Role of Mitochondrial Complex IV in Age-Dependent Obesity
Soro-Arnaiz, Ines * Li, Qilong Oscar Yang * Torres-Capelli, Mar Meléndez-Rodríguez, Florinda Veiga, Sónia Veys, Koen Sebastian, David Elorza, Ainara Tello, Daniel Hernansanz-Agustín, Pablo Cogliati, Sara Moreno-Navarrete, Jose Maria Balsa, Eduardo Fuertes, Esther Romanos, Eduardo Martínez-Ruiz, Antonio Enriquez, Jose Antonio Fernandez-Real, Jose Manuel Zorzano, Antonio De Bock, Katrien Aragonés, Julián # ×
Cell Reports vol:16 issue:11 pages:2991-3002
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.