bims-mitmed 2026-03-08 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–03–08
eleven papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.
Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
Unconventional model organisms bend our view on mitochondrial cristae.
Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.
Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.

Genet Med. 2026 Jan;pii: S1098-3600(25)00267-9. [Epub ahead of print]28(1): 101620

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

Thiloka Ratnaike, Siddharth Ramanan, Nour Elkhateeb, Ramya Narayanan, Jenny Yang, Eszter Sara Arany, Manya Mirchandani, Rachael Piper, Katherine Schon, M Eren Kule, Christopher Gilmartin, Angela Lochmüller, Emogene Shaw, Rita Horváth, Patrick F Chinnery.

   PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Keywords:  HPO; Mitochondrial disease; Phenotype similarity; Rare disease; UMAP

DOI:  https://doi.org/10.1016/j.gim.2025.101620
Nat Commun. 2026 Mar 05.

Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.

Injae Chung, Caroline S Pereira, John J Wright, Guilherme M Arantes, Judy Hirst.

Respiratory complex I is a multi-subunit energy-transducing membrane enzyme essential for mitochondrial and cellular energy metabolism. It couples NADH oxidation and ubiquinone-10 (Q10) reduction to the concomitant pumping of four protons to generate the proton-motive force that powers oxidative phosphorylation. Despite recent advances in structural knowledge of complex I, many mechanistic aspects including the reactive binding poses of Q10, how Q10 reduction initiates the proton transfer cascade, and how protons move through the membrane domain, remain unclear. Here, we use electron cryomicroscopy to determine structures of mammalian complex I, reconstituted into phospholipid nanodiscs containing exogenous Q10 and reduced by NADH, to global resolutions of 2.0 to 2.6 Å. Two conformations of a reduced Q10H2 molecule are observed, fully inserted into the Q-binding channel in the turnover-relevant closed state. By comparing the quinone species bound in oxidised and reduced complex I structures, paired with molecular dynamics simulations to investigate the charge states of key surrounding residues, we propose a series of substrate binding poses that Q10 transits through for reduction. Our highly hydrated structures exhibit near-continuous proton-transfer connections along the length of the membrane domain, enabling comparisons between them to assist in identifying the proton-transfer control points that are essential to catalysis.

DOI: https://doi.org/10.1038/s41467-026-70030-0
Mol Neurobiol. 2026 Mar 04. pii: 485. [Epub ahead of print]63(1):

A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.

Jing Wu, Cunhui Pan, Ruowei Zhu, Xi Huang, Xiaoting Lou, Li Yang.

  Leber's hereditary optic neuropathy (LHON) is a hereditary neurodegenerative disorder caused by pathogenic mitochondrial DNA (mtDNA) variants. While MT-CO2 defects are implicated in neurodegeneration, their direct association with optic atrophy has not been reported. We identify a heteroplasmic MT-CO2 variant, m.8024G > A (p.Glu147Lys), in a patient with progressive optic atrophy and explore its potential association with mitochondrial dysfunction. A 13-year-old male with progressive unilateral-then-bilateral vision loss underwent comprehensive ophthalmic/neurological evaluation, trio whole-exome sequencing, and mtDNA sequencing. The pathogenicity of the identified variant was assessed in patient-derived fibroblasts using mitochondrial stress tests, ATP/ROS assays, enzymatic profiling, BN-PAGE, mitochondrial membrane potential, mtDNA copy number, ultrastructural microscopy, and immunoblotting. Functional analyses revealed that this variant, which reduces the expression of mtDNA-encoded electron transport chain (ETC) subunits and induces severe Complex IV deficiency, reduced cellular oxygen consumption rate (OCR), impaired ATP synthesis, decreased mtDNA copy number, and elevated reactive oxygen species (ROS) production. Concurrently, mutant cells exhibited enhanced mitophagy with preserved flux, a compensatory response to persistent mitochondrial damage. Unlike canonical optic neuropathy associated with homoplasmic mtDNA mutations, this heteroplasmic variant is linked to mitochondrial dysfunction potentially related to tissue-specific heteroplasmy and altered mitophagic responses. We report a heteroplasmic m.8024G > A mutation in MT-CO2 associated with childhood-onset isolated optic atrophy. Functional analyses in patient fibroblasts show that this variant is associated with MT-CO2 structural perturbation, Complex IV dysfunction, altered mitophagy, and mitochondrial energy failure-supporting its potential pathogenic relevance. This study expands the genotypic and phenotypic spectrum of mitochondrial optic neuropathies and provides mechanistic insights into the pathogenesis of heteroplasmic mtDNA variant-related disease.

Keywords:  MT-CO2; Mitochondrial complex IV; Optic atrophy; Optic neuropathy

DOI:  https://doi.org/10.1007/s12035-026-05774-3
Mol Genet Metab Rep. 2026 Mar;46 101302

Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.

Gerardo G Piroli, Rebecca Myers, Lynda Holloway, Andrew Hayek, Ellen Linebaugh, Julie R Jones, Cindy Skinner, Steven A Skinner, Norma Frizzell, Richard Steet.

  Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.

Keywords:  Complex III; Mitochondria; Mitochondrial transplantation; Respiration; UQCRC1; UQCRC2

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101302
Acta Histochem. 2026 Feb 28. pii: S0065-1281(26)00016-4. [Epub ahead of print]128(2): 152331

Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.

Aswathy P Nair, Aishwarya Janaki P, Janani Gopalarethinam, Abishek Kumar B, Balachandar Vellingiri, Mohana Devi Subramaniam.

  Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.

Keywords:  Leber’s Hereditary Optic Neuropathy; Mitochondria transfer; Mitochondrial disease; Stem cells; Tunneling Nanotubes

DOI:  https://doi.org/10.1016/j.acthis.2026.152331
Sci Adv. 2026 Mar 06. 12(10): eaed3579

Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.

Kenneth Ehses, Jorge P López-Alonso, Odetta Antico, Yannik Lang, Till Rudack, Abdussalam Azem, Miratul M K Muqit, Iban Ubarretxena-Belandia, Rubén Fernández-Busnadiego.

Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo-electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo-electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.

DOI: https://doi.org/10.1126/sciadv.aed3579
J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):

Unconventional model organisms bend our view on mitochondrial cristae.

Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.

  Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.

Keywords:   Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae

DOI:  https://doi.org/10.1242/jcs.264310
NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3
J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 89-95

Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.

Daria Hoang, Alan Pestronk, Jafar Kafaie.

   ABSTRACT: We report a pediatric case of severe isolated mitochondrial myopathy because of the rare m.3251A>G variant of the MT-TL1 gene. A 7-year-old boy presented to the hospital with acute-on-chronic weakness and respiratory insufficiency. Initial laboratory tests were notable for elevated lactate, aldolase, and lactate dehydrogenase. Despite a negative autoimmune panel, he was presumed to have myositis and treated with steroids and intravenous immunoglobulin. He continued to deteriorate, eventually requiring intubation and ventilation. Muscle biopsy revealed numerous ragged red fibers, abnormal intracellular lipid droplets with no lymphocytic inflammation, and increased succinate dehydrogenase reactivity, reflecting mitochondrial proliferation in many fibers. Steroids were discontinued, and he was started on a mitochondrial cocktail of cofactors with clinical improvement. Genetic testing identified the m.3251A>G variant, confirming primary mitochondrial disorder. This case expands the known phenotype of the m.3251A>G mutation. We also discuss clinical and histopathological differences between mitochondrial and inflammatory myopathies.

Keywords:  MELAS; histopathology; immune myopathy; mitochondrial myopathy; muscle biopsy

DOI:  https://doi.org/10.1097/CND.0000000000000547
Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Nat Rev Neurosci. 2026 Mar 04.

Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.

Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.

Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.

DOI: https://doi.org/10.1038/s41583-026-01031-7