Shaping Up Mitochondria in Diabetic Nephropathy

Abstract

Mitochondrial medicine has experienced significant progress in recent years and is expected to grow significantly in the near future, yielding many opportunities to translate novel bench discoveries into clinical medicine. Multiple lines of evidence have linked mitochondrial dysfunction to a variety of metabolic diseases, including diabetic nephropathy (DN). Mitochondrial dysfunction presumably precedes the emergence of key histologic and biochemical features of DN, which provides the rationale to explore mitochondrial fitness as a novel therapeutic target in patients with DN. Ultimately, the success of mitochondrial medicine is dependent on a better understanding of the underlying biology of mitochondrial fitness and function. To this end, recent advances in mitochondrial biology have led to new understandings of the potential effect of mitochondrial dysfunction in a myriad of human pathologies. We have proposed that molecular mechanisms that modulate mitochondrial dynamics contribute to the alterations of mitochondrial fitness and progression of DN. In this comprehensive review, we highlight the possible effects of mitochondrial dysfunction in DN, with the hope that targeting specific mitochondrial signaling pathways may lead to the development of new drugs that mitigate DN progression. We will outline potential tools to improve mitochondrial fitness in DN as a novel therapeutic strategy. These emerging views suggest that the modulation of mitochondrial fitness could serve as a key target in ameliorating progression of kidney disease in patients with diabetes.

Figure 1.

Overview of mitochondrial fitness. Mitochondria are involved in a number of key biologic processes in the cell, including energy production, redox signaling, calcium homeostasis, inflammation, senescence, innate immune response, and mitophagy.

Figure 2.

Oxidative phosphorylation pathway and mitochondrial reprogramming in diabetic nephropathy. When electron transport chain and mitochondrial fitness are impaired, mitochondrial dysfunction ensues, leading to increased production of reactive oxygen species (ROS) and mitochondrial fragmentation, decrease in cristae formation and mitochondrial membrane potential, and reduced mitochondrial biogenesis. CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV; CoQ, coenzyme Q; CV, complex V; Cyt C, cytochrome c; DN, diabetic nephropathy; e^–, electron; GPX, glutathione peroxidase; H⁺, hydrogen ion; H₂O, water; H₂O₂, hydrogen peroxide; O₂^–, superoxide; PRX, peroxiredoxin; SOD, superoxide dismutase.

Figure 3.

Progressive changes in mitochondrial respiratory function in diabetic nephropathy. Changes associated with electron transport chain, complex activities, and ATP in diabetic nephropathy. OCR, oxygen consumption rate.

Figure 4.

A mitochondrial-centric view of diabetic nephropathy. Hyperglycemia leads to enhanced phosphorylation of Drp1. Phospho-Drp1 is then oligomerized around the mitochondrial fission furrow. Mitochondrial receptors, such as FIS1, MFF, and MID49/51, regulate the recruitment and stabilization of phospho-Drp1 on the mitochondrial outer membrane. Stabilized and activated Drp1 result in enhanced mitochondrial fission in diabetic nephropathy (DN). Mitochondrial biogenesis is also reduced in DN conditions. Specifically, PGC1α is significantly decreased in DN, resulting in the changing of transcription factors, including NRF1, NRF2, ERR, and PPAR. Then, OXPHOS, TCA cycle, and TFAM are decreased, which might decrease of mitochondrial biogenesis. The impaired mitochondria exhibit reduced mitochondrial membrane potential, promoting the accumulation of PINK1 and Parkin. However, during DN, phosphorylated FOXO1, which decreases the transcription of PINK1, is upregulated. Moreover, mitophagy is reduced in DN. These changes induce the accumulation of damaged mitochondria, leading to the increase in mitochondrial ROS production and promoting inflammatory pathways. ΔΨm, mitochondrial membrane potential; Drp1, dynamin-related protein 1; ERR, estrogen-related receptors; FIS1, mitochondrial fission factor 1; FOXO1, forkhead box class O1; GBM, glomerular basement membrane; MFF, mitochondrial fission factor; MID49/51, mitochondrial dynamics proteins 49 and 51 kDa; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; PINK1, phosphatase and tensin homolog–induced putative kinase 1; phospho-Drp1, phosphorylated Drp1; phospho-FOXO1, phosphorylated FOXO1; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; TCA, tricarboxylic acid; TFAM, mitochondrial transcription factor A.