Macrophage Migration Inhibitory Factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury

Abstract

Abstract Renal tubular epithelial cells (RTECs) injury foreboded the occurrence and development of sepsis-associated acute kidney injury (SA-AKI). Recent studies of mitochondria have demonstrated that mitophagy was an indispensable physiological function of alleviating RTECs injury. Mitophagy was suppressed progressively by the inflammation response in SA-AKI. However, the mechanism of inflammation modulating mitophagy remains poor understood. We investigated the role of macrophage migration inhibitory factor (MIF, a pro-inflammation protein) in the PINK1-Parkin pathway of mitophagy through identifying the protein-protein interactions under the condition of inhibiting or over-expressing MIF. Unexpectedly, increasing MIF directly bound with PINK1 and disturbed the interaction of PINK1 and Parkin, which restrained the Parkin recruitment to mitochondria and the occurrence of mitophagy. Furthermore, this effect caused severe RTECs apoptosis, but which could be reversed by a MIF inhibitor ISO-1 or/and a new mitophagy activator T0467. These findings identified a critical renodamaged effect of MIF on disturbing the interaction of PINK1-Parkin and a therapeutic effect of ISO-1 and T0467 on protecting against SA-AKI. This study provided a novel insight of treating SA-AKI through targeting MIF and mitophagy.