MicroRNA‐16‐5p exacerbates sepsis by upregulating aerobic glycolysis via SIRT3‐SDHA axis

Abstract

Sepsis is a life-threatening condition, and treatment for sepsis in clinic is often not available, partially due to insufficient understanding of the pathogenesis of sepsis.Extensive study to elucidate the pathogenesis is required to improve the clinical management and outcome of sepsis. In this study, we investigated the pathogenesis of sepsis using peripheral blood mononuclear cells (PBMCs) from septic patients and studied the underlying mechanism of miR-16-5p on aerobic glycolysis in lipopolysaccharide (LPS)-treated THP1 and Raw264.7 cells. The levels of RNA and protein were determined by real-time quantitative PCR and immunoblotting assay, respectively. The production of high mobility group box 1 (HMGB1) was measured by enzyme-linked immunosorbent assay. The levels of succinate and lactate were determined using colorimetric kits. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured by extracellular flux analyzer. The results showed that the expression of miR-16-5p was elevated, while sirtuin 3 (SIRT3) was decreased in PBMCs from septic patients and LPS-treated cells, along with accumulation of acetylated succinate dehydrogenase complex, subunit A.Concomitantly, an increase in HMGB1, succinate, lactate, as well as ECAR and a decrease in OCR were observed. Knockdown of miR-16-5p upregulated SIRT3 expression, facilitated SDHA deacetylation, and attenuated sepsis-related aerobic glycolysis. Further study identified that SIRT3 is targeted by miR-16-5p, and overexpression of SIRT3 rescued LPS-induced responses via deacetylation of SDHA.Our findings revealed a novel miR-16-5p-regulated SIRT3-SDHA axis in sepsis and provided novel insights for sepsis treatment.

Exosomal Circvma21 Derived From Adipose-Derived Stem Cells Alleviates Sepsis-Induced Acute Kidney Injury by Targeting Mir-16-5p

“…Song et al revealed that miR-16-5p promoted sepsis-induce lung injury, which enhanced the apoptosis, inflammation, and oxidative stress of LPS-induced airway epithelial cells (30). Importantly, our previous research showed that miR-16-5p was upregulated in septic patients and LPS-treated cells, which might aggravate sepsis process via promoting aerobic glycolysis (31). In this, we confirmed the high miR-16-5p expression in LPS-induced HK-2 cells and pointed out that its expression was reduced after ADSCs-Exo treatment.…”

METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α–INDUCED AEROBIC GLYCOLYSIS

“…Previous research has demonstrated that the reduction of extracellular fluid pH caused by lactate buildup plays a crucial role in the conversion of fibroblasts to myofibroblasts (25,30,31). Elevated lactate levels cause fibroblasts to active abnormally, leading to acute inflammatory and fibrotic reactions to sepsis (32). Our current investigation has also determined the effect of LPS-induced lactate on the activation of fibroblast.…”

The role and therapeutic potential of SIRTs in sepsis

“…This regulation increases the efficiency of the oxidative phosphorylation chain, reduces electron leakage, and thereby lowers ROS production. In LPS-stimulated macrophages, overexpression of SIRT3 through SDHA deacetylation, mitigates sepsis-associated aerobic glycolysis ( 80 ).The role of SIRT4 in inflammatory immune responses is not entirely clear yet. However, studies have found that during the endotoxin tolerance phase in THP-1 cells, SIRT4 reverses the anti-inflammatory phase’s fatty acid oxidation back to the pro-inflammatory phase’s glucose oxidation and increases the expression of fatty acid synthase ( 81 ).…”

“…The application of melatonin upregulates the expression of SIRT3, triggering the deacetylation of SOD2, augmenting its activity, and diminishing oxidative stress injury in the small intestinal tissues of septic model rats and in septic pulmonary epithelial cells—thereby protecting mitochondrial function ( 117 ). SIRT3 further enhances the efficiency of the oxidative phosphorylation chain by deacetylating the pivotal enzyme SDHA, mitigating electron leak and consequently reducing the generation of ROS during sepsis and ischemia-reperfusion ( 80 ). Researchers have substantiated that increased expression and activity of SIRT3 result in the deacetylation and enzymatic activation of mitochondrial fatty acid oxidation enzyme (LCAD), which, by modulating fatty acid oxidation, aids SIRT3 in the maintenance of energy metabolic equilibrium and the diminution of ROS production ( 118 ).…”