Molecular pathways, tissue-specific roles, and therapeutic opportunities in mitochondrial resilience-based strategies...

Insulin resistance (IR) is characterized by impaired insulin signaling in skeletal muscle, liver, and adipose tissue. Increasing evidence indicates mitochondrial dysfunction as a key factor contributing to IR. Mitochondrial resilience refers to the mitochondria's ability to adapt to metabolic stress by regulating biogenesis, dynamics, mitophagy, and redox homeostasis. Linking mitochondrial resilience with insulin signaling could be essential for maintaining metabolic health. This review aims to map and synthesize the existing literature on the relationship between mitochondrial resilience and insulin resistance, focusing on cellular and molecular mechanisms, tissue-specific roles, metabolic consequences, and translational evidence from both animal and human studies. This scoping review adhered to PRISMA-ScR guidelines and included comprehensive searches of PubMed, Scopus, Web of Science, Embase, and Google Scholar. It included experimental and observational studies, original articles, systematic reviews, and meta-analyses, while excluding non-English publications and animal studies without clinical relevance. A total of 7, 012 records were identified; after removing duplicates, screening, and assessing eligibility, 184 studies were included. The evidence shows that impaired mitochondrial biogenesis, defective mitochondrial dynamics, reduced mitophagy, and oxidative stress disturb insulin signaling and promote metabolic inflexibility. Conversely, enhancing mitochondrial resilience increases mitochondrial quantity and function. Lifestyle modification strategies and pharmacological intervention target these pathways to improve mitochondrial resilience. Importantly, understanding inter-individual differences in mitochondrial adaptive capacity may support the development of personalized therapeutic and nutritional strategies aimed at improving insulin sensitivity and metabolic outcomes. In conclusion, mitochondrial resilience provides a comprehensive framework connecting mitochondrial quality to insulin signaling and metabolic health. Focusing on mitochondrial resilience is a promising, mechanism-based strategy for preventing and managing insulin resistance and its related comorbidities.