Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells

Abstract

Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72 h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.

Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function

“…Based on the present findings, mitochondrial damage was the initial upstream signal for glomerular injury and subsequent renal fibrosis. This conclusion was in agreement with previous studies (56,57). Hyperglycemia has been reported to induce mitochondrial damage via numerous mechanisms.…”

Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

“…This functional change was induced by the ZEA-induced structural damage. ΔΨm is fundamental to ATP production (43). Over time, the mitochondrial membrane potential dissipates following ZEA treatment ( Fig.…”

Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways

“…K606-100; BioVision, Inc.). The uptake of glucose and the production of lactate were measured according to the manufacturer's protocols, and as previously described (36,37). Mitochondrial respiration was initiated by the addition of glutamate/malate, at a final concentration of 5 and 2.5 mmol/l, respectively.…”