Mitochondrial regulation of cell death: Processing of apoptosis-inducing factor (AIF)
Introduction
Since more than 25 years our research has focused on the regulation and mechanisms of apoptotic cell death and its possible implications for human disease. Much of our recent work has been concerned with mitochondrial regulation of cell death by the release of cytochrome c and other pro-apoptotic proteins, which was early found to represent an important pathway of apoptosis regulation [1], [2]. We first studied Ca2+ signaling as a component of the apoptotic program and demonstrated that release of pro-apoptotic proteins from mitochondria can occur via both Ca2+-dependent and Ca2+-independent mechanisms [3]. We also found that the export of cytochrome c from mitochondria during apoptosis proceeds by a two-step process, involving the detachment of the hemoprotein from its binding to cardiolipin in the inner mitochondrial membrane (IMM) followed by its translocation into the cytosol [4]. We observed that microinjection of cytochrome c results in the induction of apoptosis in a number of different cell types [5], and found that aberrant mitochondrial iron distribution is responsible for spontaneous cytochrome c release from mitochondria in early erythroid precursor cells in myelodysplastic syndrome [6]. Detailed analysis of the mechanisms of resistance of lung cancer cells to radio- and chemotherapy revealed a deficiency in caspase-8 expression in a majority of small cell lung cancer cells and clinical samples, and suggested that mitochondrial dysfunction is an essential step for killing non-small cell lung carcinoma (NSCLC) cells resistant to conventional treatment [7].
Hence, investigations of the role of mitochondria in cell death have long been in the focus of our research. This intracellular organelle is functioning as a switchboard in cell death signaling. In particular, the permeabilization of the outer mitochondrial membrane (OMM) and the subsequent release of pro-apoptotic proteins from the intermembrane space (IMS) of mitochondria are key events in both caspase-dependent and caspase-independent pathways [8]. Apoptosis-inducing factor (AIF) is one of the mitochondrial proteins to be released into the cytosol during apoptosis, and it was discovered as the first protein that regulates caspase-independent apoptosis [9].
Section snippets
Apoptosis-inducing factor (AIF)
AIF is encoded as a 67 kDa protein that contains a mitochondrial localization signal (MLS) in the N-terminus. Upon import into the mitochondria, the MLS is removed by a mitochondrial peptidase generating the mature 62 kDa protein [10]. Initially, AIF was regarded as a soluble protein localized in the IMS [9]. However, later it became clear that AIF is N-terminally anchored to the IMM [10], where it exerts NADH oxidase activity [11]. The crystal structure of mouse and human AIF (which share 92%
Enzymes involved in AIF processing
Several years ago it was shown that AIF and Endonuclease G are not released from permeabilized mitochondria simultaneously with cytochrome c and Smac/DIABLO, suggesting that, apart from OMM permeabilization, some additional signals are required for their appearance in the cytosol [25]. It was also reported that recombinant calpain-I could cleave and release AIF from Bid-permeabilized mitochondria [26]. In another study, detailed biochemical analysis revealed the presence of three forms of AIF
Other factors modulating the cleavage of AIF
Determination of the crystal structure of both the murine and the human AIF protein has revealed that the calpain/cathepsin cleavage site in AIF is not exposed on the surface of the protein, but rather embedded in its structure. Therefore, one possible limiting step in AIF processing might be the accessibility of the cleavage site to the protease. Indeed, it was proposed that redox-regulated conformational changes of the AIF structure, affecting its binding to pyridine nucleotides, might
Involvement of AIF in apoptosis execution
It is currently known that the AIF-mediated pathway is not important for all cell death mechanisms. Hence, the elimination of AIF does not protect from apoptosis induced by most drugs. Similarly, not all caspases are involved in the regulation of apoptosis, although overexpression of any one of the caspases culminates in cell death. However, this does not occur upon AIF overexpression. Further, knockout of any of the caspases results in an increase in cell number. In contrast, genetic
Conclusions
Like many other pro-apoptotic proteins, AIF was initially considered to be involved only in cell death signaling. However, gradually there has been accumulating evidence that AIF fulfills several other important physiological functions, both as a redox-active protein and in mitochondrial bioenergetics. The AIF-mediated death pathway is activated in a trigger-specific manner and seems to play a more prominent role in certain cell types. As also supported by current in vivo data, calpain-I
Acknowledgments
This work was supported by grants from the Swedish Research Council, the Swedish and the Stockholm Cancer Societies, the Swedish Childhood Cancer Foundation, the EC FP-6 (Oncodeath and Chemores) as well as the FP7 (Apo-Sys) programs. We apologize to authors whose primary references could not be cited due to space limitation.
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