The Emerging Role of Mitophagy in Kidney Diseases

Abstract

Mitochondria fulfill the high metabolic energy demands of the kidney and are regularly exposed to oxidative stress causing mitochondrial damage. The selective removal of damaged and dysfunctional mitochondria through a process known as mitophagy is essential in maintaining cellular homeostasis and physiological function. Mitochondrial quality control by mitophagy is particularly crucial for an organ such as the kidney, which is rich in mitochondria. The role of mitophagy in the pathogenesis of kidney diseases has lately gained significant attention. In this review, we summarize the current understanding of the implications of mitophagy during pathological conditions of the kidney, including acute and chronic kidney diseases.

Keywords: Mitophagy; acute kidney injury; chronic kidney disease; mitochondria; oxidative stress.

Figure 1.

Mechanisms of mitophagy: PINK1/Parkin-dependent and PINK1/Parkin-independent pathways. In the PINK1/Parkin dependent mitophagy, healthy mitochondria allow PINK1 to enter into the inner mitochondrial membrane (IMM) via translocase of outer membrane (TOM) and translocase of inner membrane (TIM)-23 proteins. The matrix metalloprotease (MMP) cleaves the mitochondrial targeting signal (MTS) of PINK1. Oxidative stress induces mitochondrial damage and a decline in membrane potential inhibits the import of PINK1 to the IMM. PINK1 accumulates on the outer mitochondrial membrane (OMM) and binds with TOM. PINK1 phosphorylates mitofusin 2 (MFN2), resulting in the recruitment of Parkin from the cytoplasm to the OMM. Parkin facilitates the ubiquitination of OMM proteins including voltage-dependent anion channel (VDAC) and Miro. Subsequently, adaptor protein p62 attaches to the ubiquitinated OMM proteins. Lastly, p62 binds with LC3B and promotes mitophagosome formation. In PINK1/Parkin-independent mitophagy, LC3B directly interacts with OMM proteins: FUN14 domain-containing 1 (FUNDC1), NIP3-like protein X (NIX) and BCL2/adenovirus E1B 19kDa-interacting protein 3 (BNIP3) via the LC3B interacting region (LIR). The process of mitophagy involves the formation of the isolation membrane for the recruitment of dysfunctional mitochondria into the mitophagosome, and subsequent lysosome-mediated degradation to recycle the damaged mitochondrial components.