Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence

Abstract

Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Inhibition of MDH-2 decreased reoxygenation-induced upregulation of p53 and p21, restored the levels of the proliferation marker Ki-67, and prevented the upregulation of the senescence marker beta-galactosidase and interleukin-1β production. MDH-2 inhibition reduced the reoxygenation-induced upregulation of ATP, but the alterations of critical cell metabolism enzymes allowed enough ATP production to prevent cell energy collapse. Thus, inhibition of the Krebs cycle at the level of MDH-2 protects RPTECs from anoxia-reoxygenation-induced death or senescence. MDH-2 may be a promising pharmaceutical target against ischemia-reperfusion injury.

Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells

“…Therefore, LW6 (10 µM) could have promoted glucose uptake via MDH2 inhibition rather than HIF-1α inhibition in confluent 3T3-L1 cells (Figures 4F and 5A,B). Other research groups have shown that LW6 at 30-80 µM significantly suppressed cell proliferation in human activated T cells [26] and rat pancreatic adenocarcinoma cells [52], that LW6 at 15 µM inhibited MDH2 activity in the lysates of human renal proximal tubular epithelial cells by 30%, and that LW6 at 30-60 µM inhibited it by ~80% [28]. Taken together, these findings suggest that weak and moderate inhibition of MDH2 may induce glucose uptake, whereas strong inhibition of MDH2 and HIF-1α may induce growth suppression in these cells.…”

“…To ascertain whether MDH2 can be a pharmacological target of DIF-1, we needed to determine whether MDH2 inhibition by DIF-1 inhibits cell proliferation and/or promotes glucose uptake, or has no effect on these functions. We thus compared the effects of DIF-1 and the MDH2 inhibitor LW6 [24][25][26][27][28] on the growth of HeLa cells and 3T3-L1 cells in vitro (Figure 4A-D). In both HeLa and 3T3-L1 cells, DIF-1 at 10-40 µM dose-dependently suppressed cell growth (Figure 4A,C), as described previously [16].…”

Effects of guanidinoacetic acid supplementation on liver and breast muscle fat deposition, lipid levels, and lipid metabolism-related gene expression in ducks

“…Malate dehydrogenase is an essential enzyme in the tricarboxylic acid cycle that catalyzes the malate dehydrogenation to produce oxaloacetate and NADH + H + (56,57). This reaction is reversible, but intracellularly produced oxaloacetate is constantly being used to synthesize citric acid, so this reversible reaction tends to proceed more in the direction of oxaloacetate production (58). The fatty acid β-oxidation product acetyl CoA can enter the tricarboxylic acid cycle to generate citric acid for further catabolism, thus indicating that malate dehydrogenase plays a vital role in linking glucose metabolism and fatty acid metabolism in poultry (59,60).…”

Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury

“…Additionally, pyruvate can be converted to lactate by LDH. Hypoxia/reoxygenation-induced elevation of hypoxia-inducible factor-1α (HIF-1α) can upregulate both PDKs and LDH ( Eleftheriadis et al, 2022 ), leading to increased lactate production. In LPS-induced AKI, the expression of pyruvate kinase muscle isoform 2 (PKM2), a critical enzyme responsible for catalyzing the last step of glycolysis, is significantly increased, and PKM2 can directly stimulate HIF-1α transactivation ( Luo et al, 2011 ), indicating that PKM2 can regulate PDKs and LDH to promote lactate generation by activating HIF-1α.…”