Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders. ### Competing Interest Statement The authors have declared no competing interest. * GFP : green fluorescent protein; RIOK : right open reading frame kinase; family NDUFV1 : NADH:ubiquinone oxidoreductase core subunit V1; ATP : adenosine triphosphate; GMR : glass multimer reporter; GstD5 : Glutathione S transferase D5; Mgstl : Microsomal glutathione S-transferase-like; Prx3 : peroxiredoxin 3.