Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress.

Alicia J Kowaltowski, Robert G Fenton, Gary Fiskum

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.

Free radical biology & medicine 2004 Dec 1

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Bcl-2 family proteins protect against a variety of forms of cell death, including acute oxidative stress. Previous studies have shown that overexpression of the antiapoptotic protein Bcl-2 increases cellular redox capacity. Here we report that cell lines transfected with Bcl-2 paradoxically exhibit increased rates of mitochondrial H(2)O(2) generation. Using isolated mitochondria, we determined that increased H(2)O(2) release results from the oxidation of reduced nicotinamide adenine dinucleotide-linked substrates. Antiapoptotic Bcl-2 family proteins Bcl-xL and Mcl-1 also increase mitochondrial H(2)O(2) release when overexpressed. Chronic exposure of cells to low levels of the mitochondrial uncoupler carbonyl cyanide 4-(triflouromethoxy)phenylhydrazone reduced the rate of H(2)O(2) production by Bcl-xL overexpressing cells, resulting in a decreased ability to remove exogenous H(2)O(2) and enhanced cell death under conditions of acute oxidative stress. Our results indicate that chronic and mild elevations in H(2)O(2) release from Bcl-2, Bcl-xL, and Mcl-1 overexpressing mitochondria lead to enhanced cellular antioxidant defense and protection against death caused by acute oxidative stress.

Citation

Alicia J Kowaltowski, Robert G Fenton, Gary Fiskum. Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress. Free radical biology & medicine. 2004 Dec 1;37(11):1845-53