| The overall focus of our work is to shed new light into the still somewhat mysterious mechanism of survivin-dependent cyto-protection. Contrary to the model of other inhibitor of apoptosis (IAP) proteins, we have found that a pool of survivin localizes to the mitochondria and that a phosphorylation-defective survivin Thr34>Ala dominant negative mutant results in direct dysregulation of mitochondria homeostasis, with release of cytochrome c, activation of upstream caspase-9, and formation of apoptosome assembly. Intrigued by the potent anti-tumor efficacy of the phosphorylation-defective survivin Thr34>Ala mutant, in vitro and in vivo, we have decided to investigate more in depth its potential mechanism of action. What we knew of this survivin mutant was that when over-expressed in cancer cell lines it prevented phosphorylation of endogenous survivin by the mitotic kinase p34cdc2-cyclin B, and rapidly induced caspase-dependent apoptosis. It was clear that this apoptotic response was independent of the status of p53, and did not result from dysregulation of cell cycle progression, but its true mechanism of action had remained a mystery. That both endogenous survivin and the survivin Thr34>Ala mutant prominently localized to mitochondria in subcellular fractionation experiments was a totally unexpected, paradigm-shifting observation. We had already evidence that survivin existed in several immunochemically distinct, subcellular compartments potentially involved with diverse functions, but the identification of a mitochondrial pool of survivin may explain a role of this pathway in the regulation of cytochrome c release, activation of caspase-9 and a more upstream control of mitochondrial cell death, perhaps more reminiscent of Bcl-2 family proteins than IAP members. It may also explain why a potential survivin homolog in the C. elegens does not inhibit apoptosis since the mitochondrial pathway of cell death control is not operative in the nematode. Research in my lab thus focuses on the most mechanistic aspects of the cell biology of mitochondrial targeting and function. This work has the potential to open up a new field of investigation, certainly for the survivin field and perhaps more in general for the way we think of IAP proteins and their function at inhibiting apoptosis.