Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalo-cardiomyopathies. 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 next-generation 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. Keywords: Mitochondrial diseases o ATP synthase o Nuclear DNA o Mitochondrial DNA o TMEM70.

• MeSH
• Phenotype * MeSH
• Humans MeSH
• Membrane Proteins genetics   metabolism   MeSH
• DNA, Mitochondrial genetics   MeSH
• Mitochondrial Diseases genetics   enzymology   MeSH
• Mitochondrial Proteins genetics   metabolism   MeSH
• Mitochondrial Proton-Translocating ATPases * genetics   metabolism   MeSH
• Mitochondria enzymology   genetics   MeSH
• Mutation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH
• Names of Substances
• Membrane Proteins MeSH
• DNA, Mitochondrial MeSH
• Mitochondrial Proteins MeSH
• Mitochondrial Proton-Translocating ATPases * MeSH
• TMEM70 protein, human MeSH Browser