Caveolins (CAV) are essential components of caveolae; plasma membrane invaginations with reduced fluidity, reflecting cholesterol accumulation [1]. CAV proteins bind cholesterol, and CAV’s ability to move between cellular compartments helps control intracellular cholesterol fluxes [1–3]. In humans, CAV1 mutations result in lipodystrophy, cell transformation, and cancer [4–7]. CAV1 gene-disrupted mice exhibit cardiovascular diseases, diabetes, cancer, atherosclerosis, and pulmonary fibrosis [8, 9]. The mechanism(s) underlying these disparate effects are unknown, but our past work suggested CAV1 deficiency might alter metabolism: CAV1−/− mice exhibit impaired liver regeneration unless supplemented with glucose, suggesting systemic inefficiencies requiring additional metabolic intermediates [10]. Establishing a functional link between CAV1 and metabolism would provide a unifying theme to explain these myriad pathologies [11]. 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 anti-oxidant defence. 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.