Mitochondrial proteases and neurodegeneration

Mitochondrial dysfunction and oxidative stress play central roles in ageing and neurodegeneration and mutations in a number of mitochondrial proteins act causative in neurodegenerative diseases. Despite the well-established crucial functions of mitochondria for cell homeostasis, these diseases are characterized by an unexpected cell- and tissue-specificity. We are analysing neurodegenerative disorders linked to impaired proteolytic processes in mitochondria using murine and cellular models and try to understand the molecular basis of the striking tissue-specificity of these diseases. An autosomal recessive form of hereditary spastic paraplegia, which is characterized by axonal degeneration of neurons in the corticospinal tract, has been linked to mutations in the mitochondrial AAA protease subunit paraplegin. Dominant optic atrophy is caused by mutations in the dynamin-like GTPase OPA1 in the mitochondrial inner membrane and is characterized by degeneration of retinal ganglion cells. We examine the proteolytic conversion of OPA1 by mitochondrial proteases and its relevance for pathogenesis.