Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that orchestrates ubiquitin-dependent mitophagy together with the E3 ligase Parkin. Both physiological and pathological conditions rapidly recruit PINK1, and timely PINK1 degradation in healthy mitochondria determines whether it supports or harms the cell. Thus, the tight regulation of PINK1 balances its negative effects. In this context, introducing physical exercise as one of the strategies can fine-tune PINK1/Parkin pathways by triggering transient energy stress and moderate increases in reactive oxygen species (ROS) that promote PINK1 stabilization on the outer mitochondrial membrane, enhance Parkin recruitment via sensitizing various molecular signaling, such as AMPK-PGC-1α and FOXOs. However, the mechanism underlying a specific exercise mode that triggers PINK1-mediated selective removal of mitochondrial damage remains unknown. Therefore, this review will synthesize mechanistic approaches to how different exercise paradigms modulate PINK1 function, recruit PINK1 dynamics, and regulate downstream signaling, to define exercise prescriptions as adjunctive strategies.