Mitochondria ROS and mitophagy in acute kidney injury

Abstract

Mitophagy is an essential mitochondrial quality control mechanism that eliminates damaged mitochondria and the production of reactive oxygen species (ROS). The relationship between mitochondria oxidative stress, ROS production and mitophagy are intimately interwoven, and these processes are all involved in various pathological conditions of acute kidney injury (AKI). The elimination of damaged mitochondria through mitophagy in mammals is a complicated process which involves several pathways. Furthermore, the interplay between mitophagy and different types of cell death, such as apoptosis, pyroptosis and ferroptosis in kidney injury is unclear. Here we will review recent advances in our understanding of the relationship between ROS and mitophagy, the different mitophagy pathways, the relationship between mitophagy and cell death, and the relevance of these processes in the pathogenesis of AKI.Abbreviations: AKI: acute kidney injury; AMBRA1: autophagy and beclin 1 regulator 1; ATP: adenosine triphosphate; BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BH3: BCL2 homology domain 3; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CASP1: caspase 1; CAT: catalase; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CI-AKI: contrast-induced acute kidney injury; CISD1: CDGSH iron sulfur domain 1; CL: cardiolipin; CNP: 2',3'-cyclic nucleotide 3'-phosphodiesterase; DNM1L/DRP1: dynamin 1 like; E3: enzyme 3; ETC: electron transport chain; FA: folic acid; FUNDC1: FUN14 domain containing 1; G3P: glycerol-3-phosphate; G6PD: glucose-6-phosphate dehydrogenase; GPX: glutathione peroxidase; GSH: glutathione; GSK3B: glycogen synthase kinase 3 beta; GSR: glutathione-disulfide reductase; HIF1A: hypoxia inducible factor 1 subunit alpha; HUWE1: HECT, UBA and WWE domain containing 1; IL1B: interleukin 1 beta; IMM: inner mitochondrial membrane; IPC: ischemic preconditioning; IRI: ischemia-reperfusion injury; LIR: LC3-interacting region; LPS: lipopolysaccharide; MA: malate-aspartate; MPT: mitochondrial permeability transition; MUL1: mitochondrial E3 ubiquitin protein ligase 1; mtROS: mitochondrial ROS; NLR: NOD-like receptor; NLRP3: NLR family pyrin domain containing 3; NOX: NADPH oxidase; OGD-R: oxygen-glucose deprivation-reperfusion; OMM: outer mitochondrial membrane; OPA1: OPA1 mitochondrial dynamin like GTPase; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PINK1: PTEN induced kinase 1; PLSCR3: phospholipid scramblase 3; PMP: peptidase, mitochondrial processing; PRDX: peroxiredoxin; PRKN: parkin RBR E3 ubiquitin protein ligase; RPTC: rat proximal tubular cells; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SOD: superoxide dismutase; SOR: superoxide reductase; SQSTM1/p62: sequestosome 1; TCA: tricarboxylic acid; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; TXN: thioredoxin; VDAC: voltage dependent anion channel; VCP: valosin containing protein.

Keywords: Acute kidney injury; cell death; mitochondria; mitophagy; reactive oxygen species.

Figure 1.

The generation and elimination of mitochondria ROS. In the cytosol, NADPH is primarily produced by G6PD in the glycolysis pathway. The cytosolic and mitochondrial NADPH is exchanged through two shuttles. NOXs transports electrons to oxygen from NADPH to produce superoxide free radical which was converted by SOD (SOD2 in mitochondria) to hydrogen peroxide, and finally converted by catalase to harmless H₂O. Mitochondrial ROS are produced from the leakage of electrons to form superoxide at complex I and complex III in the electron transport chain. Mitochondria utilize oxygen to generate ATP through OXPHOS. Abbreviations: ATP: adenosine triphosphate; CAT: catalase; ETC: electron transport chain; G6PD: glucose-6-phosphate dehydrogenase; MA/G3P: the malate-aspartate (MA) and the glycerol-3-phosphate(G3P) shuttle; NOX: NADPH oxidase; OXPHOS: oxidative phosphorylation; SOD: superoxide dismutase; TCA: tricarboxylic acid.

Figure 2.

PRKN-dependent mitophagy. PINK1 is constitutively processed by mitochondrial proteases, PMP and PARL, resulting in its proteasomal degradation in normal condition (a); In damaged mitochondria, PINK1 accumulates at OMM bound to the TOMM complex where it is activated through auto-phosphorylation. Activated PINK1 subsequently phosphorylates ubiquitin, which triggers recruitment of PRKN recruitment to mitochondria and activation of its E3 ligase activity. It further ubiquitinates mitochondrial substrates and initiate autophagosome formation. PRKN acts as an enhancer of this signaling through further ubiquitination of mitochondrial proteins (b). Abbreviations: IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; PARL: presenilin associated rhomboid like; PINK1: PTEN induced kinase 1; PMP: peptidase, mitochondrial processing; PRKN: parkin RBR E3 ubiquitin protein ligase; SQSTM1/p62: sequestosome 1; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane.

Figure 3.

PRKN-independent mitophagy. Receptor mediated mitophagy: BNIP3, BNIP3L and FUNDC1, are OMM receptors containing an LIR-domain that directly binds to LC3 proteins to recruit the phagophore to the damaged mitochondria and leading to its degradation; cardiolipin-mediated mitophagy: IMM CL can be translocated to the OMM through the action of PLSCR3. Once at the OMM, CL binds to LC3A to recruit the phagophore and to remove the damaged mitochondria; Ubiquitin mediated mitophagy: Some proteins have E3 ubiquitin ligases activities which can be located at damaged mitochondria to ubiquitinate OMM proteins, and subsequently recruit the phagophore to damaged mitochondria. Abbreviations: BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CL: cardiolipin; FUNDC1: FUN14 domain containing 1; E3: enzyme 3; IMM: inner mitochondrial membranes; OMM: outer mitochondrial membranes; LIR: LC3-interacting region; PLSCR3: phospholipid scramblase 3.

Figure 4.

Crosstalk between mitophagy and other type of cell death. VDAC regulates mitochondria iron homeostasis through CISD1 which may affect the iron-dependent cell death of ferroptosis. Translocator protein interacts with VDAC in PINK-PRKN-dependent mitophagy. VDAC gate the Ca²⁺ transport to control energy production and metabolism by modulating enzyme activity of TCA which impacts the production of mitochondria ROS in the electron transport chain. GSK3B increased VDAC phosphorylation to control MPT. SLC7A11/xCT regulates extracellular cystine and intracellular glutamate exchanging which influence the TCA and GSH metabolism through glutamate and cystine, respectively. BCL2 family proteins regulate apoptosis through controlling the assembly of multimeric BAX-BAK1 channels. The interaction of BECN1-BCL2 inhibits autophagy and mitophagy but increase apoptosis. BCL2 family proteins, like BNIP3, can disrupt interaction between the BECN1 and antiapoptotic BCL2 family. NLRP3 process pro-CASP1 to active CASP1, which cleaves pro-inflammatory IL1B to mature IL1B causing pyroptosis. NLRP3 binding of its LIR motif to LC3 induce mitophagy while CASP1 inhibits mitophagy to amplify mitochondrial damage. VDAC activates NLRP3 to induce pyroptosis. Abbreviations: BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CASP1: caspase 1; CISD1: CDGSH iron sulfur domain 1; GPX: glutathione peroxidase; GSH: glutathione; GSK3B: glycogen synthase kinase 3 beta; IL1B: interleukin 1 beta; LIR: LC3-interacting region; MPT: mitochondrial permeability transition; NLRP3: NLR family pyrin domain containing 3; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; SLC7A11/xCT: solute carrier family 7 member 11; TCA: tricarboxylic acid; VDAC: voltage dependent anion channel.