Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

“…NLRP3 can be activated by extracellular stimuli that induce K + efflux, such as ATP released from dying cells. 46,57 According to our results, aberrant ATP levels in the gastric mucosa of PHT models and PHG patients under hypoxic condition may be involved in NLRP3 inflammasome activation, gastric mucosal inflammation and lesion formation, and these effects could be reversed by HIF-1α inhibition with PX-478. A decrease in mitochondrial membrane potential and increased intracellular Ca 2+ can also be NLRP3 activators that elicit a particular form of mitochondrial damage.…”

“…Notably, cell death induced by K + efflux and energy metabolism blockade is distinct from pyroptosis, apoptosis, necroptosis or ferroptosis. 46 Based on our energy metabolism analysis, we showed that HIF‐1α not only mediated Drp1‐dependent mitochondrial fission and mitochondrial dysfunction in gastric mucosal diseases but also influenced energy metabolism and metabolic profiles by altering glycolysis under hypoxic condition and that blockade of Drp1‐dependent mitochondrial fission attenuated the glycolytic process. These data revealed that, in addition to HIF‐1α‐modulated glycolysis by LDHA, Drp1‐dependent mitochondrial fission/dysfunction also enhanced glycolysis, and blockade of mitochondrial fission attenuated the glycolytic process.…”

“…Energy metabolism deficiency can also affect K + channels and other kinases phosphorylation to regulate ROS generation. 46 Some reports highlight the multifaceted interaction of HIF‐1α with cell death processes, including apoptosis, necrosis, autophagy, ferroptosis and pyroptosis. 49 In our study, we further analysed the cell death outcomes of mitochondrial dysfunction‐mediated ROS production by HIF‐1α under hypoxia by evaluating the possibility of apoptosis, necrotic apoptosis, ferroptosis and pyroptosis in gastric mucosal lesions in PHT and GC, and we revealed that the protein levels of NLRP3 and cleaved caspase‐1, rather than those of MLKL, FTH and FTL, were increased in both HIF‐1α ‐transfected GES‐1 cells and cells isolated from SGC7901 xenograft mouse models but could be decreased by PX‐478 treatment in cells from SGC7901 xenograft mice.…”

“… 54 Some studies have shown that the oxidation of mitochondrial DNA by mtROS is an inducer of NLRP3 inflammasome activation. 46 The mitochondria within a cell are a major source of endogenous ROS and can be important triggers for inflammation and tissue injury, as ROS production activates the NLRP3 inflammasome and IL‐1β secretion through increased levels of thioredoxin‐interacting protein. 55 In addition, the NLRP3 inflammasome senses mitochondrial dysfunction and is positively regulated by ROS derived from dysfunctional mitochondria.…”