非表示:
キーワード:
Adenosine Triphosphate/biosynthesis
Animals
Electron Transport Complex IV/metabolism
Energy Metabolism
Humans
Leigh Disease/genetics
Membrane Potential, Mitochondrial
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria, Heart/*enzymology/pathology
Mitochondrial Proton-Translocating ATPases/*deficiency/genetics
Neoplasm Proteins/*genetics
Oxidative Phosphorylation
Oxygen Consumption
Protein Multimerization
Reactive Oxygen Species/metabolism
要旨:
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.
