Mitochondrial Dysfunction in MASLD: Evidence in Dietary Models and Potential Therapeutic Interventions

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined as the presence of excess triglyceride storage in the liver in the presence of at least one cardiometabolic risk factor. This term highlights the connection between fatty liver and metabolic dysfunction. Dietary factors, such as excessive consumption of saturated fats and sugar, contribute significantly to the accumulation of lipids in organs not specialized for fat storage, such as the liver. Hepatic lipid accumulation initiates dynamic changes in mitochondrial function and promotes the development and progression of MASLD. High-fat, high-fructose diet models have provided crucial insights into how nutritional factors induce mitochondrial dysfunction, which is characterized by impaired fatty acid oxidation, excessive generation of reactive oxygen species, and damage to mitochondrial DNA. Lifestyle modifications, including dietary adjustments such as calorie restriction and weight loss, are essential for the early prevention and long-term treatment of MASLD. However, in recent years, several pharmacological options have emerged for the treatment of MASLD, primarily for the management of its comorbidities. This review explores the mechanisms of mitochondrial dysfunction promoted by the accumulation of hepatic lipids, analyzes the evidence of mitochondrial alterations in the liver of dietary models, and summarizes some of the main therapeutic interventions for MASLD and their effects on mitochondrial function.