Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice

Quirós,P. M. ; Ramsay,A. J. ; Sala,D. ; Fernández-Vizarra,E. ; Rodríguez,F. ; Peinado,J. R. ; Fernández-García,M. S. ; Vega,J. A. ; Enríquez,J. A. (Universidad de Zaragoza) ; Zorzano,A. ; López-Otín,C.

Resumen: Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP‐independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin‐related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion–fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1‐mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1‐OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high‐fat diet or cold‐shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function.

Idioma: Inglés

DOI: 10.1038/emboj.2012.70

Año: 2012

Publicado en: EMBO JOURNAL 31, 9 (2012), 2117-2133
ISSN: 0261-4189

Factor impacto JCR: 9.822 (2012)

Categ. JCR: CELL BIOLOGY rank: 19 / 183 = 0.104 (2012) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 17 / 288 = 0.059 (2012) - Q1 - T1

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)