Almontashiri, Naif A. M., Chen, Hsiao-Huei ORCID: 0000-0003-2914-6057, Mailloux, Ryan J., Tatsuta, Takashi, Teng, Allen C. T., Mahmoud, Ahmad B., Ho, Tiffany, Stewart, Nicolas A. S., Rippstein, Peter, Harper, Mary Ellen, Roberts, Robert, Willenborg, Christina ORCID: 0000-0001-5217-6882, Erdmann, Jeanette ORCID: 0000-0002-4486-6231, Pastore, Annalisa, McBride, Heidi M., Langer, Thomas ORCID: 0000-0003-1250-1462 and Stewart, Alexandre 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). S. 834 - 848. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Almontashiri, Naif A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Hsiao-HueiUNSPECIFIEDorcid.org/0000-0003-2914-6057UNSPECIFIED
Mailloux, Ryan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tatsuta, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teng, Allen C. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahmoud, Ahmad B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ho, TiffanyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, Nicolas A. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rippstein, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harper, Mary EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roberts, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willenborg, ChristinaUNSPECIFIEDorcid.org/0000-0001-5217-6882UNSPECIFIED
Erdmann, JeanetteUNSPECIFIEDorcid.org/0000-0002-4486-6231UNSPECIFIED
Pastore, AnnalisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McBride, Heidi M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
Stewart, Alexandre F. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-439916
DOI: 10.1016/j.celrep.2014.03.051
Journal or Publication Title: Cell Reports
Volume: 7
Number: 3
Page Range: S. 834 - 848
Date: 2014
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEREDITARY SPASTIC PARAPLEGIA; CYTOCHROME-C-OXIDASE; M-AAA PROTEASE; DEPENDENT TYROSINE PHOSPHORYLATION; OXYGEN SPECIES PRODUCTION; CORONARY-ARTERY-DISEASE; OXIDATIVE STRESS; IN-VIVO; MUTATIONS; PROTEINSMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43991

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