Significance: Altered plasma triglyceride metabolism and changes in dietary fatty acid types and levels are major contributors to the development of metabolic and cardiovascular diseases such as fatty liver disease, obesity, diabetes, and atherosclerosis. Lipid accumulation in visceral adipose tissue and ectopically in other organs, as well as lipid-induced redox imbalance, is connected to mitochondrial dysfunction in a range of oxidative stress-associated metabolic and degenerative disorders. Recent Advances: Successful mitochondrial adaptive responses in the context of hypertriglyceridemia and dietary bioactive polyunsaturated fatty acids contribute to increase body energy expenditure and reduce oxidative stress, thus allowing several cell types to cope with metabolic challenges and stresses. These responses include mitochondrial redox signaling, mild uncoupling, and changes in network dynamic behavior. Critical Issues: Mitochondrial bioenergetics and redox changes in a lipid overload context are relatively well characterized. However, the turning point between adaptive and maladaptive mitochondrial responses remains a critical issue to be elucidated. In addition, the relationship between changes in fusion/fission machinery and mitochondrial function is less well understood. Future Directions: The effective mitochondrial responses described here support the research for new drug design and diet or nutraceutical formulations targeting mitochondrial mild uncoupling and effective quality control as putative strategies for cardiometabolic diseases. Antioxid. Redox Signal. 36, 953-968.
Keywords: free fatty acids; mitochondrial biogenesis; mitochondrial fusion–fission; mitochondrial uncoupling; redox signaling; triglycerides.