RESUMO
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.
Assuntos
Proteases Dependentes de ATP/metabolismo , Metaloendopeptidases/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteases Dependentes de ATP/antagonistas & inibidores , Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Proliferação de Células , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloendopeptidases/genética , Mitocôndrias/enzimologia , Dados de Sequência Molecular , Peptídeo Hidrolases/metabolismo , Fenótipo , Fosforilação , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Interferente Pequeno/metabolismoRESUMO
A major goal of cancer research is elucidating the molecular events underlying carcinogenesis, with the goal of discovering better diagnostic markers and therapeutic targets. Proteomics aims to facilitate this process by applying newly developed methods and advanced analytic tools, such as mass spectrometry, for the investigation of the protein complement en masse. Proteomics is the comprehensive study of proteins and is aimed at analyzing their structure, function, modifications, expression, interactions, and localization in complex biological systems. This article reviews the state-of-the art in mass spectrometry-based approaches and their application for cancer biomarker discovery and validation.
