title: Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health.
abstract: The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tight mitonuclear coevolution to maintain mitochondrial activities. Interruption of such coevolution plays a role in interpopulation hybrid breakdown, speciation events, and disease susceptibility. Previously, we found an elevated amino acid replacement rate and positive selection in the nuclear DNA-encoded oxidative phosphorylation (OXPHOS) complex I subunit NDUFC2, a phenomenon important for the direct interaction of NDUFC2 with the mtDNA-encoded complex I subunit ND4. This finding underlines the importance of mitonuclear coevolution to physical interactions between mtDNA and nuclear DNA-encoded factors. Nevertheless, it remains unclear whether this interaction is important for the stability and activity of complex I. Here, we show that siRNA silencing of NDUFC2 reduced growth of human D-407 retinal pigment epithelial cells, significantly diminished mitochondrial membrane potential, and interfered with complex I integrity. Moreover, site-directed mutagenesis of a positively selected amino acid in NDUFC2 significantly interfered with the interaction of NDUFC2 with its mtDNA-encoded partner ND4. Finally, we show that a genotype combination involving this amino acid (NDUFC2 residue 46) and the mtDNA haplogroup HV likely altered susceptibility to type 2 diabetes mellitus in Ashkenazi Jews. Therefore, mitonuclear coevolution is important for maintaining mitonuclear factor interactions, OXPHOS, and for human health.
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Gershoni
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Liron
authors.initials: L
authors.lastname: Levin
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Ovadia
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Toiw
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Shani
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Dadon
authors.affiliation: Institute of Aging, Division of Endocrinology, Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Bergman
authors.affiliation: Institute of Aging, Division of Endocrinology, Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.affiliation: Diabetes Unit, E. Wolfson Medical Center, Holon, Israel.
authors.forename: Julio
authors.initials: J
authors.lastname: Wainstein
authors.affiliation: Endocrine Clinic, Clalit Health Services, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Tsur
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.affiliation: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel dmishmar@bgu.ac.il.
authors.forename: Dan
authors.initials: D
authors.lastname: Mishmar
mesh_terms: D004272:DNA, Mitochondrial / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D019143:Evolution, Molecular; D005838:Genotype; D006801:Humans; D016297:Mutagenesis, Site-Directed
chemical_list: D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I
keywords: NDUFC2; coevolution; complex I; mitochondria; mitonuclear interaction; mtDNA