Mourier 2014 Hum Mol Genet

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Mourier A, Ruzzenente B, Brandt T, Kühlbrandt W, Larsson NG (2014) Loss of LRPPRC causes ATP synthase deficiency. Hum Mol Genet 23:2580-92.

» PMID:24399447 Open Access

Mourier A, Ruzzenente B, Brandt T, Kuehlbrandt W, Larsson NG (2014) Hum Mol Genet

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.

Keywords: Amplex Red

O2k-Network Lab: DE Cologne Larsson NG

Labels: MiParea: Respiration, mt-Structure;fission;fusion, Genetic knockout;overexpression  Pathology: Neurodegenerative  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria  Enzyme: Complex IV;cytochrome c oxidase  Regulation: Threshold;excess capacity  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S  HRR: Oxygraph-2k