PINK1-Parkin pathway-mediated mitophagy in sepsis: friend or foe?

The PINK1-Parkin pathway is well-known for its role in canonical mitophagy, which is involved in various mitophagy-related biological and pathological processes, including pathogen infection, inflammasome activation, oxidative stress, inflammatory response, and even sepsis-induced multiorgan dysfunction. However, the precise mechanisms by which mitophagy is orchestrated during mitochondrial damage and its role in sepsis-induced multiple organ dysfunction are not yet fully elucidated, and there is even controversy. This review proposes four key mechanistic pathways-oxidative stress, the cGAS-STING axis, NF-κB signaling, and inflammasome activation-that interact with mitophagy and contribute to sepsis pathogenesis. Another objective of the work is to explore potential candidate agents that regulate the PINK1-Parkin pathway in mitophagy, by therapeutic mechanism (e.g. PINK1 activators, Parkin recruiters, deubiquitinase inhibitors and upstream pathway modulators). The therapeutic benefits can be achieved by regulating mitophagy, which has promising protective effects against multi-organ injuries, including septic encephalopathy, cardiac dysfunction, acute lung injury, and acute kidney injury.