Role of Mitochondrial Complex IV in Age-Dependent Obesity

Soro-Arnaiz, I. ; Li, Q.O.Y. ; Torres-Capelli, M. ; Meléndez-Rodríguez, F. ; Veiga, S. ; Veys, K. ; Sebastian, D. ; Elorza, A. ; Tello, D. ; Hernansanz-Agustín, P. ; Cogliati, S. ; Moreno-Navarrete, J. ; Balsa, E. ; Fuertes, E. ; Romanos, E. ; Martínez-Ruiz, A. ; Enriquez, J.A. ; Fernandez-Real, J. ; Zorzano, A. ; De Bock, K. ; Aragonés, J.

Resumen: Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion.

Idioma: Inglés

DOI: 10.1016/j.celrep.2016.08.041

Año: 2016

Publicado en: Cell Reports 16, 11 (2016), 2991-3002
ISSN: 2211-1247

Factor impacto JCR: 8.282 (2016)

Categ. JCR: CELL BIOLOGY rank: 26 / 189 = 0.138 (2016) - Q1 - T1

Factor impacto SCIMAGO: 8.336 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/CAM/P2010-BMD-2542
Financiación: info:eu-repo/grantAgreement/ES/CICYT/SAF2007-60592
Financiación: info:eu-repo/grantAgreement/EC/FP7/282551/EU/Gaining sage on the Epoetins' saga: assessing long term risks and advancing towards better Epoetin driven treatment modalities/EPOCAN
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0065
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2011-29716
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2013-46058-R

Tipo y forma: Article (Published version)