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

doi:10.1093/gbe/evu208

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 journal › Article › peer-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 language	English
Pages (from-to)	2665-2680
Number of pages	16
Journal	Genome Biology and Evolution
Volume	6
Issue number	10
DOIs	https://doi.org/10.1093/gbe/evu208
State	Published - Oct 2014
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/gbe/evu208

Cite this

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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 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.",

keywords = "NDUFC2., coevolution, complex I, mitochondria, mitonuclear interaction, mtDNA",

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",

note = "Funding Information: We thank Mari{\"e}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). 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: {\textcopyright} The Author(s) 2014.",

year = "2014",

month = oct,

doi = "10.1093/gbe/evu208",

language = "English",

volume = "6",

pages = "2665--2680",

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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

N1 - 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.

PY - 2014/10

Y1 - 2014/10

N2 - 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.

AB - 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.

KW - NDUFC2.

KW - coevolution

KW - complex I

KW - mitochondria

KW - mitonuclear interaction

KW - mtDNA

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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