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Mutations in Parkin, an E3 ubiquitin ligase, are associated to autosomal recessive Parkinson׳s disease (PD). Parkin has been mainly implicated, along with Pink1, in mitochondrial autophagy in response to stress. In this study, a yeast model was developed to analyse the biological function of human Parkin. We observed that Parkin increases yeast chronological lifespan and oxidative stress resistance, through a mitochondrial-dependent pathway. Moreover, in response to H2O2, Parkin translocate to mitochondria, leading to a higher mitochondrial degradation. Parkin-induced H2O2 resistance is dependent on the autophagic pathway and on the mitochondrial protein Por1p. Although expression of Pink1 induces an H2O2 resistance phenotype similar to Parkin, co-expression of both proteins does not result in a synergistic effect. Concerning H2O2 resistance, this may indicate that these two proteins independently affect the same pathway. Altogether, this work establishes a yeast model for Parkin, which may provide new insights on Parkin function and potential mechanisms of pathogenicity.

Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders.