SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes.
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.
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.
Naif A M
NA
Almontashiri
Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
Hsiao-Huei
HH
Chen
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Ryan J
RJ
Mailloux
Institute for Genetics, University of Cologne, Cologne 50674, Germany.
Takashi
T
Tatsuta
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.
Allen C T
AC
Teng
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Ahmad B
AB
Mahmoud
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada.
Tiffany
T
Ho
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Nicolas A S
NA
Stewart
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada.
Peter
P
Rippstein
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Mary Ellen
ME
Harper
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y, Canada.
Robert
R
Roberts
University of Lübeck, Lübeck 23562, Germany.
Christina
C
Willenborg
University of Lübeck, Lübeck 23562, Germany.
Jeanette
J
Erdmann
National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Annalisa
A
Pastore
McGill University, Montreal, QC H3A 0G4, Canada.
Heidi M
HM
McBride
Institute for Genetics, University of Cologne, Cologne 50674, Germany.
Thomas
T
Langer
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.
Alexandre F R
AF
Stewart
D049069:ATP-Dependent Proteases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074183:ATPases Associated with Diverse Cellular Activities; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D010447:Peptide Hydrolases; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities