Pharmacologic Approaches to Improve Mitochondrial Function in AKI and CKD

Abstract

AKI is associated with high morbidity and mortality, and it predisposes to the development and progression of CKD. Novel strategies that minimize AKI and halt the progression of CKD are urgently needed. Normal kidney function involves numerous different cell types, such as tubular epithelial cells, endothelial cells, and podocytes, working in concert. This delicate balance involves many energy-intensive processes. Fatty acids are the preferred energy substrates for the kidney, and defects in fatty acid oxidation and mitochondrial dysfunction are universally involved in diverse causes of AKI and CKD. This review provides an overview of ATP production and energy demands in the kidney and summarizes preclinical and clinical evidence of mitochondrial dysfunction in AKI and CKD. New therapeutic strategies targeting mitochondria protection and cellular bioenergetics are presented, with emphasis on those that have been evaluated in animal models of AKI and CKD. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer advantages compared with targeting downstream inflammatory and fibrosis processes.

Keywords: diabetic nephropathy; fibrosis; ischemia-reperfusion; metabolism; mitochondria; reactive oxygen species.

Figure 1.

FA uptake and mitochondrial FA β-oxidation. FAs are the preferred energy substrates for the kidney. Uptake of FAs into kidney cells is facilitated by CD36. In the cytosol, FAs are activated to acyl-CoA and transported to mitochondria by the carnitine shuttle. CPT-1 on the OMM catalyzes the transesterification acyl-CoA to acylcarnitine. The complex then enters the mitochondrial matrix via facilitated diffusion by carnitine-acylcarnitine translocase (CACT). CPT-2 on the IMM reconverts the acylcarnitine into an acyl-CoA. In the mitochondrial matrix, acyl-CoAs undergo β-oxidation to generate acetyl-CoA to fuel the tricarboxylic acid cycle (TCA) and also NADH and FADH₂ that serve as electron donors to the ETC on the IMM for ATP production. NADH is also produced by the tricarboxylic acid.

Figure 2.

Role of cardiolipin (CL) in cristae structure and supercomplex formation on the IMM. The protein complexes of the ETC reside on cristae membranes, and CL provides curvatures on the IMM to increase surface area for the respiratory complexes. CL helps to organize the respiratory complexes into supercomplexes to facilitate electron transfer among the redox partners. CL also anchors the highly cationic cytochrome c (c) via electrostatic interaction to bring it in close proximity to complex 3 and complex 4 for efficient electron transfer. In addition, CL serves as a proton trap to optimize the proton gradient for complex 5 (F₀,F₁-ATPase). CL is particularly vulnerable to oxidative damage because of its high content of unsaturated FAs. Oxidized cardiolipin (CLOOH) destabilizes CL microdomains, reduces cristae curvatures, and disrupts supercomplex formation. Peroxidation of CL also reduces its affinity for cytochrome c and sets the stage for cytochrome c release into the cytosol and apoptosis. e, electron; FAD, flavin adenine dinucleotide; FADH₂, reduced flavin adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; PC, phosphatidylcholine; Q, coenzyme Q.

Figure 3.

Cellular consequences of mitochondrial dysfunction. Mitochondrial dysfunction increases ROS and causes cardiolipin peroxidation. Oxidized cardiolipin can signal a number of cellular events. (1) Oxidized cardiolipin damages cristae curvatures, effectively decreasing substrate concentration and delivery of NADH and FADH₂ to the respiratory complexes. (2) If oxidative stress is mild, oxidized cardiolipin can translocate to the OMM, where it triggers mitophagy to selectively eliminate damaged mitochondria. Damaged mitochondria are enveloped by endoplasmic reticulum membranes to form autophagosomes, which then fuse with lysosomes to form autophagolysosomes that degrade mitochondrial content. (3) Oxidized cardiolipin on the OMM can also recruit Bax to trigger mitochondrial permeability transition, which releases cytochrome c from mitochondria to initiate apoptosome activation, activation of caspase-3, and apoptosis. (4) Oxidized cardiolipin on OMM can serve as a docking station for NLRP3 inflammasome assembly, and mitochondrial ROS triggers inflammasome activation to activate caspase-1 to cleave pro–IL-1β and pro–IL-18 to cause chronic inflammation and tissue remodeling. (5) Cells will undergo necrosis in the event of profound ATP depletion, and danger molecules released from necrotic cells can also trigger inflammasome activation. FADH₂, reduced flavin adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NLRPE, NLR family pyrin domain containing 3.

Figure 4.

Mitochondrial changes in animal models of AKI and CKD. Acute stressors, such as ischemia, sepsis, and toxins, cause mitochondrial matrix swelling and loss of cristae membrane. These structural changes are associated with impaired ATP production, oxidative stress, cellular demise, and chronic tissue remodeling. Cardiolipin peroxidation sets the stage for mitochondrial permeability transition, cytochrome c release, and apoptosis. In CKD, mitochondria are small, with reduced matrix density and loss of cristae membranes. Mitochondrial dysfunction causes a drop in ATP levels and cell injury, whereas inhibition of FA oxidation results in cellular lipid accumulation and downregulation of AMPK activity, further contributing to bioenergetics failure. In both AKI and CKD, cardiolipin peroxidation causes the translocation of cardiolipin to the OMM, where it serves as a docking station for NLRP3 inflammasome assembly. Mitochondrial ROS then triggers inflammasome activation to produce IL-1β and IL-18 that sustain tissue remodeling. MPT, mitochondrial permeabiltiy transition; NLRPE, NLR family pyrin domain containing 3.