psychiatry. 2026 Apr 29.

Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.

Samantha Corrà, Valeria Balmaceda, Carlo Viscomi.

Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy with its broad and customizable tissue tropism achieved through natural and engineered serotypes offers a highly effective platform for delivering therapeutic genes to affected tissues. However, the intricate genetics and biology of mitochondria present unique challenges for the development of AAV-based therapies. While gene replacement therapy remains a viable strategy for correcting nuclear gene defects, mutations in mtDNA require specialized approaches, such as mitochondrially targeted, RNA-free base editors and nucleases capable of precise editing within the mitochondrial genome. As an alternative, allotopic expression, which involves expressing mitochondrial genes from the nuclear genome, is currently being evaluated in clinical trials but remains controversial, due to issues related to mitochondrial import and functional integration in the respiratory complexes. The clinical translation of AAV-mediated therapies for mitochondrial diseases still confronts several interrelated challenges, including efficient targeting of multiple affected organs, scalable and cost-effective vector manufacturing, and minimizing vector-associated toxicity. By integrating advanced genome editing technologies with sophisticated vector engineering and delivery strategies, AAV-based gene therapy stands as a transformative approach for addressing the broad and heterogeneous spectrum of primary mitochondrial disorders. Continued progress in overcoming current biological and technical barriers will be essential to realize the full therapeutic potential of AAVs.

DOI: https://doi.org/10.1038/s41380-026-03570-y
Protein Sci. 2026 May;35(5): e70585

Quality control of protein import into mammalian mitochondria.

Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.

  Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.

Keywords:  Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses

DOI:  https://doi.org/10.1002/pro.70585
J Mol Neurosci. 2026 Apr 30. pii: 72. [Epub ahead of print]76(2):

Expanding the Clinical Spectrum of LYRM7-Associated Mitochondrial Complex III Deficiency: Insights from New Cases and Literature Review.

Golazin Shahbodagh Khan, Shiva Bayat, Reza Azizimalamiri, Mohammad Nikoohemmat, Narges Mashayekhi, Sahar Nabilou, Ali Reza Tavasoli, Mahmoud Reza Ashrafi, Morteza Heidari.

  Mitochondrial complex III (CIII) deficiency, resulting from abnormalities in its subunits or assembly factors, presents with diverse clinical manifestations. LYRM7-associated CIII deficiency is rare and typically presents with progressive neurodegeneration. We report a case series of LYRM7-associated CIII deficiency in two brothers, highlighting inflammatory demyelinating-like presentations, intrafamilial variability, and atypical disease progression. We present an investigational case series highlighting continuing challenges in diagnosing and managing LYRM7-associated mitochondrial complex III deficiency. Whole-exome sequencing (WES) was performed for diagnostic evaluation, followed by confirmatory Sanger sequencing and literature review of previously reported cases. Two brothers from a consanguineous family presented with ataxia, visual impairment, and progressive neurological deterioration including spasticity, seizures, cognitive decline, and motor weakness. Patient 1 (P1) experienced recurrent ataxic episodes beginning at 7 years of age, initially suspected to represent an inflammatory demyelinating disorder, while patient 2 (P2) demonstrated a more aggressive disease course with rapid neurological deterioration and early mortality at 8 years of age. Neuroimaging revealed cystic white matter changes suggestive of mitochondrial leukodystrophy and longitudinally extensive transverse myelitis (LETM) in both patients, differing from typical inflammatory demyelinating patterns. Genetic testing confirmed a pathogenic LYRM7 variant. Notably, intrafamilial clinical variability and the inflammatory-like presentation in P1- including LETM and optic neuritis mimicking neuromyelitis optica spectrum disorder (NMOSD)- distinguished our cases from previously reported patients. These findings expand the phenotypic spectrum of LYRM7-associated CIII deficiency and highlight diagnostic challenges. This case series expand the clinical spectrum of LYRM7-associated complex III deficiency and highlights relapsing inflammatory-like presentations as a potential diagnostic pitfall. Our findings emphasize the importance of considering mitochondrial disorders in children presenting with recurrent demyelinating-like episodes, atypical progression, or familial patterns. Early genetic diagnosis is essential for accurate diagnosis, counseling, and management of mitochondrial disorders.

Keywords:   LYRM7 ; Inflammatory demyelinating-like presentation; Leukodystrophy; Mitochondrial complex III deficiency; Whole-exome sequencing

DOI:  https://doi.org/10.1007/s12031-026-02527-8
Front Neurosci. 2026 ;20 1775132

Mild-cerebellar ataxia due to impaired mitochondrial function caused by the MSTO1 variations.

Bin Wu, Jingwei Lv, Tong Shen, Bing Wen, Tan Wang.

   Background: MSTO1 encodes a regulator of mitochondrial fusion. Mutations in MSTO1 are linked to a rare mitochondrial disorder characterized by early-onset myopathy and cerebellar ataxia, with 31 cases reported globally to date, which underscores its exceptional rarity.
Methods: We conducted comprehensive clinical, molecular, and biochemical investigations in a patient harboring novel MSTO1 variants.
Results: We identified a patient presenting with adult-onset progressive ataxia and cerebellar atrophy who carried two novel compound heterozygous variants in the MSTO1 gene (c.756A>G, p.Glu252Glu; c.1339G>A, p.Glu447Lys). Brain MRI revealed marked cerebellar abnormalities, but the patient's clinical symptoms remained relatively mild with preserved daily function. This milder phenotype, characterized by adult onset and later disease presentation, contrasts with the more severe neurological deficits reported in a previously described case. Functional studies revealed significantly reduced MSTO1 protein expression, mtDNA depletion, and impaired mitochondrial function, as reflected by decreased mitochondrial membrane potential and respiratory capacity, suggesting a pathogenic role for these variants. Comparative analysis with fibroblasts from a previously reported case with MSTO1 mutation revealed notable differences in the severity of mitochondrial dysfunction, suggesting potential genotype-phenotype correlations.
Conclusion: Our findings provide evidence linking the novel MSTO1 variants c.756A>G and c.1339G>A to mitochondrial dysfunction and broaden the phenotypic spectrum of MSTO1-related mitochondrial disorders to encompass a milder, adult-onset form of cerebellar ataxia. These results emphasize the importance of integrated clinical and functional approaches in evaluating variant pathogenicity and in elucidating the clinical and molecular heterogeneity of MSTO1-related mitochondrial disorders.

Keywords:  MSTO1; MSTO1-related mitochondrial disorders; cerebellar ataxia; cerebellar atrophy; mitochondrial fusion

DOI:  https://doi.org/10.3389/fnins.2026.1775132
Sci Rep. 2026 Apr 28.

Specific elimination of m.8993T>G mitochondrial haplotype in NARP cybrid cells by CRISPR-Cas9 system.

Elvira Zakirova, Svetlana Sergeeva, Ksenia Morozova, Elena Kiseleva, Masashi Tanaka, Ilya Mazunin, Konstantin Orishchenko.



Keywords:  CRISPR-SpCas9; Heteroplasmy shift; Mitochondria; NARP syndrome; m.8993T>G point mutation

DOI:  https://doi.org/10.1038/s41598-026-49007-y
EMBO Rep. 2026 Apr 27.

Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.

Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.

Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.

DOI: https://doi.org/10.1038/s44319-026-00774-9
Sci Adv. 2026 May;12(18): eaeb2995

A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.

Mayra A Borrero-Landazabal, Vanessa Linke, Tereza Kadavá, Zeshi Li, Piotr Draczkowski, Kacper Kaszuba, Lea Bertgen, Remigiusz A Serwa, Albert J R Heck, Agnieszka Chacinska.

The translocase of the outer mitochondrial membrane (TOM) is the conserved entry gate for nuclear-encoded proteins. While structurally similar from yeast to humans, the human TOM complex operates in a cellular environment of vastly greater complexity. Here, we present a high-confidence map of the human TOM interactome using a membrane-permeable cross-linker to capture both stable and transient interactors. Alongside extensive overlap with known yeast partners, we uncover a set of human-specific interactors including regulatory factors and TOM-associated proteins. Mapping unique interprotein cross-links reveals conformational flexibility of the receptor TOM20 and enhanced recovery of peripheral components such as TOM70 and several associated quality control factors. Notably, we identify FKBP8 (FK506 binding protein 8) as a human-specific interactor that binds multiple TOM subunits and promotes organization of the complex. Our work redefines the human TOM complex as a dynamic, multifaceted hub coordinating biogenesis, quality control, and signaling. This expanded TOM landscape offers a rich resource for exploring mitochondrial regulation in health and disease.

DOI: https://doi.org/10.1126/sciadv.aeb2995
Nat Commun. 2026 Apr 29.

RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.

Sean R Golinski, Karla Soriano, Alex C Briegel, Madeline C Burke, Sheng Tang, Gemma L Carvill, Emma Sherrill, Claudia Lentucci, Timothy W Yu, Tojo Nakayama, Ruilong Hu, Richard S Smith.

Dysfunction of the sodium-activated potassium channel KNa1.1 (encoded by KCNT1) is associated with a severe neurodevelopmental condition characterized by frequent seizures (up to hundreds per day), treatment resistance, and increased mortality during childhood. Yet, recent progress with an RNA therapy targeting KCNT1 offers clinical promise1. We characterize the early developmental onset of KNa1.1 channels in prenatal and neonatal brain tissue, establishing a timeline for pathophysiology and a window for therapeutic intervention. Using patch-clamp electrophysiology, we observe functional prenatal KNa1.1 conductance that is developmentally regulated. In excitatory and inhibitory neurons derived from a child's induced pluripotent stem cells with a KCNT1 pathogenic variant (p.R474H), we detect gain-of-function K+ currents. We use an antisense oligonucleotide RNA therapy developed for two individuals with the p.R474H variant-which results in dramatic reductions in seizure occurrence and severity1-to profile cellular neurophysiology in patient-derived excitatory and inhibitory neurons. We observe a knockdown of p.R474H gain-of-function K+ currents, resulting in a stimulation-dependent change in spiking output in patient-derived induced excitatory and inhibitory neurons. In mid-gestation primary human neurons, ASO knockdown suppresses current-evoked firing, suggesting a potential early therapeutic target before the onset of infantile encephalopathy.

DOI: https://doi.org/10.1038/s41467-026-72334-7
Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):

Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.

Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.

Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.

DOI: https://doi.org/10.1093/nar/gkag233
Am J Physiol Endocrinol Metab. 2026 Apr 30.

Correction of Hypoxemia and Hypoglycemia Restores Muscle Mitochondrial Respiration and Remodels Mitochondrial Proteome in Growth-Restricted Sheep Fetuses.

Weicheng Zhao, Daniel B Chrisenberry, Mariangel Varela, Rosa I Luna-Ramirez, Miranda J Anderson, Paul R Langlais, Laura D Brown, Sean W Limesand.

  Placental insufficiency causes fetal hypoxemia and hypoglycemia and is a major driver of fetal growth restriction (FGR). In FGR skeletal muscle, mitochondrial respiration is reduced, partially due to altered mitochondrial protein abundance. We have shown that maternal oxygen and fetal glucose supplementation alleviates fetal hypoxemia and hypoglycemia and improves skeletal muscle satellite cell proliferation. However, its effects on muscle mitochondrial respiratory function and proteomic profiles remain unknown. Here, we tested whether correcting fetal hypoxemia and hypoglycemia restores mitochondrial oxidative phosphorylation and normalizes mitochondrial proteomic profiles in FGR sheep skeletal muscle. Placental insufficiency and FGR were induced by maternal hyperthermia during gestation. Near-term fetuses were chronically catheterized and received 7-10 days of maternal tracheal oxygen insufflation and fetal intravenous (IV) glucose infusion (FOG) or maternal air insufflation and fetal IV saline infusion (FAS). Both were compared to normally-grown control fetuses without supplementation (CON). Principal component analysis of the mitochondrial proteome indicated that FOG clustered closer to CON than to FAS. Abundances of 48 of 80 proteins that were differentially expressed in FAS vs CON returned to CON levels with FOG supplementation. Mitochondria isolated from CON and FOG muscle had similar glutamate/malate-driven state 3 (ADP stimulated) respiration, and both rates were greater than FAS mitochondria. Mitochondrial complex I activity was lower in FAS compared to CON, and FOG showed an intermediate level that was not different from either group. Together, these findings indicate that prenatal oxygen and glucose supplementation rescued mitochondrial respiratory dysfunction and partially normalized mitochondrial proteome in FGR skeletal muscle.

Keywords:  Intrauterine Growth Restriction; Intrauterine intervention; Mitochondria; Oxidative phosphorylation; Proteomics

DOI:  https://doi.org/10.1152/ajpendo.00073.2026
Nature. 2026 Apr 27.

Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.

Viviane Callier.



Keywords:  Cell biology; Evolution; Immunology

DOI:  https://doi.org/10.1038/d41586-026-01295-0
Neurobiol Dis. 2026 Apr 24. pii: S0969-9961(26)00157-9. [Epub ahead of print]224 107412

Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.

Philippe Codron, Valérie Desquiret, Delphine Prunier, Patrizia Amati-Bonneau, Viviane Nguefackngoune, Clara Rapenne, Louis Legoff, Julien Cassereau, Vincent Procaccio.

  Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease.

Keywords:  Amyotrophic lateral sclerosis; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1016/j.nbd.2026.107412
J Clin Invest. 2026 May 01. pii: e202528. [Epub ahead of print]136(9):

Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.

Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R Malloy, Stanislaw Deja, Shawn C Burgess, Matthew A Mitsche, Jay D Horton.

  Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

Keywords:  Cardiology; Fatty acid oxidation; Heart failure; Metabolism

DOI:  https://doi.org/10.1172/JCI202528
Cell Metab. 2026 Apr 29. pii: S1550-4131(26)00142-7. [Epub ahead of print]

NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.

Wencao Zhao, Wenkai Zhu, Trace Thome, Ioana Soaita, Jae Woo Jung, Michael C Noji, Jian Li, Huajun Bai, Yansen Xiao, Yifan Yang, Chelsea Thorsheim, Wei Zhou, Yijun Yang, Kristina Li, Jonathan J Edwards, Ivan A Kuznetsov, Boa Kim, Joseph A Baur, Zoltan Arany.

  Angiogenesis requires endothelial cells (ECs) to toggle between quiescence versus proliferation, migration, and invasion. While activation from quiescence is well characterized, mechanisms governing the return from proliferation to quiescence (PtoQ) remain unclear. We show here that metabolic rewiring during PtoQ renders ECs sensitive to oxidative stress, requiring nicotinamide adenine dinucleotide (NAD) turnover for protection. Limiting EC NAD does not affect proliferation or migration but prevents cell-cell contact formation and quiescence acquisition during PtoQ. In vivo and ex vivo, limiting EC NAD permits initial sprouting but impairs vascular stabilization and plexus formation. Mechanistically, NAD suppresses mitochondria-derived hydrogen peroxide (H2O2) during PtoQ. Exogenous H2O2 mimics NAD deficiency, whereas its removal rescues PtoQ. In pathological settings, inhibiting NAD synthesis limits exuberant angiogenesis of retinopathy and tumors. In summary, we unveil metabolic events critical for PtoQ, a poorly studied component of angiogenesis, and point to new ways to suppress pathological angiogenesis.

Keywords:  H(2)O(2); NAD; NADPH; NAMPT; angiogenesis; endothelial cells; metabolism; quiescence

DOI:  https://doi.org/10.1016/j.cmet.2026.04.004
Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]

TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.

  Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.04.004