SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes.
Cell Rep
; 7(3): 834-47, 2014 May 08.
Article
in En
| MEDLINE
| ID: mdl-24767997
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Metalloendopeptidases
/
Reactive Oxygen Species
/
ATP-Dependent Proteases
/
Mitochondria
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Rep
Year:
2014
Document type:
Article