Mitochondrial quality control in kidney injury and repair

Abstract

Mitochondria are essential for the activity, function and viability of eukaryotic cells and mitochondrial dysfunction is involved in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease, as well as in abnormal kidney repair after AKI. Multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis, have evolved to preserve mitochondrial homeostasis under physiological and pathological conditions. Loss of these mechanisms may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and, potentially, organ failure. Accumulating evidence suggests a role of disturbances in mitochondrial quality control in the pathogenesis of AKI, incomplete or maladaptive kidney repair and chronic kidney disease. Moreover, specific interventions that target mitochondrial quality control mechanisms to preserve and restore mitochondrial function have emerged as promising therapeutic strategies to prevent and treat kidney injury and accelerate kidney repair. However, clinical translation of these findings is challenging owing to potential adverse effects, unclear mechanisms of action and a lack of knowledge of the specific roles and regulation of mitochondrial quality control mechanisms in kidney resident and circulating cell types during injury and repair of the kidney.

Fig. 1 |. Mitochondrial functions and the effects of mitochondrial damage.

a | Mitochondria have a key role in the generation of energy in the form of ATP. The nicotinamide adenine dinucleotides (NADHs) that are formed by fatty acid oxidation and the tricarboxylic acid (TCA) cycle in the matrix of the mitochondria pass their electrons to O₂ via the electron transport chain comprising complexes I–IV, resulting in the generation of a proton gradient across the inner mitochondrial membrane (IMM) for ATP production. Cytochrome c (cyto c) exists in its free form in the intermembrane space (IMS) or is anchored to the IMM through interaction with cardiolipin, where it acts as an electron carrier between respiratory complexes III and IV. Mitochondria are a major source of reactive oxygen species (ROS). Electrons that leak from the electron transport chain react with O₂ to form a superoxide anion, which is transformed into H₂O₂ by the enzymatic antioxidant superoxidase. Emission of mitochondrial H₂O₂ to the cytosol is essential for maintaining redox homeostasis and may also have a role in signalling pathways. Mitochondria also have important roles in maintaining cellular calcium homeostasis. b | In damaged mitochondria, ROS induce cardiolipin peroxidation, which converts cyto c from an electron carrier into a peroxidase that further oxidizes cardiolipin. This process contributes to the development of mitochondrial outer membrane permeabilization (MOMP) and the subsequent release of pro-apoptotic factors such as cyto c from the IMS into the cytosol, resulting in caspase activation and apoptosis. Mitochondrial permeability transition at the IMM drives necrosis. An increase in mitochondrial ROS production by damaged mitochondria may also induce other forms of cell death, including necroptosis, pyroptosis and ferroptosis, as well as inflammation. Release of mitochondrial ROS may impair cell proliferation and/or differentiation through the regulation of various signalling pathways. Mitochondrial DNA (mtDNA) released from damaged mitochondria is a potential activator of necroptosis and ferroptosis and can also induce inflammation. Mitochondrial damage reduces ATP production and can result in the energetic failure of cells. mPTP, mitochondrial permeability transition pore; OMM, outer mitochondrial membrane.

Fig. 2 |. Mitochondrial quality control.

The mitochondrial quality control system consists of molecular and organelle quality control mechanisms. Protein quality control is maintained by chaperones that catalyse protein folding and ATP-dependent proteases that remove unwanted and damaged proteins. In settings where the capacity of protein quality control is overwhelmed, the mitochondrial unfolded protein response (UPR^mt) is induced. In this response, signals released from mitochondria trigger the transcription of nuclear genes that encode mitochondrial chaperones to enhance the protein-folding capacity. The mitochondrial antioxidant defence system consisting of superoxidase dismutases (SODs), glutathione peroxidases (GPXs) and peroxiredoxin limits reactive oxygen species (ROS) levels within the organelles and the DNA damage repair machinery repairs damaged mitochondrial DNA. When these molecular quality control mechanisms fail to restore mitochondrial homeostasis, organelle quality control mechanisms are activated. Mitochondrial fusion mediated by mitofusin 1 (MFN1), MFN2 and dynamin-like 120 kDa protein, mitochondrial (OPA1) mitigates organelle stress by enabling the contents of damaged mitochondria to be combined with those of healthy mitochondria for complementation. Fission, which is regulated by cytosolic dynamin-1-like protein (DRP1) and its receptors, segregates damaged parts of the mitochondrial network, which are then removed by mitophagy. Mitophagy is mediated by the serine/threonine-protein kinase PINK1, mitochondrial (PINK1)–parkin pathway and mitophagy receptors, including BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), BCL-2-interacting protein 3-like and FUN14 domain-containing 1 (FUNDC1). Mitochondrial biogenesis depends on specific transcription factors, including peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α). When mitochondrial damage exceeds the capacity of mitochondria quality control or when mitochondrial quality control is defective, cell death ensues. MOMP, mitochondrial outer membrane permeabilization.

Fig. 3 |. Mitochondrial fusion and fission.

During fusion, mitofusin 1 (MFN1) and MFN2 expressed on two adjacent mitochondria interact to tether the organelles. GTP hydrolysis-induced conformational changes in the MFNs drive the docking and contact of the outer mitochondrial membranes (OMMs). The MFNs then oligomerize to fuse the OMMs. Following OMM fusion, inner mitochondrial membrane fusion is mediated by dynamin-like 120 kDa protein, mitochondrial (OPA1), which interacts with cardiolipin. Mitochondrial fusion facilitates the exchange of metabolites and substrates between mitochondria to ensure optimal functioning of the mitochondrial network and is also required for the complementation of damaged mitochondrial components to mitigate mitochondrial stress. During fission, dynamin-1-like protein 1 (DRP1) is recruited from the cytosol to the mitochondria, where it oligomerizes to form a ring-like structure around the OMM that utilizes the energy from GTP hydrolysis to constrict the organelle. Mitochondrial fission is required to separate damaged or dysfunctional components of mitochondria for selective autophagic degradation via mitophagy. Mitochondrial fragmentation, as a result of excessive mitochondrial fission over fusion, leads to mitochondrial outer membrane permeabilization (MOMP) and/or cristae remodelling, ultimately resulting in cell death.

Fig. 4 |. Molecular mechanisms of mitophagy.

Mitophagy requires efficient mitochondrial recognition and sequestration of target mitochondria within autophagosomes. There are two major mechanisms for mitochondrial priming in mitophagy. In the serine/threonine-protein kinase PINK1, mitochondrial (PINK1)–parkin pathway, mitochondrial damage or depolarization leads to impairment of PINK1 import into mitochondria, resulting in PINK1 accumulation on the outer mitochondrial membrane (OMM). PINK1 then recruits parkin from the cytosol and activates its E3 ligase activity via phosphorylation. Upon activation, parkin catalyses the formation of poly-ubiquitin chains on OMM proteins, which are then recognized by adaptor proteins, such as calcium-binding and coiled-coil domain-containing protein 2 (NDP52) and optineurin on autophagic phagophores, resulting in formation of the mitophagosome. In the mitophagy receptor pathway, BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3-like and FUN14 domain-containing 1 (FUNDC1) in the OMM directly bridge mitochondria to autophagosomes via their interactions with MAP1A/MAP1B LC3B (LC3B).

Fig. 5 |. Regulation of mitochondrial biogenesis during AKI and repair.

Peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) is the master regulator of mitochondrial biogenesis. PGC1α activates the expression of transcription factors that transactivate nuclear genes for fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), mitochondrial DNA (mtDNA) transcription, replication and translation, and mitochondrial protein import and assembly. Transcription factor A, mitochondrial (TFAM) specifically regulates mitochondrial genome replication. The nuclear gene-encoded proteins are transported into mitochondria through translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM). Acute kidney injury (AKI) and repair are associated with the upregulation of tumour necrosis factor (TNF) and tumour necrosis factor ligand superfamily member 12 (TNFSF12), activation of mitogen-activated protein kinase 1 (MAPK1) and MAPK3, and downregulation of 5-hydroxytryptamine receptor 1F (5-HT1F), which suppress PGC1A transcription. β2 adrenergic receptor (ADRB2) positively regulates PGC1A transcription. Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) activate PGC1α through deacetylation and phosphorylation, respectively. PGC1α also regulates the expression of antioxidant proteins, such as superoxide dismutase and glutathione peroxidase. ERRα, oestrogen-related receptor-α; NRF1, nuclear respiratory factor 1; NRF2, nuclear factor erythroid 2-related factor 2; PPARα, peroxisome proliferator-activated receptor-α.

Fig. 6 |. Targeting mitochondrial quality control mechanisms to protect against kidney injury and accelerate kidney repair in AKI and CKD.

Potential kidney-protective strategies include inhibition of mitochondrial fragmentation using mdivi-1, augmentation of mitochondrial antioxidant capacity using mitochondrial-target antioxidants (for example, SS-31, mitoQ and SkQR1), enhancement of mitophagy using urolithin A or TAT-beclin 1 peptide, enhancement of mitochondrial biogenesis using AMP-activated protein kinase (AMPK) activators (5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin), sirtuin 1 (SIRT1) activators (SRT1720, resveratrol and quercetin), a 5-hydroxytryptamine receptor 1F (5-HT1F) agonist (LY344864), a β2 adrenergic receptor agonist (formoterol) or thiazolidinediones (rosiglitazone and pioglitazone), and augmentation of mitochondrial oxidative metabolism using mitochonic acid 5, SS-31 or niacinamide. AKI, acute kidney injury; CKD, chronic kidney disease; ROS, reactive oxygen species.