RESUMO
Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
Assuntos
Mitocôndrias , Dinâmica Mitocondrial , Peroxissomos , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Peroxissomos/metabolismo , Dinâmica Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Ácidos Graxos/metabolismo , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ciclo do Ácido Cítrico , Potencial da Membrana Mitocondrial/fisiologia , Membranas Mitocondriais/metabolismo , HumanosRESUMO
Complex metabolic diseases such as diabetes and non-alcoholic fatty liver disease have been associated with aberrant lipid metabolism and lipotoxicity. To maintain lipid homeostasis and escape lipotoxicity, cells deploy a plethora of mechanisms, the most fascinating of which relying on a sense-and-response circuit. New work by Volkmar et al reveals an auto-regulated pathway formed by a lipid hydrolase and a lipid-sensitive E3 ubiquitin ligase playing hide-and-seek to warrant membrane function in stressed cells.
Assuntos
Fígado , Ubiquitina , Retículo Endoplasmático , Hidrolases/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
From mitochondrial quality control pathways to the regulation of specific functions, the Ubiquitin Proteasome System (UPS) could be compared to a Swiss knife without which mitochondria could not maintain its integrity in the cell. Here, we review the mechanisms that the UPS employs to regulate mitochondrial function and efficiency. For this purpose, we depict how Ubiquitin and the Proteasome participate in diverse quality control pathways that safeguard entry into the mitochondrial compartment. A focus is then achieved on the UPS-mediated control of the yeast mitofusin Fzo1 which provides insights into the complex regulation of this particular protein in mitochondrial fusion. We ultimately dissect the mechanisms by which the UPS controls the degradation of mitochondria by autophagy in both mammalian and yeast systems. This organization should offer a useful overview of this abundant but fascinating literature on the crosstalks between mitochondria and the UPS.