SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes.

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.

• Authors: Naif A M Almontashiri, Hsiao-Huei Chen, Ryan J Mailloux, Takashi Tatsuta, Allen C T Teng, Ahmad B Mahmoud, Tiffany Ho, Nicolas A S Stewart, Peter Rippstein, Mary Ellen Harper, Robert Roberts, Christina Willenborg, Jeanette Erdmann, CARDIoGRAM Consortium, Annalisa Pastore, Heidi M McBride, Thomas Langer, Alexandre F R Stewart
• Journal: Cell reports (Cell Rep) Vol. 7 Issue 3 Pg. 834-47 (May 08 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 24767997 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Small Interfering
• Reactive Oxygen Species
• Adenosine Triphosphate
• Peptide Hydrolases
• ATP-Dependent Proteases
• AFG3L2 protein, human
• Metalloendopeptidases
• SPG7 protein, human
• ATPases Associated with Diverse Cellular Activities

Topics

• 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)