bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–05–10
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Generation of an iPSC line IUFi004-A-13 with homozygous NDUFS1 mutation for the study of Leigh syndrome.
  2. Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
  3. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  4. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  5. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
  6. Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.
  7. β-ureidopropionase deficiency mimicking Leigh syndrome associated with methylmalonic aciduria.
  8. HIF1-α induces mitochondrial fission in trophoblastic cells during early pregnancy and in preeclampsia.
  9. Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
  10. Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.
  11. Integration of Metabolic Pathways and Micronutrient Signals Influences Neurodevelopment by Modulating Neural Stem Cell Dynamics.
  12. Loss of mitochondrial DNA helicase in retinal macroglia drives neovascular retinopathy.
  13. Structural basis for double-stranded DNA cytosine deamination by BaDTF3 and its application in mitochondrial genome editing.
  14. Bypass Treatments for Primary Coenzyme Q10 Deficiency: An Update.
  1. Stem Cell Res. 2026 Apr 28. pii: S1873-5061(26)00098-X. [Epub ahead of print]94 104002
    Generation of an iPSC line IUFi004-A-13 with homozygous NDUFS1 mutation for the study of Leigh syndrome.
    Caleb Jerred, Haribaskar Ramachandran, Barbara Hildebrandt, Annika Zink, Natascia Ventura, Andrea Rossi, Alessandro Prigione.
      NDUFS1 is a critical component of mitochondrial respiratory chain Complex I (CI). Pathogenic variants of NDUFS1 can cause Leigh syndrome (LS), a severe pediatric mitochondrial disorder. To model NDUFS1-linked LS, we generated an iPSC line with homozygous missense mutations in exon 8 using CRISPR/Cas9. The cell line demonstrated typical morphology, expression of iPSC markers, ability to differentiate into all three germ layers, and genomic integrity. This model will enable the study of LS caused by CI in an isogenic context.
    DOI:  https://doi.org/10.1016/j.scr.2026.104002
  2. Expert Opin Ther Targets. 2026 May 08.
    Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
    Marcel V Alavi.
       INTRODUCTION: Autosomal Dominant Optic Atrophy (ADOA) is a rare hereditary optic neuropathy primarily caused by OPA1 mutations. Retinal ganglion cell (RGC) loss results in variable visual impairments, occasionally accompanied by extra-ocular manifestations. ADOA also involves a developmental component consistent with OPA1's essential role in mitochondrial fusion, cristae organization, and quality control. As such, ADOA serves as a paradigm for studying mitochondrial contributions to neurodegeneration.
    AREAS COVERED: This article provides a comprehensive overview of ADOA, covering genetic and clinical aspects while distinguishing between degenerative and developmental features of the pathology. The author examines OPA1 function and assesses emerging therapeutic strategies - ranging from gene augmentation and small-molecule therapeutics to alternative targets - before appraising translational challenges.
    EXPERT OPINION: Antisense therapies targeting OPA1 haploinsufficiency are among the more advanced ADOA treatments currently under human safety evaluation, with other modalities following closely in development. However, the field still lacks robust clinical endpoints for the highly variable and slowly progressive phenotype. Furthermore, developmental RGC loss may limit therapeutic efficacy of late-stage interventions - a challenge compounded by the difficulty of early diagnosis. Nevertheless, the FDA's recent shift toward Bayesian statistical frameworks and the emergence of neuroprotective alternative targets are expected to streamline the clinical development for ADOA.
    Keywords:  Antisense oligonucleotides; Haploinsufficiency; OMA1; OPA1; autosomal dominant optic atrophy (ADOA); gene therapies; mitochondrial dynamics; neuroprotection; retinal ganglion cells (RGCs); small molecules
    DOI:  https://doi.org/10.1080/14728222.2026.2671678
  3. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  4. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
  5. Nat Metab. 2026 May 08.
    Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
    Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.
      Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
    DOI:  https://doi.org/10.1038/s42255-026-01530-y
  6. Acta Neuropathol Commun. 2026 May 05.
    Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.
    Anna Maria Haschke, Anja von Renesse, Eugenio Graceffo, Susanne Morales-Gonzalez, Alessandro Prigione, Christoph Hübner, Werner Stenzel, Markus Schuelke.
      During muscle contraction, increased influx of calcium from the myocyte cytosol into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) links calcium homeostasis with high ATP provision. The MCU is located at the inner mitochondrial membrane and one of its structural components, the mitochondrial calcium uniporter regulator 1 (MCUR1), promotes its activity. Although MCUR1 function has been studied in cell models, mutations have not yet been associated with human disease. Here, we present a patient with proximal muscle weakness and atrophy, showing histological features of autophagic vacuoles with sarcolemmal features, who carries a homozygous MCUR1 nonsense mutation. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mtCa²⁺ uptake, that had been stimulated both by histamine or rising extracellular calcium exposure. Autophagic flux and histologic markers for autophagy (LAMP2, LCB3) were increased in the patient. However, the MCUR1 mutation did not alter MCU-complex assembly or its subcellular location, nor the resting mitochondrial membrane potential. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mtCa2+ uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans.
    Keywords:  Autophagic vacuoles; Calcium transport; Mitochondrial calcium uniporter; Mitochondrium; Vacuolar myopathy
    DOI:  https://doi.org/10.1186/s40478-026-02313-y
  7. BMJ Case Rep. 2026 May 04. pii: e272561. [Epub ahead of print]19(5):
    β-ureidopropionase deficiency mimicking Leigh syndrome associated with methylmalonic aciduria.
    Giulia Ferrera, Sara Boenzi, Eleonora Lamantea, Daniele Ghezzi, Anna Ardissone.
      β-ureidopropionase (βUP) deficiency, caused by pathogenic variants in UPB1, is a rare autosomal recessive disorder with fewer than 60 reported cases to date. Clinical presentation is highly variable, ranging from asymptomatic individuals to severe neurodevelopmental disorders. Diagnosis relies on the detection of pyrimidine degradation metabolites, such as N-carbamyl-β-alanine (NCβA) and N-carbamyl-β-aminoisobutyrate (NCβAIBA), which are not widely available in routine clinical practice.We report a 7-year-old boy with early-onset developmental delay and regression, Leigh-like basal ganglia lesions on brain MRI, and persistent elevation of urinary methylmalonic acid (MMA). Muscle biopsy revealed an isolated respiratory chain complex I deficiency. Genetic testing identified two novel biallelic UPB1 variants, and urinary analysis confirmed marked elevation of pyrimidine degradation metabolites, establishing the diagnosis of βUP deficiency.This case expands the clinical and neuroradiological spectrum of βUP deficiency and identifies elevated urinary MMA as a previously unreported finding in this disorder. Given the widespread availability of urinary organic acid analysis, MMA may represent a possibly useful and accessible biomarker to support diagnosis. βUP deficiency should be considered in the differential diagnosis of children with Leigh-like encephalopathy and unexplained MMA elevation.
    Keywords:  Clinical neurophysiology; Neuro genetics
    DOI:  https://doi.org/10.1136/bcr-2026-272561
  8. iScience. 2026 May 15. 29(5): 115674
    HIF1-α induces mitochondrial fission in trophoblastic cells during early pregnancy and in preeclampsia.
    Léa Poinsignon, Audrey Chissey, Juliette Colombel, Bertrand Lefrère, Charlotte Izabelle, Lucie Bernard, Jean-Louis Beaudeux, Thierry Fournier, Ioana Ferecatu, Isabelle Hernandez, Amal Zerrad-Saadi.
      The placenta undergoes a major oxygen transition between 7 and 9 gestation weeks (GW) and 12-14 GW. Inadequate adaptation to these environmental changes leads to oxidative stress and the release of syncytial knots, a hallmark of preeclampsia (PE). As mitochondria play a central role in redox regulation, we investigated mitochondrial network dynamics and the role of hypoxia-inducible factor 1-alpha (HIF1-α) in trophoblasts during early pregnancy and in PE. HIF1-α is stabilized in placenta before 9 GW, associated with mitochondrial hypertubulation and increased mitofusin (MFN) 1 expression. Experimental stabilization of HIF1-α using cobalt chloride induces mitochondrial fission through downregulation of MFN1 and MFN2, and upregulation of dynamin-related protein 1 (DRP1). In pre-eclamptic placentas, significantly elevated mitochondrial fission 1 protein (FIS1) levels suggest enhanced mitochondrial fission, supporting FIS1 as a potential biomarker of PE-associated placental alterations.
    Keywords:  cell biology; developmental biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115674
  9. Nat Commun. 2026 05 07. pii: 4195. [Epub ahead of print]17(1):
    Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
    Maria E Gierisch, Enrica Barchi, Mirco Marogna, Moritz H Wallnöfer, Maria Ankarcrona, Luana Naia, Florian A Salomons, Nico P Dantuma.
      The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we conduct a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter. Genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, are enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A leads to dissociation of the aggregation-prone substrate from mitochondria, which is accompanied by enhanced ubiquitin-dependent proteasomal degradation. The presence of an aggregation-prone, amphipathic helix that localizes the reporter to mitochondria is crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhances degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose that mitochondria serve as a holdout compartment for aggregation-prone proteins. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72783-0
  10. J Endocr Soc. 2026 May;10(5): bvag093
    Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.
    Ericka M Biagioni, Polina M Krassovskaia, Gillian Tiralla, Kelsey H Fisher-Wellman, Chien-Te Lin, Abby D Altazan, R Caitlin Hebert, Sripallavi Yendamuri, Maninder Singh, Owen T Carmichael, P Darrell Neufer, Kristen E Boyle, Leanne M Redman, Nicholas T Broskey.
       Purpose: Exercise-mediated adaptations to mitochondria are well established in nongravid populations; however, the extent to which these adaptations occur during pregnancy remains unclear. Therefore, the objective of this study was to compare skeletal muscle mitochondrial bioenergetics in physically active (n = 10) vs sedentary (n = 9) pregnant women.
    Methods: Groups were matched for age, race, and pregravid body mass index and were studied in the second (T2; weeks 21-25) and third trimester (T3; weeks 31-35). Free-living physical activity was assessed by accelerometry and aerobic fitness by peak oxygen uptake (VO2peak) testing. In vivo mitochondrial capacity was assessed by 31P-magnetic resonance spectroscopy. Primary skeletal muscle myotubes were obtained via muscle biopsy between late T2 and early T3. Mitochondrial in vitro respiration was assessed by high-resolution respirometry, and mitochondrial content was measured by Western blot and enzyme activity.
    Results: Despite a decline in physical activity across gestation, active women maintained a higher VO2peak at T2 (P < .05) and T3 (P < .01) compared with sedentary. There were no differences in phosphocreatine recovery time between groups or timepoints. Myotube mitochondrial respiratory capacity was similar between groups; however, compared with sedentary mothers, active mothers demonstrated increased expression of mitochondrial complexes I, II, and IV proteins (all P < .05). Additionally, myotube mitochondrial efficiency (adenosine triphosphate-to-oxygen consumption ratio) measures were positively correlated with maternal VO2peak at T3 (r = 0.49, P < .05), suggesting a link between fitness and mitochondrial efficiency.
    Conclusion: These findings suggest that late pregnancy may blunt mitochondrial adaptations to aerobic exercise despite a preservation of cardiovascular fitness. Future studies are needed to determine whether increasing activity throughout gestation can enhance mitochondrial respiration.
    Keywords:  exercise; metabolism; mitochondria; myotube; pregnancy
    DOI:  https://doi.org/10.1210/jendso/bvag093
  11. Mol Neurobiol. 2026 May 08. pii: 615. [Epub ahead of print]63(1):
    Integration of Metabolic Pathways and Micronutrient Signals Influences Neurodevelopment by Modulating Neural Stem Cell Dynamics.
    Sayed Chandini, Debangana Dey, Tina Gulati, Amit Mishra, Yogita K Adlakha.
      Central nervous system (CNS) development commences in third week of gestation with neural stem cells (NSCs), which, through symmetric division, expand the pool of stem cells and generate diverse types of neuronal and glia cells of CNS via asymmetric division. During neurodevelopment, spatiotemporal coordination is fundamental for appropriate morphogenesis and producing neuronal connections. Besides gene regulatory networks, external and internal factors guide NSCs during self-renewal, fate determination and differentiation. Recent studies indicate metabolism as one of the common converging integrators in NSCs to trigger modifications in response to external factors. One such external factor is micronutrients that profoundly affect different stages of neurodevelopment, including, differentiation, neural migration and maturation. This review aims to provide a summary of recent insights into how metabolism and micronutrients regulate different events of neurodevelopment including proliferation, fate determination and differentiation. Notably, we focus on illustrating the implications of mitochondria as key determinants of NSC fate and functionality. We also highlight the recent development on how metabolism orchestrates the epigenome of NSCs during proliferation and differentiation. We further explore the role of nutraceuticals in mitigating the risk of neurodevelopmental and adult neurological disorders, highlighting recent innovations in their therapeutic applications. An in-depth grasp of these molecular processes is fundamental to improving translational strategies for treating neurological disorders.
    Keywords:  Metabolism; Micronutrients; Mitochondria; NSC; Nutraceutical; One carbon metabolism; Vitamin B; Vitamin D
    DOI:  https://doi.org/10.1007/s12035-026-05904-x
  12. EMBO Mol Med. 2026 May 08.
    Loss of mitochondrial DNA helicase in retinal macroglia drives neovascular retinopathy.
    Sofiia Olander, Sinem Karaman, Fumi Suomi, Kevin Aguilar, Aleksandra Zhaivoron, Maiken Nedergaard, Lina Smeds, Jussi Tiihonen, Albert Quintana, Juan Hidalgo, Kari Alitalo, Petri Ala-Laurila, Gulayse Ince-Dunn, Anu Suomalainen.
      Retinopathy is a common symptom in mitochondrial diseases, and a leading cause of blindness in working-age individuals, often arising as a consequence of diabetes. Here, we demonstrate that postnatal loss of the replicative helicase of mitochondrial DNA in the astrocytes and Müller glia induces neovascular retinopathy. In these retinas, the macroglia show pathological reactivation, leading to hallmark features of neovascularization with blood-retina-barrier leakage, secondary microgliosis, and complement cascade activation. Similar reactivation of astrocytes in the cerebral cortex does not compromise vascular integrity, indicating tissue-specific roles of mitochondrial metabolism in macroglia for vascular homeostasis. Three secreted angiogenic factors-Fgf2, Pgf, and Lcn2-known to contribute to diabetic retinopathy, were induced. Spike recordings of the most sensitive retinal ganglion cells revealed normal rod function and intact retinal coding. These findings highlight the critical role of glial mitochondrial metabolism in neovascular retinopathy, with important implications for therapy development for mitochondrial and common forms of vision loss.
    DOI:  https://doi.org/10.1038/s44321-026-00438-0
  13. Nat Commun. 2026 May 05.
    Structural basis for double-stranded DNA cytosine deamination by BaDTF3 and its application in mitochondrial genome editing.
    Lulu Yin, Chae Jin Lim, Ke Shi, Jae Hee Yoon, Bong-Kook Ko, Seungmin Ryou, Jin-Soo Kim, Hideki Aihara.
      Bacterial deaminase toxin family (BaDTF) proteins are weapons used in bacterial warfare, and they are useful tools in base editing, epigenetics analyses, and genomic footprinting applications. Our previous studies revealed the mechanisms of 5'-TC-specific cytosine deamination in double-stranded (ds)DNA by DddA from BaDTF1 and sequence context-independent single-stranded (ss)DNA cytosine deamination by SsdA from BaDTF2. Here, we show that a representative member of BaDTF3, DddB, deaminates cytosines specifically in dsDNA, but with a broad sequence context preference. Our crystal structure of DddB bound to dsDNA reveals a distinct mechanism of substrate engagement, in which a helix-hairpin-helix motif inserted into the minor groove of dsDNA promotes flipping of the target cytosine into the enzyme active site. Based on the structural information, we generate both monomeric and split DddB-derived cytosine base editors (BdCBE) and demonstrate that they can perform CRISPR-free mitochondrial base editing in human cells, with an expanded targeting scope compared to the DddA-derived DdCBEs. Our studies highlight the mechanistic diversity among BaDTF proteins and expand the repertoire of dsDNA deaminase enzymes for genome editing and other applications.
    DOI:  https://doi.org/10.1038/s41467-026-72730-z
  14. Int J Mol Sci. 2026 Apr 15. pii: 3526. [Epub ahead of print]27(8):
    Bypass Treatments for Primary Coenzyme Q10 Deficiency: An Update.
    David Mantle, Neve Cufflin, Iain P Hargreaves.
      Primary coenzyme Q10 (CoQ10) deficiency results from mutations in genes involved in the CoQ10 biosynthetic pathway. In humans, at least 10 genes (PDSS1, PDSS2 to COQ10) are required for the biosynthesis of functional CoQ10, a mutation in any one of which can result in a deficit in CoQ10 status and present as primary CoQ10 deficiency. Furthermore, the genes NDUFA9 and HPDL, whilst not part of the PDSS1, PDSS2 to COQ10 gene sequence, have also been shown to have a crucial role in CoQ10 biosynthesis. A major problem in treating primary CoQ10 deficiencies is the poor bioavailability of supplemental CoQ10, both in terms of lack of absorption from the digestive tract and inability to cross the human blood-brain barrier. Bypass strategies aim to circumvent this problem by using more bioavailable precursor analogues that can enter the cell and be incorporated into the CoQ10 synthesis pathway downstream of the affected enzyme, examples being 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid or vanillic acid, which, in contrast to CoQ10, are small, water-soluble molecules. In this article, we have, therefore, reviewed potential bypass mechanisms for primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10, together with NDUFA9 and HPDL, using such precursors. Most of the published data relating to the bypass therapy of primary CoQ10 deficiency is derived from cell lines or animal models, and few human studies have so far been undertaken. In addition, further research is required to investigate the potential mechanisms by which bypass compounds such as 4-HB may access the human blood-brain barrier (BBB), for example, using in vitro co-culture BBB model systems incorporating CoQ10-deficient neurons. Overall, the objective of this article is, therefore, to systematically review the available data for each of the primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10 together with NDUFA9 and HPDL, in particular to identify the clinical potential of such studies.
    Keywords:  2,4-dihydroxybenzoic acid; 4-hydroxybenzoic acid; blood–brain barrier; bypass mechanisms; coenzyme Q10; primary deficiency; vanillic acid
    DOI:  https://doi.org/10.3390/ijms27083526
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