ArticleHuman molecular genetics2022
Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- Modelling mitochondrial diseases in neuronsJournal of neuromuscular diseases · 2025Pooled it
- Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.Cell · 2026Article
- Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.Communications biology · 2025Article
- Moderate Chronic Treadmill Exercise Slows Dopaminergic Neuron Loss in a Rat Model of Parkinson's Disease and Alters RNA Content of Circulating Plasma Exosomes.Journal of neuroscience research · 2025Article
- Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.Acta neuropathologica communications · 2025Article
- Disease models of Leigh syndrome: From yeast to organoids.Journal of inherited metabolic disease · 2024Review
- Advances and challenges in modeling inherited peripheral neuropathies using iPSCs.Experimental & molecular medicine · 2024Review
- Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies.International journal of molecular sciences · 2024Review
- Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.Journal of biomedical science · 2023Review
- A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.Nature biomedical engineering · 2023Article
- Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges.Brain sciences · 2023Review
- A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype.International journal of molecular sciences · 2023Article
- Mitochondrial protein dysfunction in pathogenesis of neurological diseases.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. Here we investigated the functional consequences of an unusual heteroplasmic truncating mutation m.9154C>T in MT-ATP6, which caused peripheral neuropathy, ataxia and IgA nephropathy. ATP synthase not only generates cellular ATP, but its dimerization is required for mitochondrial cristae formation. Accordingly, the MT-ATP6 truncating mutation impaired the assembly of ATP synthase and disrupted cristae morphology, supporting our molecular dynamics simulations that predicted destabilized a/c subunit subcomplex. Next, we modeled the effects of the truncating mutation using patient-specific induced pluripotent stem cells. Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). Interestingly, MN differentiation beyond progenitor stage was impaired by Notch hyperactivation in the MT-ATP6 mutant, but not by rotenone-induced inhibition of mitochondrial respiration, suggesting that altered mitochondrial morphology contributed to Notch hyperactivation. Finally, we also identified a lower mutation threshold for a metabolic shift in mature MN, affecting lactate utilization, which may be relevant for understanding the mechanisms of mitochondrial involvement in peripheral motor neuropathies. These results establish a critical and disease-relevant role for ATP synthase in human cell fate decisions and neuronal metabolism.
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