Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase

Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalocardiomyopathies. Since ATP synthase subunits are encoded by both mitochondrial and nuclear DNA, pathogenic variants can be found...

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Bibliographic Details
Published in:Physiological research 2024-08, Vol.73 (Suppl 1), p.S243-S278
Main Authors: Tauchmannová, Kateřina, Pecinová, Alena, Houštěk, Josef, Mráček, Tomáš
Format: Article
Language:English
Subjects:
Age
Alzheimer's disease
ATP synthase
Biosynthesis
Diabetes
Disease
DNA sequencing
Enzymes
Evolution
Genes
Genomes
Metabolic disorders
Mitochondrial DNA
Mutation
Pediatrics
Phenotypes
Phosphorylation
Proteins
Protons
Review
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Summary:Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalocardiomyopathies. Since ATP synthase subunits are encoded by both mitochondrial and nuclear DNA, pathogenic variants can be found in either genome. In addition, the biogenesis of ATP synthase requires several assembly factors, some of which are also hotspots for pathogenic variants. While variants of MT-ATP6 and TMEM70 represent the most common cases of mitochondrial and nuclear DNA mutations respectively, the advent of nextgeneration sequencing has revealed new pathogenic variants in a number of structural genes and TMEM70, sometimes with truly peculiar genetics. Here we present a systematic review of the reported cases and discuss biochemical mechanisms, through which they are affecting ATP synthase. We explore how the knowledge of pathophysiology can improve our understanding of enzyme biogenesis and function.
ISSN:0862-8408
1802-9973
DOI:10.33549/physiolres.935407