The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Mitochondria are heterogeneous and highly dynamic organelles, playing critical roles in adenosine triphosphate (ATP) synthesis, metabolic modulation, reactive oxygen species (ROS) generation, and cell differentiation and death. Mitochondrial dysfunction has been recognized as a contributor in many diseases. The kidney is an organ enriched in mitochondria and with high energy demand in the human body. Recent studies have been focusing on how mitochondrial dysfunction contributes to the pathogenesis of different forms of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). AKI has been linked to an increased risk of developing CKD. AKI and CKD have a broad clinical syndrome and a substantial impact on morbidity and mortality, encompassing various etiologies and representing important challenges for global public health. Renal mitochondrial disorders are a common feature of diverse forms of AKI and CKD, which result from defects in mitochondrial structure, dynamics, and biogenesis as well as crosstalk of mitochondria with other organelles. Persistent dysregulation of mitochondrial homeostasis in AKI and CKD affects diverse cellular pathways, leading to an increase in renal microvascular loss, oxidative stress, apoptosis, and eventually renal failure. It is important to understand the cellular and molecular events that govern mitochondria functions and pathophysiology in AKI and CKD, which should facilitate the development of novel therapeutic strategies. This review provides an overview of the molecular insights of the mitochondria and the specific pathogenic mechanisms of mitochondrial dysfunction in the progression of AKI, CKD, and AKI to CKD transition. We also discuss the possible beneficial effects of mitochondrial-targeted therapeutic agents for the treatment of mitochondrial dysfunction-mediated AKI and CKD, which may translate into therapeutic options to ameliorate renal injury and delay the progression of these kidney diseases.

The term AKI was first used by William MacNider in 1918 in a situation of acute mercury poisoning and has recently been used to replace the term acute renal failure (ARF) [ 17 ]. AKI is a broad clinical syndrome that rarely has a sole and distinct pathophysiology, with an incidence of about 2000 per million population. Patients with AKI normally have a mixed etiology, including specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal pathology (e.g., prerenal azotemia and acute postrenal obstructive nephropathy) [ 1 , 18 ]. The diagnostic approach of AKI at present is based on an acute drop of glomerular filtration rate (GFR) within a short time, which is also reflected with an acute rise in serum creatinine levels and/or a decline in urine output [ 17 , 19 ]. AKI can be classified by three main categories: pre-renal, intrinsic, and post-renal AKI [ 3 , 20 ]. The pre-renal and post-renal AKI are the consequence of extra-renal disease mediated decrease of GFR, whereas ‘intrinsic’ AKI represents true kidney disease. AKI is characterized by renal hemodynamics, renal tubular damage, renal congestion, and inflammation [ 21 ]. The pathogenesis of AKI involves in the injury and death of renal tubular cells in the proximal tubule [ 21 , 22 ]. In AKI, the primary site of damage is the plasma membrane, whereas other cellular components, including nucleus, cytoskeleton, endoplasmic reticulum (ER), and mitochondria, are also key targets [ 22 ]. A wide array of patient-specific and context-specific factors can increase the risk of AKI, which can be classified as non-modifiable and potentially modifiable factors, including extremes of age, proteinuria, comorbid diseases, anemia, critical illness, sepsis, and fluid overload [ 23 ]. CKD is characterized by a gradual loss of kidney function over time and has been defined as eGFR < 60 mL/min/ 1.73 m 2 , irrespective of the presence or absence of kidney damage, and this includes stage 3 CKD (eGFR = 30–59 mL/min/1.73 m 2 ), stage 4 CKD (eGFR = 15–29 mL/ min/1.73 m 2 ), and stage 5 CKD (eGFR < 15 mL/min/1.73 m 2 or persons on chronic dialysis), which is also known as end-stage renal disease (ESRD). The definition of ESRD is the final, permanent stage of chronic kidney disease, where kidney function has declined to the point that the kidneys can no longer function on their own [ 24 ]. In addition to being a high risk for progression to ESRD, CKD is also an independent risk factor for cardiovascular disease and all-cause mortality. The pathological of CKD features including renal structural and physiological characteristics, as well as the principles of renal tissue injury and repair. Chronic and sustained insults from chronic and progressive nephropathies lead to kidney damage, which is then perpetuated by the process of hyperfiltration and hypertrophy of the remaining nephrons. Initial hyperfiltration activates renin–aldosterone system and causes an increase in arterial filling pressure to the nephrons, resulting in a change in the glomerular architecture and structure as well as in podocytes to further damage the filtration system. Angiotensin II and protein uptake at the tubules causes inflammation and fibrosis of the glomerulus and tubules, leading to a further decrease in renal function. The progression of CKD can be accelerated as a consequence of four mechanisms, including systemic and intraglomerular hypertension, glomerular hypertrophy, intrarenal precipitation of calcium phosphate, and altered prostanoid metabolism [ 25 ]. In the last decade, evidence from both clinical and experimental studies suggested a causal link between AKI and CKD, termed as AKI to CKD transition, which is due to incomplete or maladaptive repair after AKI. As AKI has been widely identified as an important risk factor for the occurrence and development of CKD, the potential mechanisms that underlie the progression of AKI and its transition to CKD have also been proposed. They include hypoxia and endothelial dysfunction, nephron loss, alterations of renal resident cell phenotypes and their functions, cell cycle arrest, persistent inflammation, mitochondrial fragmentation, epigenetic modifications, and fibrosis via myofibroblasts recruitment and matrix deposition. In addition, organelle stress signaling caused by ER and mitochondrial stress via induction of tubular cell senescence and subsequent tubular inflammation also contributes to AKI to CKD transition [ 26 , 27 , 28 ]. The kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) have been identified as possible biomarkers of AKI to CKD transition [ 29 ]. Since prevention of AKI to CKD transition is essential for maintaining kidney function, it is therefore crucial to elucidate the molecular mechanisms underlying this transition, which would facilitate the identification of nove

Mitochondria are highly dynamic organelles that can modulate their morphology to create a tubular network coordinated by fission and fusion events [ 32 ]. The balance between these two opposite processes are mainly regulated by large GTPases belonging to the Dynamin family, which regulate mitochondrial number, distribution, and size within the cytoplasm and is referred to as ‘mitochondrial dynamics’, in response to metabolic and signaling cues in the cell environment. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria mainly mediated by dynamin-related protein 1 (Drp1), a large dynamin-related GTPase. During mitochondrial fission, Drp1 is recruited to the OMM and then GTP hydrolysis enhances this membrane constriction leading to the recruitment of Dynamin 2 to terminate membrane scission. Conversely, mitochondrial fusion is driven by a two-step process caused by several guanosine triphosphate hydrolases (GTPase), including mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), which contribute to the outer mitochondrial membrane fusion, and optic atrophy 1 (Opa1), which contributes to the inner membrane fusion. Moreover, some membrane lipid components, such as phosphatidic acid and cardiolipin, and several factors that can undergo post-translational modifications, such as Drp1 phosphorylation [ 33 ] and SUMOylation/deSUMOylation [ 34 , 35 ], are also involved in the regulation of these processes. The deregulation of these two opposite processes and pathogenic mutations of genes encoding the core fission and fusion machinery components have been linked to AKI and CKD and will be described in detail later.

Mitochondria are very sensitive to changes in environmental factors, which may cause mitochondrial dysfunction [ 39 ]. Mitochondrial dysfunction may result in a decrease of ATP generation, an increase of reactive oxygen species level and an induction of apoptosis, all of which contribute to the development and progression of AKI and CKD as well as AKI to CKD transition. Therefore, it is important to understand the roles of mitochondrial biology and pathophysiology in AKI and CKD, which should facilitate novel discoveries for effective therapies of these diseases. 4.1. The Roles of Mitochondrial Structure, Dynamics, and Biogenesis in AKI Mitochondria has been recognized as a critical player in AKI with dual roles as the primary source of energy for each cell and as a key regulator of cell death. First, the changes of mitochondria structure have been observed in AKI. Ischemia as a leading cause of AKI diminishes the amounts of mitochondria and induces mitochondria structural changes, typically swelling and showing the disappearance of the inter mitochondrial membrane cristae, due to ATP depletion and membrane potential reduction [ 40 ] ( Figure 2 ). In addition, the opening of mitochondrial permeability transition pores (mPTP) due to mitochondrial swelling and dysfunction is a key event that contributes to AKI progression through releasing pro-apoptotic mediators, including cytochrome c, which can induce renal cell apoptosis [ 41 ]. mPTP is a nonspecific channel for signal transduction or material transfer between mitochondrial matrix and cytoplasm. In ADR-induced nephropathy rats, treatment with mPTP inhibitor cyclosporine A (CSA) significantly inhibited cytochrome c release and cell apoptosis as well as improved mitochondrial function [ 42 ]. Second, the disruption of the balance between fission and fusion events has been associated with AKI progression. The protein Drp1 that could regulate mitochondrial fission was rapidly activated while the proteins, Mfn and Opa1, which could regulate mitochondrial fusion, were decreased following AKI, resulting in mitochondrial fragmentation [ 43 , 44 ] ( Figure 2 ). Cellular stress leads to the oligomerization of Bax and Bak, two proteins of the pro-apoptotic Bcl-2 family, which are susceptible to insert into fragmented mitochondria and consequently outer membrane permeabilization [ 45 ]. The permeabilization of mitochondrial outer membrane (MOMP) by pro-apoptotic Bcl-2 family proteins results in the release of apoptogenic factors, such as cytochrome c, which further bind apoptotic peptidase activating factor 1 (Apaf-1) to recruit and activate caspase 9 to trigger the intrinsic apoptotic pathway [ 46 , 47 , 48 ] ( Figure 2 ). Knockout of Bax or Bak prevented mitochondrial fragmentation along with suppressed cytochrome c release in AKI [ 49 ]. Inhibition of mitochondrial fragmentation pharmacologically or by genetically preventing inflammation and cell death shows a significant renoprotective effect in AKI model induced by ischemic reperfusion or nephrotoxic [ 44 , 49 , 50 , 51 ]. Third, the dysregulation of mitochondrial biogenesis has also been observed in AKI. In kidneys, PGC-1α is predominantly expressed in proximal tubules and drives mitochondrial biogenesis by its transcriptional co-activators, such as nuclear respiratory factor 1 (NRF1) and nuclear respiratory factor 2 (NRF2). The target genes of NRF1/2 regulate oxidative phosphorylation, fatty acid oxidation (FAO), and the biogenesis of nicotinamide adenine dinucleotide (NAD+), a central metabolic coenzyme/cosubstrate involved in cellular energy, which refer to oxidative metabolism to renal protection [ 52 , 53 , 54 , 55 ] ( Figure 2 ). PGC-1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids, whereas PGC-1α deficiency or AKI attenuates the de novo pathway. The effect of PGC-1α and its association with mitochondrial biogenesis in AKI was supported by the results generated from in Pgc1α -/- mice following ischemia-reperfusion injury [ 54 ]. In cisplatin-induced AKI, treatment with AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) and the antioxidant agent acetyl-l-carnitine (ALCAR), which activates sirtuin3 (SIRT3) increased PGC-1α activity and improves renal function [ 56 ]. Global or tubule-specific PGC-1α knockout mice had normal basal renal function but suffered persistent injury due to prolonged sepsis [ 57 ]. In sepsis-associated AKI, endotoxic insults selectively suppress the expression of PGC-1α and then affected PGC-1a mediating the recruitment of NRF1 and NRF2 on genes that regulate oxidative phosphorylation [ 57 , 58 ] ( Figure 2 ). Mitochondrial FAO in proximal tubular cells is a major source of ATP generation. The impairment of mitochondrial FAO has been linked to ATP depletion-induced AKI, and its long-term sequelae leads to CKD [ 59 ]. In cisplatin-induced AKI, downregulation of PGC-1α decreased the transcription of FAO genes, including carni

Damaged mitochondria release harmful molecules, such as ROS, DNA, and cardiolipin, which can activate NOD-like receptors (NLR) and elevate the levels of proinflammatory cytokines and chemokines, such as IL-18 and IL-1β, to induce persistent renal injury [ 80 ] ( Figure 2 ). The innate immune system has been implicated in both AKI and CKD and persistent inflammation after AKI prevents tissue repair and tubular apoptosis. On one hand, inflammation plays a critical role in the initiation and progression of renal fibrosis, when mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation, leading to persistent endothelial injury, podocyte damage, microvascular rarefaction, and ultimately, progressive glomerular and interstitial fibrosis. On the other hand, upon kidney injury, oxidant stress, abundant cytokines, or hypoxia, deteriorate the mitochondrial membrane potential by excreting ROS and releasing pro-apoptotic factors, such as cytochrome c and apoptosis-inducing factor (AIF), which promote caspase dependent and independent apoptosis. In this perspective, persistent mitochondrial dysfunction result in persistent tubular damage, which may affect renal recovery from AKI and further progression to CKD. In a study with AKI to CKD transition experimental model, the investigators performed a long (nine months) follow-up, exploring the role of mitochondria in rats [ 80 ]. They confirmed that AKI is not merely an acute phenomenon but results in long-lasting morphologic and functional consequences. AKI induced peritubular and glomerular capillary loss, podocyte damage, and increased profibrotic and proinflammatory cytokines from one to nine months, leading to progressive glomerular and interstitial fibrosis. Transmission electron microscopy revealed major alterations of mitochondria including loss of cristae and matrix density in endothelial cells, podocytes, and tubular cells up to nine months after the injury. Similar data was also presented in the Lan et al. study [ 40 ], which showed that persistence in mitochondrial morphologic alterations and significant reductions in mitochondrial number and metabolic dysfunctions at 14 days after IRI plays a key role in the development of renal tubular atrophy and the transition to CKD after AKI. Studies have also focused on the role and mechanisms of impaired protein kinase B (PKB/AKT1) signaling, which works together with mitochondrial proteins, in the regulation of ATP production and oxidative phosphorylation in renal tubular epithelial cells. Mitochondrial AKT1 inhibition led to activation of caspases and tubular cell death, and renal fibrosis after ischemia-reperfusion injury [ 81 ]. Altogether, these studies suggest long-term mitochondrial damage may affect the pathophysiology and recovery from AKI and result in the gradual progression to CKD. In addition, studies show that mitochondrial dysfunction disrupts the crosstalk between mitochondria and ER, leading to tubular inflammation and fibrosis as well as the AKI to CKD transition. ER is a major organelle that controls protein synthesis, folding, and degradation via the unfolded protein response (UPR) pathway. The UPR promotes cellular survival by restoring ER and mitochondrial homeostasis through distinct signaling networks, but if unsuccessful, the UPR induces cell death [ 82 ]. UPR pathways is regulated by three distinctive transmembrane sensors: activating transcription factor 6 (ATF6), PRKR-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1), which can be activated under ER stress [ 83 ] ( Figure 2 ). Various types of kidney damage are associated with dysfunction of the ER and the activation of the UPR. In cisplatin-induced AKI model, cisplatin-induced mitochondrial damage and mtDNA leakage into the cytosol in renal tubular cells, and damaged mtDNA subsequently increased the activation of cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, resulting in the activation of UPR response and then renal inflammation and AKI progression [ 84 ]. The activation of ATF6α caused by pathogenic conditions significantly reduces mitochondrial fatty acid β-oxidation activity through suppressing the expression of peroxisome proliferator–activated receptor-α (PPARα) and thereby induced tubular inflammation and fibrosis after acute kidney injury induced by lipotoxicity [ 70 ]. Furthermore, activated ATF6 can be translocated to the Golgi apparatus for cleavage to form an active fragment (ATF6 p50). The activation of IRE1 and PERK induces the splicing of the X-box binding protein 1 (XBP1) mRNA and phosphorylates eIF2α, which promotes the translation of activating transcription factor 4 (ATF4) and suppresses the translation of other mRNAs to reduce unfolded proteins, respectively. ATF6 p50, spliced XBP1, and ATF4 could induce the transcription of various UPR target genes that regulate inflammation and apoptosis ( Figur

Given the abundant evidence for a critical role of mitochondrial dysfunction in various acute and chronic kidney injuries, mitochondria, thus, have been recognized as a promising target to improve treatment of patients with kidney diseases. Currently, numerous novel mitochondria-targeted compounds are being exploited in AKI and CKD. Based on the roles and mechanisms, these agents have been classified as compounds for cardiolipin protection, inhibitors of mitochondrial fragmentation, compounds for promoting mitochondrial biogenesis, and inhibitors of mPTP and mitochondria oxidants ( Figure 3 and Table 1 ). 6.1. Cardiolipin Protection Agents Cardiolipin (CL), one of the major phospholipids localized and synthesized in the inner mitochondrial membrane was first isolated from beef heart in the early 1940s [ 125 ]. CL interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain and ATP production [ 126 ]. Its deficiency results in mitochondrial dysfunction, including the changes of mitochondrial membrane morphology, stability and dynamics, mitochondrial biogenesis, and protein import, as well as a decrease in respiratory performance and an increase in ROS generation [ 126 , 127 ]. Ischemia could induce mitochondria degenerative changes with matrix swelling and loss of the IMM cristae in all renal cells due to ATP depletion and dysregulation of osmotic influx of water [ 128 ]. Given that mitochondrial structure and function are closely linked, a promising target to preserve mitochondrial structure might contribute to maintain normal mitochondrial function and improve mitochondrial function following ischemia. The development of compounds to protect cardiolipin and to optimize efficiency of the electron transport chain and thereby restore cellular bioenergetics has been an innovative discovery. Szeto-Schiller (SS) peptides are among novel mitoprotective drugs. SS-31 (also known as elamipretide) as a synthetic tetrapeptide ( d -Arg-2′6′-dimethylTyr-Lys-Phe-NH2) can selectively bind to CL through electrostatic and hydrophobic interactions on the inner mitochondrial membrane to protect cristae curvature, stabilize mitochondrial structure, facilitate the transport of electrons, and minimize ROS production, which has been reported to attenuates cardiac damage in experimental models of heart failure [ 129 , 130 ]. SS-31 has been tested in experimental AKI and CKD. In ischemic reperfusion-induced AKI model, administration of SS-31 before the injury protected endothelial and epithelial mitochondria, preserved peritubular and glomerular capillaries, and prevented inflammation [ 131 ]. In another study, treatment with SS-31 one month after ischemia and maintaining for six weeks showed the protection of mitochondrial integrity, restoration of peritubular and glomerular capillaries, preservation of podocyte architecture, and suppression of inflammation and the progression of glomerulosclerosis and tubular interstitial fibrosis [ 80 ], suggesting that SS-31 showed a renoprotective by restoring mitochondrial structure and function, inhibiting proinflammatory and profibrotic response in AKI to CKD transition. In CKD models, treatment with SS-31 overcame lipotoxicity, glomerulosclerosis, and tubular lesions and injury in kidneys induced by a high-fat diet and urinary tract obstruction (UUO) [ 96 , 97 , 98 ]. Treatment with SS-31 improves renal function either by accelerating the recovery of ATP or scavenging ROS and suppressing mitochondrial permeability transition. In addition to SS-31, another SS family drug, SS-20, has also been tested in AKI and CKD. Treatment with SS-20 could increase the efficiency of the electron transport chain and improve the coupling of oxidative phosphorylation, which are also considered to be mechanisms that reduce IR injury. SS-20 could reduce mitochondrial matrix swelling and preserved cristae membranes, which enhanced mitochondrial ATP synthesis under ischemic conditions. Treatment with SS-20 could also significantly reduce renal interstitial fibrosis after ischemia [ 99 ].

Mitochondria biogenesis refers to a process of generating new mitochondrial mass and replicating mtDNA, in which, activation is necessary for the increased metabolism and energy demands during the recovery from acute organ injury. The AMPK/SIRT/PGC-1α axis plays crucial roles in mitochondrial biogenesis. As mentioned above, PGC-1α have been identified as a critical regulator that coordinately regulates mitochondrial biogenesis, reduces oxidative stress, and anti-inflammatory [ 54 ]. The expression and activity of PGC-1α can be regulated by Sirtuin1 (SIRT1), a NAD-dependent deacetylase. In IRI-AKI, treatment with SIRT1 activator, SRT1720 restores the expression of PGC-1α in kidneys, leading to enhanced mitochondria biogenesis characterized by the increase of mitochondrial mass and ATP levels, and improved renal function [ 103 ]. Other activators of mitochondria biogenesis include resveratrol, AICAR, and formoterol. Treatment with resveratrol [ 105 ], a natural plant phytoalexin, protects mice against aldosterone-induced podocyte injury by upregulating PGC-1α and restores mitochondrial respiratory capacity and decreases the production of mitochondria ROS and lipid peroxidation in AKI [ 68 , 135 ]. Pretreatment with AICAR, an AMPK activator, attenuated I/R injury-induced nitrosative stress and monocyte/macrophage infiltration, and ameliorated the development of acute tubular necrosis [ 108 ]. Formoterol is a potent agonist of β2-adrenoreceptor, which can induce mitochondrial biogenesis by increasing mtDNA copy numbers, oxygen consumption rate, and PGC-1α expression in both the renal proximal tubular cells and cardiomyocytes [ 110 ]. Treatment with formoterol rescued injury and tubular necrosis, decreased nitrosative stress, and ameliorated renal function in IRI-AKI [ 111 ]. All these drugs have also been tested in CKD models. For example, either SRT1720 or AICAR treatment exerted protective effects against tubulointerstitial fibrosis by decreasing oxidative stress [ 104 , 109 ]. In diabetic nephropathy, treatment with resveratrol prevents lipotoxicity-related apoptosis and oxidative stress [ 105 , 106 , 107 ]. Formoterol treatment was also shown to be renoprotective in diabetic nephropathy, which reduced proteinuria and kidney profibrotic proteins by restoring mitochondrial fusion/fission protein level [ 112 ]. In addition, another group of drugs known as “fibrates”, including bezafibrate and fenofibrate, which could increase mitochondrial fatty acid oxidation and mitochondrial biogenesis, have also been shown to have renoprotective effects in diabetic experimental models [ 113 ]. Thus, mitochondria biogenesis activators can be promising therapeutic targets.

Opening of high conductance mPTP initiates onset of the mitochondrial permeability transition (MPT) and leads to cellular necrosis and apoptosis after oxidative stress, Ca 2+ toxicity, and ischemia/reperfusion [ 136 ]. mPTP putatively consists of the voltage-dependent anion channel, the adenine nucleotide translocator (ANT), and cyclophilin D. The inhibitors of mPTP have been shown to ameliorate renal IRI and drug-induced AKI [ 42 , 114 ]. Cyclosporine-A (CSA), a potent inhibitor of the mPTP, blocking the interaction of cyclophilin D with the ANT, results in blocking the conformational change of ANT [ 137 ], which is currently under clinical trial for its effect on reperfusion injury on acute myocardial infarction ( NCT01595958 ) and severe traumatic brain injury ( NCT01825044 ). Low dose of CSA suppressed mPTP opening and mitochondria swelling, reduced podocyte damage [ 42 ], attenuated the oxidative stress, and worked against subsequent ischemia/reperfusion injury [ 114 ]. However, high-dose CSA treatment results in nephrotoxicity and apoptosis by shifting mitochondrial dynamics toward fission [ 138 ] and specific metabolic changes, including the decrease of the activity of the mitochondrial Krebs cycle, oxidative phosphorylation [ 139 ], electron transferring, and the shutting down of oxidative aerobic pathway [ 140 ]. These studies suggested a dosage limitation usage of CSA in patients with renal disease. Notably, in db/db mice, treatment with cyclophilin D inhibitor alisporivir did not improve renal function nor pathology in kidneys indicating that cyclophilin D has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes [ 141 ]. Thus, the value of mPTP inhibitors application in CKD needs further investigation to be evaluated. Other agents like 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a selective inhibitor of glycogen synthase kinase 3β (GSK-3β), which is a ubiquitous serine–threonine protein kinase that phosphorylates cyclophilin D and promotes mPTP opening, also prevent acute kidney dysfunction in AKI [ 115 , 116 , 117 ]. Moreover, TDZD-8 could suppress renal fibrosis developed as a result of acute kidney injury, which represents a therapeutic approach for AKI to CKD transition [ 117 ].

Mitochondrial dysfunction in renal cells plays a critical role in the pathophysiology of AKI and CKD as well as AKI to CKD transition. Various aspects of mitochondrial biology, including mitochondrial structure, dynamics, and biogenesis are involved in the progression of AKI and CKD. In addition, mitochondrial oxidative stress, and its crosstalk with other organelles, such as ER, also contribute to AKI, CKD, and AKI to CKD transition. Recent understanding of mitochondrial biology and function under the conditions of kidney diseases have revealed the mechanisms and prospective role of mitochondria-based drugs, named as mitochondria-targeting therapeutic agents, for the treatment of these kidney diseases, which may have translational potential in the future. We should point out that even though the current evidence is encouraging, the understanding of various aspects of mitochondrial biology and function is still quite immature. For example, it remains unclear how mtDNA abnormalities are relevant to kidney injury in AKI and CKD. In addition, the clinical manifestations of mitochondrial dysfunction in kidney diseases vary in terms of symptoms, severity, and age of onset. Moreover, though studies have shown that mitochondrial dysfunction contributes to AKI and CKD, and preclinical studies suggest that mitochondria targeting therapies have the potential for prevention and management of these renal diseases, there are no translational studies showing the clinical relevance and applications of these mechanisms in humans. Thus, it is necessary to better understand mitochondrial biology and function with a focus on the mechanisms of upstream regulators and downstream effectors of mitochondrial dysfunction in renal cells and kidney diseases. We expect that these findings may translate into future therapeutic options to ameliorate renal injury and delay the progression of AKI and CKD.