Mitochondrial Dysfunction and Diabetic Nephropathy: Nontraditional Therapeutic Opportunities

Figure 1

Hyperglycemia serves as the primary factor that influences mitochondrial dysfunction in DN. The increased level of glucose enhances glycolysis, and the subsequent activation of the TXNIP, AGE, and PKC pathways reinforces the decrease in ATP levels. Insufficient ATP levels stimulate the ETC to overwork in response to the energy supply for the kidneys. In turn, excessive ROS production occurs following the overactivation of the ETC, which results in decreased ATP production, mutation of mtDNA, abnormal opening of the mitochondrial permeability transition pore, and ultimately mitochondrial fragmentation and swelling. Decreases in the levels of OPA1, MFN1, and MFN2 may contribute to the decrease in mitochondrial fusion observed in DN. Activation of DRP1 promotes mitochondrial fragmentation and fission. Damaged mitochondria are cleared by mitophagy. However, an excess number of damaged mitochondria that is higher than the rate of mitophagy may result in cell death. Abbreviations: DN: diabetic nephropathy; DRP1: dynamin 1-like protein; PGC-1α: PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; AMPK: 5-AMP-activated protein kinase; SIRT1: sirtuin-1; PINK1: putative kinase protein 1; Cyt c: cytochrome c; ROS: reactive oxygen species; MFN1 and 2: mitofusin proteins 1 and 2; OPA1: optic atrophy protein 1; MFF: mitofission proteins; FIS1: mitochondrial fission 1; PPAR: peroxisome proliferator-activated receptor; Parkin: E3 ubiquitin-protein ligase parkin; ER: endoplasmic reticulum; TXNIP: thioredoxin-interacting protein; AGE: advanced glycation end; PKC: protein kinase C; ETC: electron transport chain.