title: Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility.
abstract: Caveolins (CAVs) are essential components of caveolae, plasma membrane invaginations with reduced fluidity, reflecting cholesterol accumulation. CAV proteins bind cholesterol, and CAV's ability to move between cellular compartments helps control intracellular cholesterol fluxes. In humans, CAV1 mutations result in lipodystrophy, cell transformation, and cancer. CAV1 gene-disrupted mice exhibit cardiovascular diseases, diabetes, cancer, atherosclerosis, and pulmonary fibrosis. The mechanism or mechanisms underlying these disparate effects are unknown, but our past work suggested that CAV1 deficiency might alter metabolism: CAV1(-/-) mice exhibit impaired liver regeneration unless supplemented with glucose, suggesting systemic inefficiencies requiring additional metabolic intermediates. Establishing a functional link between CAV1 and metabolism would provide a unifying theme to explain these myriad pathologies. Here we demonstrate that impaired proliferation and low survival with glucose restriction is a shortcoming of CAV1-deficient cells caused by impaired mitochondrial function. Without CAV1, free cholesterol accumulates in mitochondrial membranes, increasing membrane condensation and reducing efficiency of the respiratory chain and intrinsic antioxidant defense. Upon activation of oxidative phosphorylation, this promotes accumulation of reactive oxygen species, resulting in cell death. We confirm that this mitochondrial dysfunction predisposes CAV1-deficient animals to mitochondrial-related diseases such as steatohepatitis and neurodegeneration.
authors.affiliation: Equip de Proliferació i Senyalització Cel·lular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Bosch
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.forename: Albert
authors.initials: A
authors.lastname: Herms
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández
authors.forename: Alba
authors.initials: A
authors.lastname: Fajardo
authors.forename: Adam
authors.initials: A
authors.lastname: Kassan
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.forename: David
authors.initials: D
authors.lastname: Balgoma
authors.forename: Elisabet
authors.initials: E
authors.lastname: Barbero
authors.forename: Elena
authors.initials: E
authors.lastname: González-Moreno
authors.forename: Nuria
authors.initials: N
authors.lastname: Matias
authors.forename: Francesc
authors.initials: F
authors.lastname: Tebar
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gross
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.forename: Albert
authors.initials: A
authors.lastname: Pol
mesh_terms: D000818:Animals; D017209:Apoptosis; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics*; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D051242:Caveolin 1; D002784:Cholesterol; D005947:Glucose