Regulation and function of the mitochondrial protease HtrA2/Omi in the control of cell death

The serine protease HtrA2 is released from mitochondria following apoptotic stimuli. Once in the cytosol, HtrA2 has been implicated in promoting cell death by a caspase-dependent and -independent mechanism. However, mice lacking expression of HtrA2 show no evidence of reduced rates of cell death. On the contrary, loss of HtrA2 causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. This suggests that the protease function of HtrA2 in the mitochondria, and not its pro-apoptotic action in the cytosol, is critical. Mammalian HtrA2 is therefore likely to function in vivo in a manner similar to its bacterial homologues, which are involved in protection against cell stress. The bacterial DegS homologue senses unfolded proteins, activating a proteolytic cascade leading to induction of stress response genes. Transcriptional profiling of wild type and HtrA2 knockout (KO) cells identified the stress-inducible transcription factor CHOP being differentially regulated when mitochondrial stress was triggered. CHOP up-regulation was found in HtrA2 KO mouse brains but not in other tissues. Transcriptional profiling of brain tissue revealed a number of putative ATF4 target genes being up-regulated in HtrA2 KO, among these CHOP. Promoter analysis identified a C/EBP-ATF composite site in the majority of the genes within this signature. Therefore, loss of HtrA2 might impact on nuclear gene expression specifically in brain, subverting normal cellular homeostasis leading to disease. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PD) resulting in partial loss of proteolytic activity. Affinity purification shows that the mitochondrial kinase PINKl interacts with HtrA2. PINKl mutations are associated with the PARK6 PD susceptibility locus. HtrA2 is phosphorylated in a PINKl-dependent manner at residues adjacent to positions found mutated in PD patients. Phosphorylation ofHtrA2 and thereby modulation of its proteolytic activity seems necessary for the function of HtrA2 in the mitochondria contributing to increased resistance of cells to mitochondrial stress.EThOS - Electronic Theses Online ServiceGBUnited Kingdo