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

Abstract

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.

Keywords: AKI; AKI to CKD transition; CKD; mitochondria.

Figure 1

Structure of mitochondria. Mitochondria have an inner and outer membrane with an intermembrane space between them. The outer membrane contains transporters, enzymes for lipid metabolism and proteins (known as porins) that regulate the movement of ions into and out of the mitochondrion. The space within the inner membrane of the mitochondrion is known as the matrix, which contains the DNA, ribosomes, and calcium granules. The inner membrane also contains transporters, a variety of enzymes that regulate the movement of metabolites into and out of the matrix, electron transport chain for energy production via oxidative phosphorylation, and ATP synthase, which generates ATP in the matrix. mtDNA: mitochondria DNA.

Figure 2

Schematic illustration of pathophysiological processes of mitochondrial dysfunction, including alterations of mitochondrial structure, dynamics, biogenesis, organelle crosstalk, and oxidative stress, in the AKI, CKD, and AKI to CKD transition. AKI: acute kidney injury; CKD: chronic kidney disease; ATP: adenosine triphosphate; ΔΨm: mitochondrial membrane potential; Mfn1: mitofusin 1; Opa1: optic atrophy 1; Drp1: dynamin related protein 1; mtDNA: mitochondria DNA; AMPK: AMP-activated protein kinase; PGC-1α: PPARgamma-coactivator-1α; Sirt3: sirtuin 3; NRF1: nuclear respiratory factor 1; NRF2: nuclear respiratory factor 2; MRPL12: mitochondrial ribosomal protein L12; cGAS; cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase; STING: stimulator of interferon genes; ER: endoplasmic reticulum; UPR: unfolded protein response; PPARα: peroxisome proliferator–activated receptor-α; IRE1: inositol-requiring enzyme 1; PERK: PRKR-like ER kinase; ATF6α activating transcription factor 6α; XPB1: the X-box binding protein 1; eIF2α: eukaryotic initiation factor 2α; ATF4: activating transcription factor 4; ONOO-: peroxynitrite; O2-:superoxide; SOD: superoxide dismutase; GSH: glutathione; ROS: reactive oxygen species.

Figure 3

Schematic illustration of the potential compounds that target the dysfunction of mitochondrial structure, fragmentation and biogenesis as well as mPTP opening and mitochondrial antioxidant capacity in AKI and CKD. AKI: acute kidney injury; CKD: chronic kidney disease; ROS: reactive oxygen species. mPTP: mitochondrial permeability transition pore; CSA: Cyclosporine-A; TDZD-8: 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; CoQ10: Coenzyme Q10 MitoQ: mitochondrial coenzyme Q; SkQR1: 10-(6′-plastoquinonyl) decylrhodamine 19.