Role of Mitochondrial Complex IV in Age-Dependent Obesity.
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.
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Ines
I
Soro-Arnaiz
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Qilong Oscar Yang
QOY
Li
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Mar
M
Torres-Capelli
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Florinda
F
Meléndez-Rodríguez
Institute for Research in Biomedicine (IRB, Barcelona), Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain; CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Carlos III Health Institute, Barcelona 08036, Spain.
Sónia
S
Veiga
Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
Koen
K
Veys
Institute for Research in Biomedicine (IRB, Barcelona), Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain; CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Carlos III Health Institute, Barcelona 08036, Spain.
David
D
Sebastian
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Ainara
A
Elorza
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Daniel
D
Tello
Immunology Department, Hospital of La Princesa, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Pablo
P
Hernansanz-Agustín
Centro Nacional de Investigaciónes Cardiovasculares (CNIC) Carlos III, Madrid 28029, Spain.
Sara
S
Cogliati
Department of Diabetes, Endocrinology and Nutrition, CIBEROBN Fisiopatología de la Obesidad y Nutrición, Institut d'Investigació Biomédica of Girona, Girona 17007, Spain.
Jose Maria
JM
Moreno-Navarrete
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Eduardo
E
Balsa
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Esther
E
Fuertes
Phenotyping Unit, IIS Aragón, Zaragoza 50013, Spain.
Eduardo
E
Romanos
Immunology Department, Hospital of La Princesa, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
Antonio
A
Martínez-Ruiz
Centro Nacional de Investigaciónes Cardiovasculares (CNIC) Carlos III, Madrid 28029, Spain.
Jose Antonio
JA
Enriquez
Department of Diabetes, Endocrinology and Nutrition, CIBEROBN Fisiopatología de la Obesidad y Nutrición, Institut d'Investigació Biomédica of Girona, Girona 17007, Spain.
Jose Manuel
JM
Fernandez-Real
Institute for Research in Biomedicine (IRB, Barcelona), Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain; CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Carlos III Health Institute, Barcelona 08036, Spain.
Antonio
A
Zorzano
Health Sciences and Technology Department, Laboratory of Exercise and Health, Swiss Federal Institute of Technology (ETH), Zurich 8603, Switzerland.
Katrien
K
De Bock
Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain. Electronic address: jaragones.hlpr@salud.madrid.org.
Julián
J
Aragonés
D052438:Adipocytes, White / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D048429:Cell Size; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004822:Epididymis / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003576:Electron Transport Complex IV
COX5B; HIF-1; aging; human adipose tissue; mitochondrial complex IV; mitochondrial dysfunction; obesity; white adipocytes