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Almontashiri, N.* ; Chen, H.-H.* ; Mailloux, R.* ; Tatsuta, T* ; Teng, A.* ; Mahmoud, A* ; Ho, T.* ; Stewart, N.A.* ; Rippstein, P.* ; Harper, M.E.* ; Roberts, R.* ; Willenborg, C.* ; Erdmann, J.* ; CARDIoGRAM Consortium (Döring, A. ; Illig, T. ; Klopp, N. ; Meisinger, C. ; Meitinger, T. ; Peters, A. ; Wichmann, H.-E.) ; Pastore, A.* ; McBride, H.* ; Langer, T.* ; Stewart, A.F.R.*

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

Cell Rep. 7, 834-847 (2014)
Publ. Version/Full Text Volltext DOI
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Hereditary Spastic Paraplegia; Cytochrome-c-oxidase; M-aaa Protease; Dependent Tyrosine Phosphorylation; Oxygen Species Production; Coronary-artery-disease; Oxidative Stress; In-vivo; Mutations; Proteins
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 7, Issue: 3, Pages: 834-847 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)