Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis

Mitochondria have been shown to play a key role in apoptosis induction. However, the sequence of changes that occur in the mitochondria in the initial step of apoptosis has not been clearly elucidated. Here, we showed that mitochondrial respiratory chain (MRC) complex I was inhibited during the early phase of TNF- or serum withdrawal apoptosis. The importance of complex I inhibition in apoptosis is also supported by the observation that rotenone, an inhibitor of complex I but not that of other complexes, could induce apoptosis in a manner comparable to TNF. We hypothesized that inhibition of complex I could affect electron flow through other complexes leading to cytochrome c release by an antioxidant-sensitive pathway and caspase 3 activation followed by the induction of membrane permeability transition (MPT). This hypothesis is supported by the following observations: (1) TNF and rotenone induced MPT and cytochrome c release; (2) TNF-induced complex I inhibition was observed prior to cytochrome c release and MPT induction; (3) MPT induction was inhibited by a caspase 3 inhibitor, z-DEVD-CH2F, and an antioxidant pyrrolidine dithiocarbamate (PDTC), whereas cytochrome c release was only inhibited by PDTC. Thus, these results suggest that MRC complex I plays a key role in apoptosis signalings.