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 journalArticle

41 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2665-2680
Number of pages16
JournalGenome Biology and Evolution
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2014

Fingerprint

NADH dehydrogenase (ubiquinone)
oxidative phosphorylation
Oxidative Phosphorylation
coevolution
Mitochondrial DNA
mitochondrial DNA
human health
nuclear genome
Health
amino acid
Amino Acids
amino acids
Jews
DNA
Retinal Pigments
human growth
diabetes
Mitochondrial Membrane Potential
Disease Susceptibility
site-directed mutagenesis

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gershoni, M., Levin, L., Ovadia, O., Toiw, Y., Shani, N., Dadon, S., ... Mishmar, D. (2014). Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. Genome Biology and Evolution, 6(10), 2665-2680. https://doi.org/10.1093/gbe/evu208

Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. / Gershoni, Moran; Levin, Liron; Ovadia, Ofer; Toiw, Yasmin; Shani, Naama; Dadon, Sara; Barzilai, Nir; Bergman, Aviv; Atzmon, Gil; Wainstein, Julio; Tsur, Anat; Nijtmans, Leo; Glaser, Benjamin; Mishmar, Dan.

In: Genome Biology and Evolution, Vol. 6, No. 10, 01.10.2014, p. 2665-2680.

Research output: Contribution to journalArticle

Gershoni, M, Levin, L, Ovadia, O, Toiw, Y, Shani, N, Dadon, S, Barzilai, N, Bergman, A, Atzmon, G, Wainstein, J, Tsur, A, Nijtmans, L, Glaser, B & Mishmar, D 2014, 'Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health', Genome Biology and Evolution, vol. 6, no. 10, pp. 2665-2680. https://doi.org/10.1093/gbe/evu208
Gershoni, Moran ; Levin, Liron ; Ovadia, Ofer ; Toiw, Yasmin ; Shani, Naama ; Dadon, Sara ; Barzilai, Nir ; Bergman, Aviv ; Atzmon, Gil ; Wainstein, Julio ; Tsur, Anat ; Nijtmans, Leo ; Glaser, Benjamin ; Mishmar, Dan. / Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. In: Genome Biology and Evolution. 2014 ; Vol. 6, No. 10. pp. 2665-2680.
@article{595325d5647e4aba9ad4d14d4bd390b2,
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.",
keywords = "coevolution, complex I, mitochondria, mitonuclear interaction, mtDNA, NDUFC2",
author = "Moran Gershoni and Liron Levin and Ofer Ovadia and Yasmin Toiw and Naama Shani and Sara Dadon and Nir Barzilai and Aviv Bergman and Gil Atzmon and Julio Wainstein and Anat Tsur and Leo Nijtmans and Benjamin Glaser and Dan Mishmar",
year = "2014",
month = "10",
day = "1",
doi = "10.1093/gbe/evu208",
language = "English (US)",
volume = "6",
pages = "2665--2680",
journal = "Genome Biology and Evolution",
issn = "1759-6653",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health

AU - Gershoni, Moran

AU - Levin, Liron

AU - Ovadia, Ofer

AU - Toiw, Yasmin

AU - Shani, Naama

AU - Dadon, Sara

AU - Barzilai, Nir

AU - Bergman, Aviv

AU - Atzmon, Gil

AU - Wainstein, Julio

AU - Tsur, Anat

AU - Nijtmans, Leo

AU - Glaser, Benjamin

AU - Mishmar, Dan

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

KW - coevolution

KW - complex I

KW - mitochondria

KW - mitonuclear interaction

KW - mtDNA

KW - NDUFC2

UR - http://www.scopus.com/inward/record.url?scp=84917720368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84917720368&partnerID=8YFLogxK

U2 - 10.1093/gbe/evu208

DO - 10.1093/gbe/evu208

M3 - Article

C2 - 25245408

AN - SCOPUS:84917720368

VL - 6

SP - 2665

EP - 2680

JO - Genome Biology and Evolution

JF - Genome Biology and Evolution

SN - 1759-6653

IS - 10

ER -