Charcot Marie Tooth disease 4A - GDAP1-mediated redox-dependent interaction of mitochondria with the cytoskeleton

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Charcot-Marie-Tooth disease 4A is an autosomal-recessive polyneuropathy caused by mutation of the mitochondrial protein GDAP1 (Ganglioside-induced differentiation associated protein 1). To date, no specific therapy exists to treat this devastating disease. We recently showed that patient-derived motoneurons carrying GDAP1 mutations display more tubular mitochondria, reduced mitochondrial Ca2+ levels, and an inhibited pyruvate dehydrogenase complex (PDC). The PDC dysfunction results in a rewired cellular metabolism characterized by glutamine dependence and increased reliance on fatty acid β-oxidation to supply acetyl-CoA for the tricarboxylic acid cycle. We identified Cofilin-1 (CFL1), an actin-polymerizing protein, and other proteins of the actin cytoskeleton as novel interaction partners of GDAP1. Disrupted GDAP1-CFL1 interaction leads to a reduced presence of filamentous actin in the proximity of mitochondria, precluding access of the major fission factor DRP1 to mitochondria. Thus, this novel interaction can explain the defective mitochondrial fission and the more tubular mitochondrial shape observed in various GDAP1 loss of function models but it is unclear if this also mediates the metabolic changes. As GDAP1 is a putative glutathione transferase, we hypothesize that GDAP1, upon interacting with proteins of the cytoskeleton, regulates actin dynamics via post-translational modification of cytoskeletal proteins. In line with this hypothesis, we have identified putative target proteins by redox proteomics; about a fourth of which overlap with the interactome. In this project, we will concentrate on a subset of these potential interactors and study if GDAP1 regulates their redox state and function and if this mediates the reduced mitochondrial Ca2+ levels and inhibition of the PDC. We also aim to identify diets and compounds that can revert the metabolic dysfunction instigated by GDAP1 loss of function and study their effect in (patient-derived) models of GDAP1 deficiency and in a recently established fly model. Together, this project aims to further characterize the pathophysiology of a human disease and identify potential drug targets for its treatment.