SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

Naif A.M. Almontashiri; Hsiao Huei Chen; Ryan J. Mailloux; Takashi Tatsuta; Allen C.T. Teng; Ahmad B. Mahmoud; Tiffany Ho; Nicolas A.S. Stewart; Peter Rippstein; Mary Ellen Harper; Robert Roberts; Christina Willenborg; Jeanette Erdmann; Annalisa Pastore; Heidi M. McBride; Thomas Langer; Alexandre F.R. Stewart

doi:10.1016/j.celrep.2014.03.051

SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

Naif A.M. Almontashiri, Hsiao Huei Chen, Ryan J. Mailloux, Takashi Tatsuta, Allen C.T. Teng, Ahmad B. Mahmoud, Tiffany Ho, Nicolas A.S. Stewart, Peter Rippstein, Mary Ellen Harper, Robert Roberts, Christina Willenborg, Jeanette Erdmann, Annalisa Pastore, Heidi M. McBride, Thomas Langer, Alexandre F.R. Stewart^*

^*Corresponding author for this work

Institute of Cardiogenetics

39 Citations (Scopus)

Abstract

Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

Original language	English
Journal	Cell Reports
Volume	7
Issue number	3
Pages (from-to)	834-847
Number of pages	14
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2014.03.051
Publication status	Published - 2014

Funding

We thank Florian Bonn for his contribution to yeast complementation studies, Vincent Soubannier for help with confocal microscopy, and Thomas Lagace for providing oleate and Nile Red. This research was supported by a graduate scholarship from Taibah University, Saudi Arabia and a University of Ottawa Endowed Graduate Award at the Heart Institute (to N.A.M.A.), grants MOP77682 (to A.F.R.S.), MOP179197 (to H.-H.C.), and MOP82810 (to R.R.) from the Canadian Institutes of Health Research, Deutsche Forschungsgemeinschaft SFB635, C4 (to T.L.), the European Research Council AdG No. 233078 (to T.L.), and the Medical Research Council, UK U117584256 (to A.P.). This project used the UPCI Cancer Biomarkers Facility/Mass Spectrometry Platform Laboratory and was supported in part by award P30CA047904 from the National Cancer Institute, USA.

UN SDGs

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

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

Research Areas and Centers

Research Area: Medical Genetics

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10.1016/j.celrep.2014.03.051

Cite this

Almontashiri, N. A. M., Chen, H. H., Mailloux, R. J., Tatsuta, T., Teng, A. C. T., Mahmoud, A. B., Ho, T., Stewart, N. A. S., Rippstein, P., Harper, M. E., Roberts, R., Willenborg, C., Erdmann, J., Pastore, A., McBride, H. M., Langer, T., & Stewart, A. F. R. (2014). SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes. Cell Reports, 7(3), 834-847. https://doi.org/10.1016/j.celrep.2014.03.051

@article{4aa0b74d66654c5fbbf2f3519ce4481d,

title = "SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes",

abstract = "Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.",

author = "Almontashiri, \{Naif A.M.\} and Chen, \{Hsiao Huei\} and Mailloux, \{Ryan J.\} and Takashi Tatsuta and Teng, \{Allen C.T.\} and Mahmoud, \{Ahmad B.\} and Tiffany Ho and Stewart, \{Nicolas A.S.\} and Peter Rippstein and Harper, \{Mary Ellen\} and Robert Roberts and Christina Willenborg and Jeanette Erdmann and Annalisa Pastore and McBride, \{Heidi M.\} and Thomas Langer and Stewart, \{Alexandre F.R.\}",

note = "Funding Information: We thank Florian Bonn for his contribution to yeast complementation studies, Vincent Soubannier for help with confocal microscopy, and Thomas Lagace for providing oleate and Nile Red. This research was supported by a graduate scholarship from Taibah University, Saudi Arabia and a University of Ottawa Endowed Graduate Award at the Heart Institute (to N.A.M.A.), grants MOP77682 (to A.F.R.S.), MOP179197 (to H.-H.C.), and MOP82810 (to R.R.) from the Canadian Institutes of Health Research, Deutsche Forschungsgemeinschaft SFB635, C4 (to T.L.), the European Research Council AdG No. 233078 (to T.L.), and the Medical Research Council, UK U117584256 (to A.P.). This project used the UPCI Cancer Biomarkers Facility/Mass Spectrometry Platform Laboratory and was supported in part by award P30CA047904 from the National Cancer Institute, USA. ",

year = "2014",

doi = "10.1016/j.celrep.2014.03.051",

language = "English",

volume = "7",

pages = "834--847",

journal = "Cell Reports",

issn = "2211-1247",

number = "3",

}

Almontashiri, NAM, Chen, HH, Mailloux, RJ, Tatsuta, T, Teng, ACT, Mahmoud, AB, Ho, T, Stewart, NAS, Rippstein, P, Harper, ME, Roberts, R, Willenborg, C, Erdmann, J, Pastore, A, McBride, HM, Langer, T & Stewart, AFR 2014, 'SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes', Cell Reports, vol. 7, no. 3, pp. 834-847. https://doi.org/10.1016/j.celrep.2014.03.051

TY - JOUR

T1 - SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

AU - Almontashiri, Naif A.M.

AU - Chen, Hsiao Huei

AU - Mailloux, Ryan J.

AU - Tatsuta, Takashi

AU - Teng, Allen C.T.

AU - Mahmoud, Ahmad B.

AU - Ho, Tiffany

AU - Stewart, Nicolas A.S.

AU - Rippstein, Peter

AU - Harper, Mary Ellen

AU - Roberts, Robert

AU - Willenborg, Christina

AU - Erdmann, Jeanette

AU - Pastore, Annalisa

AU - McBride, Heidi M.

AU - Langer, Thomas

AU - Stewart, Alexandre F.R.

N1 - Funding Information: We thank Florian Bonn for his contribution to yeast complementation studies, Vincent Soubannier for help with confocal microscopy, and Thomas Lagace for providing oleate and Nile Red. This research was supported by a graduate scholarship from Taibah University, Saudi Arabia and a University of Ottawa Endowed Graduate Award at the Heart Institute (to N.A.M.A.), grants MOP77682 (to A.F.R.S.), MOP179197 (to H.-H.C.), and MOP82810 (to R.R.) from the Canadian Institutes of Health Research, Deutsche Forschungsgemeinschaft SFB635, C4 (to T.L.), the European Research Council AdG No. 233078 (to T.L.), and the Medical Research Council, UK U117584256 (to A.P.). This project used the UPCI Cancer Biomarkers Facility/Mass Spectrometry Platform Laboratory and was supported in part by award P30CA047904 from the National Cancer Institute, USA.

PY - 2014

Y1 - 2014

N2 - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

AB - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

UR - https://www.scopus.com/pages/publications/84899987055

U2 - 10.1016/j.celrep.2014.03.051

DO - 10.1016/j.celrep.2014.03.051

M3 - Journal articles

C2 - 24767997

AN - SCOPUS:84899987055

SN - 2211-1247

VL - 7

SP - 834

EP - 847

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

Abstract

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