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MBC in Press, published online ahead of print September 8, 2004
Mol. Biol. Cell 10.1091/mbc.E04-04-0294

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Submitted on April 8, 2004
Revised on August 5, 2004
Accepted on August 30, 2004

Roles of the Mammalian Mitochondrial Fission and Fusion Mediators Fis1, Drp1, and Opa1 in Apoptosis

Yang-ja Lee,*{dagger} Seon-Yong Jeong,*{dagger} Mariusz Karbowski,* Carolyn L. Smith,{ddagger} and Richard J. Youle*{sect}

*Biochemistry Section, Surgical Neurology Branch, and {ddagger}Light Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: Keith Yamamoto

During apoptosis the mitochondrial network fragments. Using short hairpin RNAs (shRNAs) for RNA interference (RNAi) we manipulated the expression levels of three proteins, hFis1, Drp1, and Opa1, that are involved in mitochondrial fission and fusion in mammalian cells, and we characterized their functions in mitochondrial morphology and apoptosis. Down-regulation of hFis1 powerfully inhibits cell death to an extent significantly greater than down-regulation of Drp1 and at a stage of apoptosis distinct from that induced by Drp1 inhibition. Cells depleted of Opa1 are extremely sensitive to exogenous apoptosis induction and some die spontaneously by a process that requires hFis1 expression. Wild-type Opa1 may function normally as an antiapoptotic protein, keeping spontaneous apoptosis in check. However, if hFis1 is down-regulated, cells do not require Opa1 to prevent apoptosis, suggesting that Opa1 may be normally counteracting the proapoptotic action of hFis1. We also demonstrate in this study that mitochondrial fragmentation per se does not result in apoptosis. However, we provide further evidence that multiple components of the mitochondrial morphogenesis machinery can positively and negatively regulate apoptosis.

{dagger}These authors contributed equally to this work.

{sect}Corresponding author. E-mail: youle{at}ninds.nih.gov






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