(32) THE ROLE OF MITOCHONDRIAL RESPIRATORY FUNCTION IN APOPTOSIS

Masahiro Higuchi
University of Texas, Houston, TX 77030

The involvement of mitochondria in the cell death response remains controversial. Here we demonstrate that mitochondria play a critical role in TNF-induced apoptosis. Depletion of respiration from human ML-1a cells by deleting mitochondrial DNA-derived protein completely abrogated TNF-induced apoptosis, whereas reconstitution of mitochondria in respiration-deficient cells following fusion with platelets restored TNF-induced apoptosis. In contrast, inhibition of proliferation and induction of differentiation by TNF were observed in respiration-free cells. The role of mitochondria in apoptosis has also been extended to the Fas-mediated pathway and serum starvation. TNF damaged the mitochondrial respiration chain complex I in the early stage of apoptosis. An obligatory role for complex I dysfunction in apoptosis was defined, since a specific inhibitor of complex I, but not inhibitors of other complexes, induced cytochrome c release and apoptosis. These observations define an early pathway in which TNF causes complex I dysfunction which in turn induces apoptosis.