RESUMEN
The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.
Asunto(s)
Conducta Animal , Ataxia Cerebelosa/enzimología , Cerebelo/enzimología , Proteínas Mitocondriales/deficiencia , Músculo Esquelético/enzimología , Ubiquinona/deficiencia , Animales , Células COS , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/fisiopatología , Ataxia Cerebelosa/psicología , Cerebelo/fisiopatología , Cerebelo/ultraestructura , Chlorocebus aethiops , Modelos Animales de Enfermedad , Tolerancia al Ejercicio , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Metabolismo de los Lípidos , Masculino , Aprendizaje por Laberinto , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/química , Proteínas Mitocondriales/genética , Modelos Moleculares , Actividad Motora , Fuerza Muscular , Músculo Esquelético/fisiopatología , Fenotipo , Unión Proteica , Conformación Proteica , Proteómica/métodos , Reconocimiento en Psicología , Prueba de Desempeño de Rotación con Aceleración Constante , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Convulsiones/enzimología , Convulsiones/genética , Convulsiones/fisiopatología , Relación Estructura-Actividad , Factores de Tiempo , Transfección , Ubiquinona/química , Ubiquinona/genéticaRESUMEN
While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis.