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.
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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
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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 | | | |
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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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