Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex i integrity and impacts human health

Moran Gershoni, Liron Levin, Ofer Ovadia, Yasmin Toiw, Naama Shani, Sara Dadon, Nir Barzilai, Aviv Bergman, Gil Atzmon, Julio Wainstein, Anat Tsur, Leo Nijtmans, Benjamin Glaser, Dan Mishmar

Research output: Contribution to journalArticlepeer-review

Abstract

The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tightmitonuclear coevolution tomaintainmitochondrial 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 andpositive selection in the nuclearDNA-encodedoxidative phosphorylation (OXPHOS)complex I subunitNDUFC2, 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 diminishedmitochondrialmembrane potential, and interfered with complex I integrity.Moreover, site-directedmutagenesis of a positively selected amino acid inNDUFC2significantly interfered with the interaction ofNDUFC2 with its mtDNA-encoded partnerND4. Finally,we showthat a genotype combination involving this amino acid (NDUFC2 residue 46) and themtDNA 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.

Original languageEnglish
Pages (from-to)2665-2680
Number of pages16
JournalGenome Biology and Evolution
Volume6
Issue number10
DOIs
StatePublished - Oct 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank Mariël van den Brandt for her excellent technical support with the BN-PAGE experiments and Dr. Raz Zarivach for critical comments. We also thank Itamar Raz, Ardon Rubenstein, Ilana Harman-Boehm, Joseph Cohen, Oscar Minuchin, Yair Yerushalmi, Andreas Buchs and Clara Norymberg, members of the Israel Diabetes Research Group, who played active roles in this research. This work was supported by a grant from the National Institutes of Health (AG028872 to A.B., AG042188 to G.A., AG021654-01 to N.B., AG-18728-02A1 to N.B.) and Israeli Science Foundation (ISF 387/08, 610/12 to D.M). The authors extend their thanks for the Ori foundation for granting a scholarship of excellence to M.G. The grant foundations had no competing interest in the study and did not interfere with the study design.

Funding Information:
We thank Mari?l van den Brandt for her excellent technical support with the BN-PAGE experiments and Dr. Raz Zarivach for critical comments. We also thank Itamar Raz, Ardon Rubenstein, Ilana Harman-Boehm, Joseph Cohen, Oscar Minuchin, Yair Yerushalmi, Andreas Buchs and Clara Norymberg, members of the Israel Diabetes Research Group, who played active roles in this research. This work was supported by a grant from the National Institutes of Health (AG028872 to A.B., AG042188 to G.A., AG021654- 01 to N.B., AG-18728-02A1 to N.B.) and Israeli Science Foundation (ISF 387/08, 610/12 to D.M).

Publisher Copyright:
© The Author(s) 2014.

Keywords

  • NDUFC2.
  • coevolution
  • complex I
  • mitochondria
  • mitonuclear interaction
  • mtDNA

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics

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