title: Loss of LRPPRC causes ATP synthase deficiency.
abstract: Defects of the oxidative phosphorylation system, in particular of cytochrome-c oxidase (COX, respiratory chain complex IV), are common causes of Leigh syndrome (LS), which is a rare neurodegenerative disorder with severe progressive neurological symptoms that usually present during infancy or early childhood. The COX-deficient form of LS is commonly caused by mutations in genes encoding COX assembly factors, e.g. SURF1, SCO1, SCO2 or COX10. However, other mutations affecting genes that encode proteins not directly involved in COX assembly can also cause LS. The leucine-rich pentatricopeptide repeat containing protein (LRPPRC) regulates mRNA stability, polyadenylation and coordinates mitochondrial translation. In humans, mutations in Lrpprc cause the French Canadian type of LS. Despite the finding that LRPPRC deficiency affects the stability of most mitochondrial mRNAs, its pathophysiological effect has mainly been attributed to COX deficiency. Surprisingly, we show here that the impaired mitochondrial respiration and reduced ATP production observed in Lrpprc conditional knockout mouse hearts is caused by an ATP synthase deficiency. Furthermore, the appearance of inactive subassembled ATP synthase complexes causes hyperpolarization and increases mitochondrial reactive oxygen species production. Our findings shed important new light on the bioenergetic consequences of the loss of LRPPRC in cardiac mitochondria.
authors.affiliation: Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany and.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ruzzenente
authors.forename: Tobias
authors.initials: T
authors.lastname: Brandt
authors.forename: Werner
authors.initials: W
authors.lastname: Kühlbrandt
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D007888:Leigh Disease / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D055503:Protein Multimerization; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C486222:Lrpprc protein, mouse; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases