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

doi:10.1016/j.isci.2023.107955

Drosophila Mpv17 forms an ion channel and regulates energy metabolism

iScience. 2023 Sep 16;26(10):107955. doi: 10.1016/j.isci.2023.107955. eCollection 2023 Oct 20.

Authors

Samantha Corrà¹, Vanessa Checchetto², Michele Brischigliaro³, Chiara Rampazzo², Emanuela Bottani⁴, Cristina Gagliani⁵, Katia Cortese⁵, Cristiano De Pittà², Marco Roverso⁶, Diego De Stefani³, Sara Bogialli⁶, Massimo Zeviani^{7

8}, Carlo Viscomi^{1

3}, Ildiko Szabò², Rodolfo Costa^{2

9

10}

Affiliations

¹ Veneto Institute of Molecular Medicine (VIMM), Padova, Italy.
² Department of Biology, University of Padova, Padova, Italy.
³ Department of Biomedical Sciences, University of Padova, Padova, Italy.
⁴ Department of Diagnostic and Public Health, University of Verona, Verona, Italy.
⁵ Department of Experimental Medicine, University of Genova, Genova, Italy.
⁶ Department of Chemical Sciences, University of Padova, Padova, Italy.
⁷ Department of Neurosciences, University of Padova, Padova, Italy.
⁸ IRCCS Materno Infantile Burlo Garofolo, Trieste, Italy.
⁹ Institute of Neuroscience, National Research Council of Italy (CNR), Padova, Italy.
¹⁰ Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

Abstract

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.

Keywords: model organism; molecular biology; physiology.