RESUMO
Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.
Assuntos
Ferro , Mitocôndrias , Animais , Humanos , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteases Dependentes de ATP/metabolismo , Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Homeostase , Glutationa/metabolismo , Mamíferos/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismoRESUMO
The Actinobacteriophages Elezi, Asa16, and Niobe infect Arthrobacter globiformis B-2979 and are closely related to Eraser and London in Cluster AZ. They have flexible noncontractile tails, are predicted to be temperate phages, and their genome sizes range between 43,471 bp and 43,602 bp.