Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches.
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.
Kucharczyk
Roza
R
Institut de Biochimie et Génétique Cellulaires, CNRS-Université Bordeaux2, Bordeaux 33077, France.
Zick
Michael
M
Bietenhader
Maïlis
M
Rak
Malgorzata
M
Couplan
Elodie
E
Blondel
Marc
M
Caubet
Stéphane-Duvezin
SD
di Rago
Jean-Paul
JP
D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000378:metabolism / Q000628:therapy; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D004272:DNA, Mitochondrial; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; D025261:Mitochondrial Proton-Translocating ATPases