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 t he initial step of apoptosis has not been clearly elucidated, Here, we showed that mitochondrial respiratory chain (MRC) complex I was inhib ited 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 T NF, We hypothesized that inhibition of complex I could affect electron flow through other complexes leading to cytochrome c release by an an tioxidant-sensitive pathway and caspase 3 activation followed by the i nduction 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 wa s observed prior to cytochrome c release and MPT induction; (3) MPT in duction was inhibited by a caspase 3 inhibitor, z-DEVD-CH2F, and an an tioxidant pyrrolidine dithiocarbamate (PDTC), whereas cytochrome c rel ease was only inhibited by PDTC, Thus, these results suggest that MRC complex I plays a key role in apoptosis signalings.