Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release

Dear Editor,

During the last years, research on the molecular mechanisms governing caspase-dependent and -independent cell death has yielded a significant quantity of exciting works. As part of those efforts, apoptosis-inducing factor (AIF) was the first identified mitochondrial protein involved in caspase-independent cell death.¹ Under physiological conditions, AIF is a mitochondrial FAD-dependent oxidoreductase that plays a role in oxidative phosphorylation.² However, after a cellular insult, AIF is released from mitochondria and translocates to cytosol and nucleus where it achieves its proapoptotic function.^{1, 3} Importantly, AIF seems a key factor in neuronal cell death⁴ and is involved in the early stages of development.⁵ Although alternative studies demonstrate that AIF could also be released in a caspase-dependent manner,^{6, 7} AIF has been generally implicated in the caspase-independent mode of cell death. In this context, two recent papers from Otera et al.⁸ and Uren et al.⁹ demonstrated that AIF is a membrane-integrated protein that needs to be cleaved for becoming a soluble and apoptogenic protein. In fact, Otera et al.⁸ states that AIF is released from mitochondria by a two-step process. First, AIF is cleaved in the mitochondrial matrix by the mitochondrial processing peptidase to form an inner-membrane-anchored form. In a second step, AIF is processed, by an unidentified protease, in the intermembrane space of mitochondria (IMS) to yield a soluble and proapoptotic protein released to cytosol. But how is AIF cleaved in the IMS? Is it by a caspase? Apparently not. A third study from Polster et al.¹⁰ reported that after incubation of isolated mitochondria with different amounts of Ca²⁺, mitochondrial AIF release occurs through an N-terminal cleavage mediated by the Ca²⁺-dependent protease calpain I (also called μ-calpain). These data provide a critical clue to understanding the regulation of AIF action. However, we here demonstrate that the mechanism governing AIF cleavage in the mitochondrial IMS is more complex than initially expected.

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