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Cell Rep. 2014 May 8;7(3):834-47. doi: 10.1016/j.celrep.2014.03.051. Epub 2014 Apr 24.

SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes.

Author information

1
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Center for Genetics and Inherited Diseases, Department of Applied Medical Sciences, Taibah University, Almedinah, P.O. Box 41477, Saudi Arabia.
2
Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
3
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
4
Institute for Genetics, University of Cologne, Cologne 50674, Germany.
5
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
6
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada.
7
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
8
University of Lübeck, Lübeck 23562, Germany.
9
National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
10
McGill University, Montreal, QC H3A 0G4, Canada.
11
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: astewart@ottawaheart.ca.

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.

PMID:
24767997
DOI:
10.1016/j.celrep.2014.03.051
[Indexed for MEDLINE]
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