Cadmium targeting MLKL-Drp1 axis to trigger mitochondrial oxidative stress contributes to necroinflammation in rat kidney.

INTRODUCTION

Acute kidney injury (AKI) induced by cadmium (Cd) manifests excessive inflammation with no effective therapy. Necroptosis, a novel manner of necrosis that regulates cell death, has been revealed important functions in the inflammation i.e., necro-inflammation.

OBJECTIVES

Targeting necroptosis may be a potential therapeutic strategy for Cd-induced AKI, but the role of necroptosis in Cd-evoked nephrotoxicity is poorly understood. Thus, in vivo and in vitro studies were performed to clarify this issue.

METHODS AND

RESULTS

Data from RNA-sequencing analysis and its validation showed that necroptosis and NOD-Like Receptor Protein 3 (NLRP3) inflammasome activation were involved in Cd-induced AKI. Further investigations revealed that mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis drove Cd-induced inflammatory cascades in renal tubular epithelial cells, triggering necroinflammation. Significant mitochondrial dysfunction and mitochondrial ROS (mtROS) overproduction due to MLKL activation were observed in this process. Notably, Cd-induced necroinflammation could be attenuated by mitochondria-targeted antioxidant, suggesting the key role of MLKL-dependent mtROS overproduction. Cd exposure triggered MLKL mitochondrial translocation-dependent dynamin-related protein 1 (Drp1) recruitment, driving excessive mitochondrial fragmentation and mtROS overproduction. And the effects were significantly ameliorated by the Drp1 inhibitor. In addition, mitochondrial calcium efflux due to activated MLKL-Drp1 axis impaired mtROS scavenging, further aggravating Cd-induced mtROS accumulation.

CONCLUSION

These findings reveal that MLKL-Drp1 interaction is involved in Cd-induced necroinflammation via a novel mechanism to disrupt mitochondrial homeostasis, highlighting the therapeutic potential of targeting MLKL-Drp1 axis in Cd-induced nephrotoxicity.