Mitochondria are important participants in apoptosis, releasing cytochrome c into the cytoplasm and undergoing extensive fragmentation. However, mechanisms underlying these processes remain unclear. Here, we demonstrate that cytochrome c release during apoptosis precedes mitochondrial fragmentation. Unexpectedly, OPA1, a dynamin-like GTPase of the mitochondrial intermembrane space important for maintaining cristae structure, is co-released with cytochrome c. To mimic the loss of OPA1 occurring after its release, we knocked down OPA1 expression using RNA interference. This triggered structural changes in the mitochondrial cristae and caused increased fragmentation by blocking mitochondrial fusion. Because cytochrome c is mostly sequestered within cristae folds but released rapidly and completely during apoptosis, we examined the effect of OPA1 loss on cytochrome c release, demonstrating that it is accelerated. Thus, our results suggest that an initial mitochondrial leak of OPA1 leads to cristae structural alterations and exposure of previously sequestered protein pools, permitting continued release in a feed-forward manner to completion. Moreover, our findings indicate that the resulting OPA1 depletion causes a block in mitochondrial fusion, providing a compelling mechanism for the prominent increase in mitochondrial fragmentation seen during apoptosis.
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