The hallmarks of mitochondrial dysfunction in chronic kidney disease

Abstract

Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases because they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease, with special emphasis on its role in the development of diabetic nephropathy. We examine the current understanding of the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure are closely linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and long noncoding RNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases.

Keywords: acute kidney injury; chronic kidney disease; diabetes; diabetic nephropathy; mitochondria; oxidative stress.

Figure 1. Mitochondrial dynamics

Left panel: Mitochondrial Fission. Drp1 oligomerizes and forms a ring around the mitochondrion in order to constrict and partition the mitochondrion using GTPase activity. Right Panel: Mitochondrial Fusion: MFN1 and MFN2 are found on the mitochondrial outer membrane and can interact as homo or heterodimers. OPA1 facilitates the fusing of the inner membrane. Fis1=Mitochondrial fission protein 1, Mff=Mitochondrial fission protein, MiD49 and MiD51=Mitochondrial dynamics proteins of 49 and 51 kDa, Mfn1/2=Mitofusion proteins 1 or 2, VDAC=Voltage-dependent anion channel, InsP₃R=Inositol 1,4,5-trisphosphate receptor.

Figure 2. PGC-1α and mitochondrial biogenesis

The master regulator, PGC-1α, drives mitochondrial biogenesis by co-activating transcription factors whose target genes increase biogenesis, oxidative phosphorylation, and fatty acid oxidation. ERRα=Estrogen Related Receptor Alpha, PPARα=Peroxisome Proliferator Activated Receptor Alpha, NRF1 and NRF2=Nuclear Respiratory Factors 1 and 2, AMP=Adenosine monophosphate, ATP=Adenosine triphosphate, NAD⁺=nicotinamide adenine dinucleotide, NADH=dihydronicotinamide adenine dinucleotide, OxPHOS=oxidative phosphorylation.

Figure 3. Mitochondrial ROS generation

Electron escape during mitochondrial electron transport at complexes I and III generates superoxide anions both in the intermembrane space and matrix. CI, CII, CIII, CIV, CV=Complexes I–V, cytC=cytochrome C, Q=ubiquitone, O2^′−=superoxide, GR=Glutathione reductase, Gpx=Glutatione peroxidase, SOD=Superoxide Dismutase, GSH=glutathione, GSSG=glutathione disulfide, FAD= flavin adenine dinucleotide, FADH₂=Dihydroflavine adenine dinucleotide, H₂O₂=hydrogen peroxide, NAD⁺=nicotinamide adenine dinucleotide, NADH=dihydronicotinamide adenine dinucleotide.

Figure 4. Hallmarks of mitochondrial dysfunction in CKD

The interrelated hallmarks provide a framework for further understanding the diverse aspects of mitochondrial dysfunction in CKD.