First, the AMPK-PGC-1α axis acts as a core regulator: exercise activates AMPK (p-AMPKα Thr172 elevation in T2DM), which not only initiates mitophagy via ULK1 phosphorylation (to clear damaged mitochondria) but also upregulates PGC-1α—this coordinates biogenesis (CS elevation) and mitophagy to optimize the quality and quantity of mitochondria, thereby enhancing respiratory efficiency (Hendlinger et al., 2025; Gurd et al., 2022). This evidence concerns the gene PPARGC1A and type 2 diabetes mellitus.