Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment

M. Lopez-Cruzan, R. Sharma, M. Tiwari, S. Karbach, D. Holstein, C. R. Martin, J. D. Lechleiter, B. Herman

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Abstract

Caspase-2 plays an important role in apoptosis induced by several stimuli, including oxidative stress. However, the subcellular localization of caspase-2, particularly its presence in the mitochondria, is unclear. It is also not known if cytosolic caspase-2 translocates to the mitochondria to trigger the intrinsic pathway of apoptosis or if caspase-2 is constitutively present in the mitochondria that then selectively mediates this apoptotic effect. Here, we demonstrate the presence of caspase-2 in purified mitochondrial fractions from in vitro-cultured cells and in liver hepatocytes using immunoblots and confocal microscopy. We show that mitochondrial caspase-2 is functionally active by performing fluorescence resonance energy transfer analyses using a mitochondrially targeted substrate flanked by donor and acceptor fluorophores. Cell-free apoptotic assays involving recombination of nuclear, cytosolic and mitochondrial fractions from the livers of wild type and Casp2−/− mice clearly point to a direct functional role for mitochondrial caspase-2 in apoptosis. Furthermore, cytochrome c release from Casp2−/− cells is decreased as compared with controls upon treatment with agents inducing mitochondrial dysfunction. Finally, we show that Casp2−/− primary skin fibroblasts are protected from oxidants that target the mitochondrial electron transport chain. Taken together, our results demonstrate that caspase-2 exists in the mitochondria and that it is essential for mitochondrial oxidative stress-induced apoptosis.

Original languageEnglish (US)
Article number16005
JournalCell Death Discovery
Volume2
Issue number1
DOIs
StatePublished - Dec 12 2016
Externally publishedYes

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Lopez-Cruzan, M., Sharma, R., Tiwari, M., Karbach, S., Holstein, D., Martin, C. R., Lechleiter, J. D., & Herman, B. (2016). Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment. Cell Death Discovery, 2(1), [16005]. https://doi.org/10.1038/cddiscovery.2016.5