Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction

Abstract

Podocytes are a crucial cellular component in maintaining the glomerular filtration barrier, and their injury is the major determinant in the development of albuminuria and diabetic kidney disease (DKD). Podocytes are rich in mitochondria and heavily dependent on them for energy to maintain normal functions. Emerging evidence suggests that mitochondrial dysfunction is a key driver in the pathogenesis of podocyte injury in DKD. Impairment of mitochondrial function results in an energy crisis, oxidative stress, inflammation, and cell death. In this review, we summarize the recent advances in the molecular mechanisms that cause mitochondrial damage and illustrate the impact of mitochondrial injury on podocytes. The related mitochondrial pathways involved in podocyte injury in DKD include mitochondrial dynamics and mitophagy, mitochondrial biogenesis, mitochondrial oxidative phosphorylation and oxidative stress, and mitochondrial protein quality control. Furthermore, we discuss the role of mitochondria-associated membranes (MAMs) formation, which is intimately linked with mitochondrial function in podocytes. Finally, we examine the experimental evidence exploring the targeting of podocyte mitochondrial function for treating DKD and conclude with a discussion of potential directions for future research in the field of mitochondrial dysfunction in podocytes in DKD.

Keywords: diabetic kidney disease; injury; mitochondrial dysfunction; podocytes; therapeutic strategies.

FIGURE 1

Mitochondrial damage of podocytes during diabetic kidney disease. Mitochondria are highly dynamic organelles that respond to pathophysiologic cues by altering mitochondrial content, fusion, fission, mitophagy, and the unfolded protein response. Fission and fusion complement each other to maintain mitochondrial morphology, whereas mitophagy selectively clears damaged mitochondria from the network (Nisoli et al., 2004). Excessive mitochondrial fission combined with decreased mitochondrial fusion is a prototypical feature of podocytes in diabetic kidney disease (Wang et al., 2012; Ayanga et al., 2016; Qin et al., 2019; Audzeyenka et al., 2021). In addition, the inhibition of mitophagy leads to the lack of a proper mitochondrial turnover in the diabetic kidney (Li et al., 2016; Li W. et al., 2017). Another key feature of mitochondrial dysfunction of podocytes in diabetic kidney disease is the reduced efficiency of mitochondrial biogenesis (Sun et al., 2014; Li S.-Y. et al., 2017; Zhang et al., 2018). Under high glucose condition, intracellular ROS production, mitochondrial DNA damage and protein and lipid peroxidation were enhanced (Tan et al., 2010; Dugan et al., 2013; Coughlan et al., 2016). In addition, mitochondrial protein homeostasis is challenging because of the continuous exposure of mitochondrial proteins to mitochondrial ROS. Mitochondria within a cell cannot exist in isolation. They interact with endoplasmic reticulum via the formation of mitochondrial-associated membranes (MAMs). The disturbance of MAMs leads to abnormal intracellular Ca²⁺ influx, mitochondrial damage, and apoptosis (Inoue et al., 2019). A combination of the above factors resulted in podocyte injury and the progression of diabetic kidney disease. The podocyte mitochondria in diabetic condition is illustrated schematically with blue frame and text. DRP1, dynamin-1-like protein; MFNs, mitofusin proteins 1 and 2; ETC, electron transport chain; HSPs, heat shock proteins; MAM, mitochondria associated ER membrane; NOXs, NADPH oxidases; OPA1, optic atrophy protein 1; PGC-1α, peroxisome proliferator activated receptor γ coactivator-1α; PINK1, PTEN-induced putative kinase protein 1; ROS, reactive oxygen species; UPR, unfolded protein response (Created with BioRender.com).