Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease

Abstract

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), mitochondrial reactive oxygen species (mtROS), biogenesis, fission and fusion, mitophagy and urinary mitochondrial biomarkers. Both glucose- and non-glucose-induced mitochondrial dysfunction will be discussed. In terms of glucose-induced mitochondrial dysfunction, the energetic shift from OXPHOS to aerobic glycolysis, called the Warburg effect, occurs and the resulting toxic intermediates of glucose metabolism contribute to DKD-induced injury. In terms of non-glucose-induced mitochondrial dysfunction, we will review the roles of lipotoxicity, hypoxia and vasoactive pathways, including endothelin-1 (Edn1)/Edn1 receptor type A signaling pathways. Although the relative contribution of each of these pathways to DKD remains unclear, the goal of this review is to highlight the complexity of mitochondrial dysfunction in DKD and to discuss how markers of mitochondrial dysfunction could help us stratify patients at risk for DKD.

Keywords: Warburg effect; diabetic kidney disease; mitochondrial dysfunction; mitochondrial reactive oxygen species.

Figure 1

Mitochondrial dysfunction in DKD. Whether the level of mitochondrial ROS is increased or decreased is controversial and can vary depending on the stage of DKD. OXPHOS, mitophagy and biogenesis are generally decreased. Increased fission and decreased fusion causes fragmentation of mitochondria. OXPHOS: oxidative phosphorylation, ROS: reactive oxygen species, ↑: increased, ↓: decreased.

Figure 2

Electron transport chain (ETC) in mitochondrial inner membrane. NADH and FADH₂ from the TCA cycle donate electrons to Complexes I and II. As electrons are transported through the ETC, a proton gradient is generated, which Complex V or ATP synthase couples to ATP synthesis. Electron leakage from the ETC causes the production of ROS. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cyt C, cytochrome complex; ROS, reactive oxygen species; UQ, ubiquinone; TCA cycle, tricarboxylic acid cycle.

Figure 3

Glycolysis and branching pathways. In the high-glucose environment of DKD, glycolysis is increased and OXPHOS is decreased, leading to the accumulation of toxic metabolites produced in the branching pathways of glycolysis. AGE, advanced glycation end-product; DAG, diacylglycerol; GAPDH, glygeraldehyde-3-phosphate dehydrogenase; OXPHOS, oxidative phosphorylation; PKC, protein kinase C; PKM, pyruvate kinase M; TCA cycle, tricarboxylic acid cycle; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.