Mutations in MPV17 are a major cause of mitochondrial DNA (mtDNA) depletion syndromes (MDDS), a group of inherited genetic disorders resulting from mtDNA instability.
To investigate the role of MPV17 in mtDNA maintenance, we generated and characterized a Drosophila melanogaster knockout model for Mpv17 (dMpv17), showing that the absence of dMpv17 led to severe mtDNA depletion in the fat body, but not in other tissues, accompanied by increased glycolytic flux and reduced survival under starvation conditions.
Accordingly, the expression of key genes involved in glycogenolysis and glycolysis was upregulated in dMpv17 knockout flies. Moreover, we demonstrated that dMpv17 formed a channel in planar lipid bilayers under physiological ionic conditions, and that its electrophysiological properties were affected by pathogenic mutations. Notably, the reconstituted channel transported uridine but not orotate across the membrane.
Our findings indicate that dMpv17 forms a channel involved in the translocation of key metabolites and highlight its crucial role in energy homeostasis and mitochondrial function.
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