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Free keywords:
ATP-Dependent Proteases/antagonists & inhibitors/genetics/*metabolism
ATPases Associated with Diverse Cellular Activities
Adenosine Triphosphate/metabolism
Amino Acid Sequence
Animals
Cell Proliferation
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Metalloendopeptidases/genetics/*metabolism
Mitochondria/enzymology/*metabolism
Molecular Sequence Data
Peptide Hydrolases/metabolism
Phenotype
Phosphorylation
Polymorphism, Single Nucleotide
RNA Interference
RNA, Small Interfering/metabolism
Reactive Oxygen Species/*metabolism
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.
