Deficiency of mitochondrial ATP synthase of nuclear genetic origin

Abstract

We present clinical and laboratory data from 14 cases with an isolated deficiency of the mitochondrial ATP synthase (7–30% of control) caused by nuclear genetic defects. A quantitative decrease of the ATP synthase complex was documented by Blue-Native electrophoresis and Western blotting and was supported by the diminished activity of oligomycin/aurovertin-sensitive ATP hydrolysis in fibroblasts (10 cases), muscle (6 of 7 cases), and liver (one case). All patients had neonatal onset and elevated plasma lactate levels. In 12 patients investigated 3-methyl-glutaconic aciduria was detected. Seven patients died, mostly within the first weeks of life and surviving patients showed psychomotor and various degrees of mental retardation. Eleven patients had hypertrophic cardiomyopathy; other clinical signs included hypotonia, hepatomegaly, facial dysmorphism and microcephaly. This phenotype markedly differs from the severe central nervous system changes of ATP synthase disorders caused by mitochondrial DNA mutations of the ATP6 gene presenting mostly as NARP and MILS.

Introduction

Disorders of the mitochondrial oxidative phosphorylation (OXPHOS) system cause a highly diverse group of diseases that affect primarily energy-demanding tissues, such as the central nervous system, skeletal muscle, and heart. Genetic defects of OXPHOS result from either mutations in mitochondrial DNA (mtDNA) or nuclear genes, which have attracted increasing attention in recent years [1]. Nuclear DNA mutations are more commonly involved in pediatric mitochondrial diseases than are mtDNA mutations [2]. Mendelian OXPHOS disorders can affect all respiratory chain complexes, mostly complex I and complex IV, while disorders of ATP synthase have been reported less often [3].

The ATP synthase, complex V of the mitochondrial respiratory chain, is the key enzyme of mammalian energy conversion as it provides over 95% of cellular ATP. It consists of 16 different polypeptides, six of which comprise the globular F₁-catalytic portion, while the other 10 form the membrane-spanning F_o portion and two connecting stalks [4] (Fig. 1). The F_o part translocates the protons and transduces the energy of the proton electrochemical gradient to the F₁ part, where ADP is phosphorylated to ATP. Only two of the F_o subunits, subunit a and subunit A6L are the products of mitochondrial genes ATP6 and ATP8, respectively [5]. All the other ATP synthase subunits are nuclearly encoded. Biosynthesis of ATP synthase is a highly ordered process which involves ATP synthase-specific assembly proteins. Several of them are known in yeast and recent studies described two human F₁-specific assembly factors, ATP11 and ATP12, encoded by ATPAF1 and ATPAF2 genes [6], [7], [8], [9].

Isolated dysfunction of ATP synthase can be caused either by mutations in mtDNA genes or by genetic defects of nuclear origin. Several mutations in the mtDNA ATP6 gene have been described [10] that alter the function of the proton channel and result in loss of ATP-synthetic activity, whilst retaining hydrolytic activity [11], [12] and the total amount of the enzyme. These maternally transmitted disorders occur frequently and typically affect the central and peripheral nervous systems [10]. Patients present with neuropathy, ataxia, and retinitis pigmentosa (NARP), maternally inherited Leigh syndrome (MILS), or bilateral striatal necrosis.

The nuclear origin of ATP synthase deficiency was demonstrated for the first time in 1999 in an infant with severe lactic acidosis, cardiomyopathy and hepatomegaly [13]. Up to now, only few cases have been reported with isolated ATP synthase deficiency due to nuclear genetic defects [3]. They are characterized by a markedly decreased content of an otherwise structurally and functionally normal enzyme. The primary cause appears to be a defect at the early stage of enzyme assembly involving the formation of the F₁ catalytic part of the enzyme [13].

In this paper, we summarize data on 14 patients with ATP synthase deficiency. Seven patients have been reported [3], [13], [14], [15], [16], the other 7 patients have been diagnosed recently and are described for the first time. We compared and analyzed available information on clinical presentation, tissue involvement, metabolic profiles, and specific methods to evaluate the structure and function of ATP synthase in order to highlight the dominant clinical and laboratory features and the differences from patients with mtDNA-based defects. The increasing number of cases reviewed in this article indicates that these biosynthetic defects may be more frequent than originally thought. In one patient, the gene defect was localized to the assembly factor ATP12 [16]. In other cases the mutated genes remain unknown.