Mitophagy, Inflammasomes and Their Interaction in Kidney Diseases: A Comprehensive Review of Experimental Studies

Abstract

Mitophagy is an important mechanism for mitochondrial quality control by regulating autophagosome-specific phagocytosis, degradation and clearance of damaged mitochondria, and involved in cell damage and diseases. Inflammasomes are important inflammation-related factors newly discovered in recent years, which are involved in cell innate immunity and inflammatory response, and play an important role in kidney diseases. Based on the current studies, we reviewed the progress of mitophagy, inflammasomes and their interaction in kidney diseases.

Keywords: acute kidney injury; chronic kidney disease; diabetic kidney disease; inflammasomes; kidney diseases; mitophagy.

Figure 1

Overview of mitophagy. Ubiquitination dependent mitophagy: It is mediated by PINK1/ parkin. When mitochondrial damage, PINK1 stabilizes and accumulates at the OMM to be phosphorylated and activated, thus recruiting parkin from the cytoplasm to the mitochondrial membrane, which driving the ubiquitination of mitochondrial proteins, leading to autophagy. Receptor-dependent mitophagy: BNIP3/Nix mediates the translocation of DRP1 to mitochondria, split mitochondria into small fragments, then activate PINK1/Parkin pathway and initiate mitophagy. FUNDC1 and FKBP8 can interact with LC3 to initiate mitophagy. PHB2 mediates stabilization of PINK1 on the OMM, and recruits Parkin. Then, PHB2 is externalized to the OMM and combines to LC3, leading to mitophagy. CL can be externalized to the OMM and directly bind to LC3 to induce mitophagy.

Figure 2

Overview of inflammasome pathway. The “canonical” inflammasome pathway: After PRRs recognize PAMPs and DAMPs, NLRs, AIM2 and pyrin form inflammasome complexes with ASC, pro-caspase 1 through PYD and/or CARD, and then activate caspase-1. Inflammatory factor such as IL-1β and IL-18 are matured and secreted, and eventually results in inflammation and cell death. The “non-canonical” inflammasome pathway: Inflammasomes directly bind to LPS to activate caspase-11, caspase-4 and caspase-5 through the CARD, resulting in cell death.