A Theoretical Model of Mitochondrial ATP Synthase Deficiencies. The Role of Mitochondrial Carriers

Jean-Pierre Mazat,Edgar Yoboue,Stéphane Ransac,Anne Devin

doi:10.3390/pr9081424

Abstract

The m.8993T>G mutation of the mitochondrial MT-ATP6 gene is associated with NARP syndrome (neuropathy, ataxia and retinitis pigmentosa). The equivalent point mutation introduced in yeast Saccharomyces cerevisiae mitochondrial DNA considerably reduced the activity of ATP synthase and of cytochrome-c-oxidase, preventing yeast growth on oxidative substrates. The overexpression of the mitochondrial oxodicarboxylate carrier (Odc1p) was able to rescue the growth on the oxidative substrate by increasing the substrate-level phosphorylation of ADP coupled to the conversion of α-ketoglutarate (AKG) into succinate with an increase in Complex IV activity. Previous studies showed that equivalent point mutations in ATP synthase behave similarly and can be rescued by Odc1p overexpression and/or the uncoupling of OXPHOS from ATP synthesis. In order to better understand the mechanism of the ATP synthase mutation bypass, we developed a core model of mitochondrial metabolism based on AKG as a respiratory substrate. We describe the different possible metabolite outputs and the ATP/O ratio values as a function of ATP synthase inhibition.

Highlights

Mitochondria support aerobic respiration and produce most of the cellular ATP by oxidative phosphorylation, i.e., the coupling of a series of redox reactions and the electron transport chain (ETC) with ATP synthase through a transmembraneous proton gradient.The ETC is mainly fed by the NADH and succinate generated in the TCA cycle and a few other possible dehydrogenases.ATP synthase organizes into a matrix domain (F1 inside mitochondria) where ATP is synthesized and a membrane-embedded domain (Fo) moves protons across the membrane [1,2,3,4]
In order to better understand the mechanism of the ATP synthase mutation bypass, we developed a core model of mitochondrial metabolism based on AKG as a respiratory substrate
In order to have a better understanding of the rescue mechanism by Odc1p, we developed in this paper a metabolic model of yeast mitochondria that characterizes the different possible metabolic pathways bypassing oxidative phosphorylation ATP deficiency in isolated yeast mitochondria using α-ketoglutarate (AKG) as a respiratory substrate

Summary

Introduction

Mitochondria support aerobic respiration and produce most of the cellular ATP by oxidative phosphorylation, i.e., the coupling of a series of redox reactions and the electron transport chain (ETC) with ATP synthase through a transmembraneous proton gradient.The ETC is mainly fed by the NADH and succinate generated in the TCA cycle and a few other possible dehydrogenases.ATP synthase organizes into a matrix domain (F1 inside mitochondria) where ATP is synthesized and a membrane-embedded domain (Fo) moves protons across the membrane [1,2,3,4]. Dozens of point mutations in the mitochondrial MT-ATP6 gene (coded by the ATP6 gene in yeast mtDNA) have been identified as leading to deleterious neuromuscular disorders [5]. This gene codes for the subunit A in ATP synthase. The m.8993T>G mutation of the mitochondrial MT-ATP6 gene affecting the mitochondrial energy transduction has been studied [8]. This mutation has been associated in humans with numerous cases of neuropathy, ataxia and retinitis pigmentosa (NARP) and maternally-inherited Leigh syndrome

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