Mitochondrial ATP synthase disorders: Molecular mechanisms and the quest for curative therapeutic approaches

Abstract

In mammals, the majority of cellular ATP is produced by the mitochondrial F1F(O)-ATP synthase through an elaborate catalytic mechanism. While most subunits of this enzymatic complex are encoded by the nuclear genome, a few essential components are encoded in the mitochondrial genome. The biogenesis of this multi-subunit enzyme is a sophisticated multi-step process that is regulated on levels of transcription, translation and assembly. Defects that result in diminished abundance or functional impairment of the F1F(O)-ATP synthase can cause a variety of severe neuromuscular disorders. Underlying mutations have been identified in both the nuclear and the mitochondrial DNA. The pathogenic mechanisms are only partially understood. Currently, the therapeutic options are extremely limited. Alternative methods of treatment have however been proposed, but still encounter several technical difficulties. The application of novel scientific approaches promises to deepen our understanding of the molecular mechanisms of the ATP synthase, unravel novel therapeutic pathways and improve the unfortunate situation of the patients suffering from such diseases.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Approximately 10% of individuals have either the MT-ATP6 (mitochondrially encoded ATP synthase 6) m.8993T>G or m.8993T>C variants which represent the only established genetic cause of a Complex V-mediated LS (Santorelli et al 1993;Rahman et al 1996;Thorburn and Rahman 2014). The MT-ATP6 gene encodes a subunit of the 550 kKDa multi-subunit Complex V (ATP synthase or F 1 F o ATPase), which is one of the key enzymes involved in the aerobic generation of energy, synthesizing ATP from ADP using the proton gradient generated across the mitochondrial inner membrane (Kucharczyk et al 2009). Unlike many pathogenic mtDNA variants, the m.8993T>G and m.8993T>C variants display a strong genotype-phenotype correlation, with a lack of tissue or age-dependent variation in mutant load (White et al 1999a) which enables accurate prediction of the probability of severe outcome and empirical recurrence risks (White et al 1999b).…”

Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C

“…Both mutations change a leucine residue into proline near the C-terminal end of the human homolog of yeast Atp6p, at positions 220 and 222 respectively. These leucine residues show moderate evolutionary conservation as manifested by the presence of different amino acids at corresponding positions in other species (like Ser, Val, Ile, and Gly at position 220; Ala, Met, Ser and Ile at position 222) (see [29] for amino acids alignments). In current folding models [29], these residues belong to the last -helical transmembrane segment (helix V) of Atp6p.…”

“…These leucine residues show moderate evolutionary conservation as manifested by the presence of different amino acids at corresponding positions in other species (like Ser, Val, Ile, and Gly at position 220; Ala, Met, Ser and Ile at position 222) (see [29] for amino acids alignments). In current folding models [29], these residues belong to the last -helical transmembrane segment (helix V) of Atp6p. This segment would contact the Atp9p-ring and is presumed to play a key role in proton transport through the F O [43].…”

“…This segment would contact the Atp9p-ring and is presumed to play a key role in proton transport through the F O [43]. Nearby the leucine 220 and 222 of the human homolog of yeast Atp6p are two residues within helix V, leucine 217 and tyrosine 221, that have possible crucial importance as indicated by their strict evolutionary conservation [29]. It is therefore not very surprising that replacing leucine 220 or 222 by an -helix breaker residue like proline is detrimental to human health.…”

“…The leucine residues 220 and 222 of the human homolog of yeast Atp6p that are modified by the T9185C and T9191C mutations correspond respectively to serine 250 and leucine 252 of Atp6p [29]. The TCA and TTA codons specifying these residues were converted into proline CCA codon (see Materials and Methods).…”