Abstract
SummaryValosin-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’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.
Highlights
Valosin-containing protein (VCP), referred to as p97, is a highly expressed member of the type II AAA+ (ATPase associated with multiple activities) ATPase family
Single missense mutations in the VCP gene are the cause of frontotemporal dementia (IBMPFD) (Kimonis et al, 2000; Watts et al, 2004) and may account for 1%–2% of familial amyotrophic lateral sclerosis (ALS) (Johnson et al, 2010)
A significant decrease in DJm was observed in all VCP-deficient cell models studied (SH-SY5Y cells = 72% ± 8%, n > 20 cells in 3 independent experiments compared to either untransfected cells or cells transfected with scramble (SCR) control siRNA; primary neurons = 62% ± 9% and primary astrocytes = 74% ± 4%, n R 5 cells in 3 independent experiments compared to cells transfected with SCR control shRNA; fibroblasts from patient 1 = 86% ± 2%, n = 7; fibroblasts from patient 2 = 85% ± 2%, n = 8; fibroblasts from patient 3 = 91% ± 2%, n = 5, compared to age-matched control fibroblasts) (Figures 1A– 1C)
Summary
Valosin-containing protein (VCP), referred to as p97, is a highly expressed member of the type II AAA+ (ATPase associated with multiple activities) ATPase family. Single missense mutations in the VCP gene are the cause of frontotemporal dementia (IBMPFD) (Kimonis et al, 2000; Watts et al, 2004) and may account for 1%–2% of familial amyotrophic lateral sclerosis (ALS) (Johnson et al, 2010). We demonstrate that VCP deficiency induces the uncoupling of respiration from oxidative phosphorylation. This results in decreased mitochondrial membrane potential, leading to higher respiration and lower ATP levels due to reduced ATP production.
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