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 Stewart, Peter Rippstein, Mary Ellen Harper, Robert Roberts, Christina Willenborg, Jeanette Erdmann, Annalisa Pastore, Heidi M. McBride, Thomas Langer, Alexandre F.R. Stewart

Research output: Contribution to journalArticle

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 languageEnglish
JournalCell Reports
Volume7
Issue number3
DOIs
Publication statusPublished - 8 May 2014

Bibliographical note

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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    Almontashiri, N. A. M., Chen, H-H., Mailloux, R. J., Tatsuta, T., Teng, A. C. T., Mahmoud, A. B., Ho, T., Stewart, N., 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). https://doi.org/10.1016/j.celrep.2014.03.051