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SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

Almontashiri, NAM and Chen, HH and Mailloux, RJ and Tatsuta, T and Teng, ACT and Mahmoud, AB and Ho, T and Stewart, NAS and Rippstein, P and Harper, ME and Roberts, R and Willenborg, C and Erdmann, J and Pastore, A and McBride, HM and Langer, T and Stewart, AFR (2014) SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes. Cell Reports, 7 (3). 834 - 847.

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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. © 2014 The Authors.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Almontashiri, NAM
Chen, HH
Mailloux, RJ
Tatsuta, T
Teng, ACT
Mahmoud, AB
Ho, T
Stewart, NAS
Rippstein, P
Harper, ME
Roberts, R
Willenborg, C
Erdmann, J
Pastore, A
McBride, HM
Langer, T
Stewart, AFR
Centers: Other Centers, Institutes, Offices, or Units > Center for Clinical Pharmacology
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 7
Number: 3
Page Range: 834 - 847
DOI or Unique Handle: 10.1016/j.celrep.2014.03.051
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 01 Jun 2015 21:45
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/24724

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