bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–07–26
twelve papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
  2. Delineation and Phenotypic Expansion of TOP3A-Related Mitochondrial Disease in Childhood.
  3. Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
  4. Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
  5. Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
  6. Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.
  7. Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
  8. Mitochondria poor but capacity rich? The paradox of podocyte respiration.
  9. The role of cytosolic mitochondrial DNA as a mitochondrial danger signal for stromal fibroblasts in forming the tumor-promoting microenvironment following radiation exposure.
  10. Distinct sources and effects of mitochondrial reactive oxygen species.
  11. HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
  12. ER-mitochondria contact sites and organelle stress in asthma.
  1. Mol Genet Metab. 2026 Jul 19. pii: S1096-7192(26)00503-2. [Epub ahead of print]149(1-2): 110220
    TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
    Claire-Marine Bérat, Giulia Barcia, Pauline Gaignard, Zahra Assouline, Elisa De La Cruz, Marie-Céline François-Heude, Agathe Roubertie, Claude Cances, Louis Dufour, Marianne Alison, Olivier Patat, Aurélien Trimouille, Samira Ait-El-Mkadem Saadi, Agnès Rötig, Marie Hully, Cécile Rouzier, Isabelle Desguerre, Nathalie Boddaert, Manuel Schiff.
       BACKGROUND: TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management.
    OBJECTIVE: To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes.
    METHODS: We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease.
    RESULTS: The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes.
    CONCLUSION: TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
    Keywords:  Dystonia; Leigh syndrome; Mitochondrial disease; Mitochondrial respiratory chain complex III; Spastic paraparesis; TTC19
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110220
  2. Am J Med Genet A. 2026 Jul 20.
    Delineation and Phenotypic Expansion of TOP3A-Related Mitochondrial Disease in Childhood.
    Rodrigo T Starosta, Marisa W Friederich, Graeme Preston, Lily Walson, Julie Hong Yin, Steven Lang, Hanna J Tadros, Yue Wang, Elizabeth Mizerik, David Mirsky, Daniella H Hock, David A Stroud, Rossana Sanchez Russo, Fernando Scaglia, Eva Morava, Johan L K Van Hove.
      TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.
    Keywords:  Leigh disease; TOP3A; cardiac transplantation; cardiomyopathy; helicase; mitochondrial DNA maintenance
    DOI:  https://doi.org/10.1002/ajmg.a.70248
  3. J Neurol Sci. 2026 Jul 13. pii: S0022-510X(26)00377-1. [Epub ahead of print]489 126095
    Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
    Giulia Ferrera, Federica Invernizzi, Manuela Spagnolo, Eleonora Lamantea, Isabella Moroni, Anna Ardissone.
       OBJECTIVE: Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking.
    METHODS: We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed.
    RESULTS: Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1).
    INTERPRETATION: Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
    Keywords:  Complex I; Leukoencephalopathy; Mitochondrial disorders; Riboflavin; Treatable
    DOI:  https://doi.org/10.1016/j.jns.2026.126095
  4. JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):
    Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
    David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.
      Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.
    Keywords:  Cell biology; Metabolism; Mitochondria; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.199182
  5. Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194
    Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
    Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.
      Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.
    Keywords:  Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120194
  6. J Peripher Nerv Syst. 2026 Sep;31(3): e70150
    Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.
    Adriana P Rebelo, Katie Lutz, Tiffany Grider, Craig M Zaidman, Michael E Shy, Stephan Zuchner.
       BACKGROUND AND AIMS: SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor-predominant axonal neuropathy presentation associated with biallelic SCO2 variants.
    METHODS: Clinical, genetic, and functional studies were performed in a 15-year-old female presenting with axonal neuropathy. Functional studies were conducted in patient-derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX.
    RESULTS: The patient presented with a motor-predominant axonal neuropathy consistent with Charcot-Marie-Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient-derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss-of-function mechanism.
    INTERPRETATION: These findings demonstrate that SCO2-related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.
    DOI:  https://doi.org/10.1111/jns.70150
  7. Nat Struct Mol Biol. 2026 Jul 23.
    Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
    Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.
      Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.
    DOI:  https://doi.org/10.1038/s41594-026-01849-w
  8. Kidney Int. 2026 Aug;pii: S0085-2538(26)00427-8. [Epub ahead of print]110(2): 291-293
    Mitochondria poor but capacity rich? The paradox of podocyte respiration.
    Antonio S Novaes, Ilse S Daehn.
      Campbell et al. show that podocyte mitochondria, isolated using a cell-specific MITO-Tag approach, possess high intrinsic respiratory capacity despite their low abundance. The study demonstrates that conventional culture conditions suppress mitochondrial respiration and increase oxidative stress, suggesting that current experimental systems may underestimate mitochondrial function in podocytes. The authors provide evidence that mitochondrial respiratory capacity in podocytes declines in male mice with aging, indicating that mitochondria could play a role in age-associated glomerular injury.
    DOI:  https://doi.org/10.1016/j.kint.2026.05.008
  9. J Radiat Res. 2026 Jul 21. pii: rrag054. [Epub ahead of print]
    The role of cytosolic mitochondrial DNA as a mitochondrial danger signal for stromal fibroblasts in forming the tumor-promoting microenvironment following radiation exposure.
    Tsutomu Shimura.
      Inflammation plays an essential role in detecting foreign pathogens, which triggers a defensive response, eliminates infected tissue and facilitates tissue repair. However, when acute inflammation progresses to chronic inflammation, it contributes to the development of diseases, such as cancer. Both the inflammatory response and gene mutations are key elements of radiation-induced carcinogenesis; however, the molecular mechanisms underlying the initiation of the inflammatory response following radiation have not been fully understood yet. We hypothesize that cytosolic mitochondrial DNA is a mediator of the inflammatory response in radiation-induced tumor microenvironment formation. Using normal human fibroblasts and mice, we recently demonstrated that radiation fragmented mitochondrial DNA, which was subsequently released into the cytoplasm. Unlike nuclear DNA, cytosolic mitochondrial DNA is considered foreign by the DNA sensor cyclic GMP-AMP synthase, cGAS, and triggers an immune response similar to that evoked by viral DNA. Thus, cytosolic mitochondrial DNA is a mediator of inflammation in various physiological and pathological contexts. In addition, mitochondrial DNA fragments are released into the extracellular matrix. Such mitochondrial danger signals generated by fibroblasts in response to radiation exposure contribute to inflammation. Here, this review discusses the manner in which mitochondrial danger signals alter the microenvironment of tissue stem cells, or the stem cell niche, and contributes to the formation of the tumor microenvironment. In addition, the mechanisms underlying radiation-induced carcinogenesis are addressed.
    Keywords:  cytosolic mitochondrial DNA; inflammation; mitochondria danger signal; radiation-induced carcinogenesis; tumor microenvironment
    DOI:  https://doi.org/10.1093/jrr/rrag054
  10. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]
    Distinct sources and effects of mitochondrial reactive oxygen species.
    Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.
      Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.
    Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
  11. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2619864123
    HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
    Jiamin Yi, Qin Yang, Chunzhuang Zhou, Yunfei Zhu, Yingfeng Tu, Lin Zhao, Min Tang, Junhong Qin, Tao Long, Tianxing Li, Ping Li, Zikang Gong, Qilin Wang, Xin Yong, Da Jia.
      The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify an AMBRA1-RMC1-HUWE1 signaling axis that directs HUWE1-mediated ubiquitination to mitochondria to regulate neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, and H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, AMBRA1 acts as a mitochondrial scaffold that recruits RMC1, enabling HUWE1 localization to mitochondria through direct interaction with RMC1. Disruption of this recruitment by disease-associated HUWE1 variants prevents mitochondrial targeting and impairs mitochondrial substrate ubiquitination. Notably, Urolithin A treatment ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Together, our findings define an AMBRA1-organized mitochondrial recruitment pathway in which RMC1 links HUWE1 to mitochondria, explain noncatalytic HUWE1-associated XLID, and suggest mitochondrial quality-control enhancement as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1073/pnas.2619864123
  12. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
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