Drosophila Mpv17 forms an ion channel and regulates energy metabolism
Samantha Corrà,
Vanessa Checchetto,
Michele Brischigliaro,
Chiara Rampazzo,
Emanuela Bottani,
Cristina Gagliani,
Katia Cortese,
Cristiano De Pittà,
Marco Roverso,
Diego De Stefani,
Sara Bogialli,
Massimo Zeviani,
Carlo Viscomi,
Ildiko Szabò,
Rodolfo Costa
Affiliations
Samantha Corrà
Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
Vanessa Checchetto
Department of Biology, University of Padova, Padova, Italy
Michele Brischigliaro
Department of Biomedical Sciences, University of Padova, Padova, Italy
Chiara Rampazzo
Department of Biology, University of Padova, Padova, Italy
Emanuela Bottani
Department of Diagnostic and Public Health, University of Verona, Verona, Italy
Cristina Gagliani
Department of Experimental Medicine, University of Genova, Genova, Italy
Katia Cortese
Department of Experimental Medicine, University of Genova, Genova, Italy
Cristiano De Pittà
Department of Biology, University of Padova, Padova, Italy
Marco Roverso
Department of Chemical Sciences, University of Padova, Padova, Italy
Diego De Stefani
Department of Biomedical Sciences, University of Padova, Padova, Italy
Sara Bogialli
Department of Chemical Sciences, University of Padova, Padova, Italy
Massimo Zeviani
Department of Neurosciences, University of Padova, Padova, Italy; IRCCS Materno Infantile Burlo Garofolo, Trieste, Italy
Carlo Viscomi
Veneto Institute of Molecular Medicine (VIMM), Padova, Italy; Department of Biomedical Sciences, University of Padova, Padova, Italy
Ildiko Szabò
Department of Biology, University of Padova, Padova, Italy; Corresponding author
Rodolfo Costa
Department of Biology, University of Padova, Padova, Italy; Institute of Neuroscience, National Research Council of Italy (CNR), Padova, Italy; Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK; Corresponding author
Summary: Mutations in MPV17 are a major contributor to mitochondrial DNA (mtDNA) depletion syndromes, a group of inherited genetic conditions due to mtDNA instability. To investigate the role of MPV17 in mtDNA maintenance, we generated and characterized a Drosophila melanogaster Mpv17 (dMpv17) KO model showing that the absence of dMpv17 caused profound mtDNA depletion in the fat body but not in other tissues, increased glycolytic flux and reduced lifespan in starvation. Accordingly, the expression of key genes of glycogenolysis and glycolysis was upregulated in dMpv17 KO flies. In addition, we demonstrated that dMpv17 formed a channel in planar lipid bilayers at physiological ionic conditions, and its electrophysiological hallmarks were affected by pathological mutations. Importantly, the reconstituted channel translocated uridine but not orotate across the membrane. Our results indicate that dMpv17 forms a channel involved in translocation of key metabolites and highlight the importance of dMpv17 in energy homeostasis and mitochondrial function.
