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 - http://www.scopus.com/inward/record.url?scp=84899987055&partnerID=8YFLogxK
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 -
