ATP Synthase Diseases of Mitochondrial Genetic Origin.

Alain Dautant,Jean-Paul Di Rago,Déborah Tribouillard-Tanvier,Thomas Meier,Alexander Hahn,Roza Kucharczyk

doi:10.3389/fphys.2018.00329

Abstract

Devastating human neuromuscular disorders have been associated to defects in the ATP synthase. This enzyme is found in the inner mitochondrial membrane and catalyzes the last step in oxidative phosphorylation, which provides aerobic eukaryotes with ATP. With the advent of structures of complete ATP synthases, and the availability of genetically approachable systems such as the yeast Saccharomyces cerevisiae, we can begin to understand these molecular machines and their associated defects at the molecular level. In this review, we describe what is known about the clinical syndromes induced by 58 different mutations found in the mitochondrial genes encoding membrane subunits 8 and a of ATP synthase, and evaluate their functional consequences with respect to recently described cryo-EM structures.

Highlights

Mitochondria support aerobic respiration and produce the bulk of cellular ATP by oxidative phosphorylation (OXPHOS) (Saraste, 1999)
Electrons provided by the oxidation of fatty acids and carbohydrates are shuttled to oxygen along four respiratory chain (RC) complexes (I–IV) embedded in the inner mitochondrial membrane (IMM), producing water and releasing the energy necessary to pump protons from the mitochondrial matrix to the intermembrane space (IMS)
This review focuses on mutations in the MT-ATP8 and MTATP6 genes encoding subunits 8 and a of ATP synthase, respectively, that were identified in patients with various disorders

Summary

INTRODUCTION

Mitochondria support aerobic respiration and produce the bulk of cellular ATP by oxidative phosphorylation (OXPHOS) (Saraste, 1999). Owing to its good fermenting capacity, yeast models of human mitochondrial diseases can be kept alive when provided with sugars like glucose even when oxidative phosphorylation is completely inactivated (Baile and Claypool, 2013; Lasserre et al, 2015) This approach was used to investigate the impact on ATP synthase of nine ATP6 mutations identified in patients (Rak et al, 2007; Kucharczyk et al, 2009a,b,c, 2010, 2013; Kabala et al, 2014; Lasserre et al, 2015; Niedzwiecka et al, 2016; Wen et al, 2016). 8989G>C 8993T>G aI106T aW109R aK122E aA126T aP136S aM140T aV142I aS148N aA155P aL156R

20–96 Reduced Defective

98–99 Reduced nd

Findings

CONCLUSIONS