Mitophagy's impact on obesity-related tissues.

Obesity, a global health crisis, results from an energy imbalance, leading to metabolic dysfunction and associated conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. A strong link exists between obesity and mitochondrial dysfunction, characterized by reduced mitochondrial mass, impaired oxidative capacity, and decreased ATP production. Mitophagy, a specific type of autophagy targeting mitochondria for degradation, plays a complex, tissue-specific role in regulating metabolism and mitigating the harmful effects of obesity. Both insufficient and excessive mitophagy can negatively influence disease progression. In white adipose tissue, mitophagy functions as a quality control mechanism that reduces oxidative stress and helps maintain insulin sensitivity. However, chronic obesity impairs mitophagy due to overactivation of mTORC1 and inhibition of AMPK, leading to inflammation and insulin resistance. In brown adipose tissue, mitophagy is essential for thermogenesis and energy expenditure, but excessive activation in obesity may impair thermogenesis. In the liver, mitophagy is crucial for preserving mitochondrial function and preventing metabolic dysfunction-associated steatotic liver disease. In the heart, mitophagy supports cardiac function, particularly in obesity-related cardiomyopathy. In skeletal muscle, obesity worsens impairments in mitochondrial quality control, disrupting the clearance of damaged mitochondria. Therefore, there is a pressing need for therapies that restore mitophagic balance in a context- and depot-specific manner, as the dysregulation of mitophagy contributes not only to local dysfunction but also to broader metabolic phenotypes.