Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

Abstract

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

Bioinformatic analyses reveal lysosomal-associated protein transmembrane 5 as a potential therapeutic target in lipotoxicity-induced injury in diabetic kidney disease

“…Additionally, CD36-mediated lipid uptake in podocytes has been shown to activate the NLRP3 inflammasome, leading to the release of the pro-inflammatory cytokine IL-1β [ 46 ]. Strategies aimed at inhibiting fatty acid synthesis and mitigating lipid accumulation have demonstrated promise in ameliorating DKD [ 47 , 48 ]. These findings suggest that interventions targeting lipid metabolism could offer a viable approach to improving renal outcomes in patients with diabetes.…”

Mitochondrial metabolic reprogramming in diabetic kidney disease

“…The kidney is one of the largest oxygen-consuming organs in the organism after the heart, in which the renal tubular epithelial cell (TEC) is the core site of energy metabolism in the kidney and requires large amounts of energy to sustain their reabsorption function [ 4 ]. In normal conditions, TECs primarily depend on FAO to produce substantial amounts of ATP to fulfill their physiological requirements.…”

“…Under DKD disease conditions, the energy metabolic pattern of TECs is altered and metabolic reprogramming occurs to provide energy and counteract oxidative stress. In brief, a high glucose environment induces a metabolic switch from fatty acid oxidation to glycolysis in renal proximal tubular epithelial cells (PTECs) [ 4 , 18 ].…”

“…Metabolic reprogramming is a mechanism by which cells change metabolic patterns to meet energy needs for cell survival and growth [ 3 ]. Recently, it has been found that metabolic reprogramming was triggered by impaired mitochondrial biogenesis in a high-glucose environment and played a crucial role in the pathogenesis of DKD [ 4 – 6 ]. It is characterized by abnormal metabolism of the three major nutrients and suppression of mitochondrial oxidative phosphorylation (OXPHOS), which contributes to the onset and development of DKD.…”

“…However, this compensatory response also causes damage to kidney. Additionally, abnormalities in fatty acid β-oxidation (FAO) and amino acid metabolism can lead to the buildup of lipids and uremic toxins in the kidney, which can contribute to renal cell damage and apoptosis [ 4 , 8 ].…”