Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels

作者：Bartolome Fernando; Wu Hsiu Chuan; Burchell Victoria S; Preza Elisavet; Wray Selina; Mahoney Colin J; Fox Nick C; Calvo Andrea; Canosa Antonio; Moglia Cristina; Mandrioli Jessica; Chio Adriano; Orrell Richard W; Houlden Henry; Hardy John; Abramov Andrey Y^*; Plun Favreau Helene

来源：Neuron, 2013, 78(1): 57-64.

DOI：10.1016/j.neuron.2013.02.028

Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget%26apos;s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.

• 出版日期2013-4-10