The Subcellular Distribution Of Apoptosis-inducing Factor Is Regulated By C-Abl Kinase

Abstract:The apoptosis-inducing factor (AIF) was discovered by Kroemer and coworkers in1996. In the presence of pan-caspase inhibitor z-vad.fmk, AIF plays an important role in inducing the caspase-independent cell death. AIF is also involved in the maintenance of mitochondrial morphology, energy metabolism homeostasis regulation and oxidative stress responses.Non-receptor tyrosine kinase c-Abl, an important member in Src non-receptor tyrosine kinase protein family, is encoded by c-abl gene located in chromosome9in human species. c-Abl kinase plays a wide range of roles in cellular processes regulation, including cell proliferation, cell cohesion, genotoxic or oxidative stress, and cell death et al. In oxidative stress, c-Abl is activated and recruited to mitochondrial, mediating ROS-induced loss of mitochondrial transmembrane potential, depletion of ATP, and a necrosis-like cell death. However, the mechanisms of c-Abl-mediated mitochondrial regulation remains unclear.Our previous findings have demonstrated that the non-receptor tyrosine kinase c-Abl could interact with and phosphorylate AIF. In this study, we showed that c-Abl kinase selective inhibitor STI571could remarkably alternate AIF subcelluar distribution and mitochondrial morphology, impede the mitochondrial localization of AIF precursor, and induce the loss of mitochondrial transmembrane potential and cellular ROS (reactive oxidative species) level increase. However, the expression of the mitochondrial-anchored COX-AIF in the cells could particially rescue the damages contributed by STI571treatment. Further, it was demonstrated that c-Abl kinase could phosphorylate AIF precursor, but not the AIF without mitochondrial localization signal, indicating that the phosphorylation site of AIF is probably located in the1-120a.a. Moreover, we found that the ubiquity lation of AIF was notably inhibited by Parkin, and the interaction between AIF and Parkin was reinforced by c-Abl kinase.Here we proposed that c-Abl regulates mitochondrial structure and function through phosphorylating AIF precursor and promoting its transportation from cytoplasma to mitochondrial. At the same time, c-Abl plays a critical role in keeping AIF stability by enhancing the interaction between Parkin and AIF and protecting it from being degraded by proteasome. Our findings provide a new clue for understanding c-Abl-mediated mitochondrial regulation and celluar oxidative species elimination.