Neurodegenerative disorders pose a major socio-economic challenge projected to sharply increase in the future. As an example, glaucoma threatens over 60 million people worldwide with blindness and the associated psychological and social burdens. What triggers this and other types of neurodegeneration is still debated, but mitochondrial dysfunction is generally accepted as an important pathogenic factor. While proper mitochondrial function critically depends on morphogens shaping the mitochondrial network, dysregulated mitochondrial morphology has been linked to the induction of apoptosis and neurodegeneration

Recently published data supports the idea that mitochondrial fission and fusion and mitochondrial quality control play key roles in the maintenance of functionally competent mitochondria, in the induction of apoptosis, and subsequently, in neurodegeneration. Screening for regulators of mitochondrial function, we identified a novel class of ubiquitin ligases involved in the regulation of mitochondrial morphology and protein turnover. We hypothesize that these ubiquitin ligases are involved in maintaining the mitochondrial network and thus affect cellular viability and neurodegeneration.

MARCH5 and MARCH9 – two novel mitochondrial ubiquitin ligases - have impact on mitochondrial morphology. We want to focus on the further characterization of these ligases with regard to substrate spectrum, mode of action and their potential role in apoptosis. In addition, we propose to study the involvement of MARCH5 and MARCH9 in regulating mitochondrial fission and fusion, and especially their pathogenic role in neurodegeneration by employing an in vitro model for high pressure glaucoma.

This study will not only provide valuable new insight into the regulation of mitochondrial morphology and function but will also help to better understand the process of neurodegeneration including the molecular pathogenesis of glaucoma.