Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure

Abstract

Liver sinusoids serve as the first line of defense against extrahepatic stimuli from the intestinal tract. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space that integrate cytokine-mediated inflammatory responses in the sinusoids and relay these signals to the liver parenchyma. Oxidative stress has been shown to promote inflammation during acute liver failure (ALF). Whether and how oxidative stress is involved in HSC inflammation during ALF remains unclear. Level of systemic oxidative stress is reflected by superoxide dismutase (SOD). Thus, ALF patients were recruited to investigate the correlation between plasma SOD levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from ALF patients who had undergone liver transplantation. SOD2 expression and HSCs activation were investigated by immunohistochemistry. Inflammation, mitophagy, and apoptosis were investigated by immunoblot analysis and flow cytometry in HSCs treated with lipopolysaccharide (LPS) and reactive oxygen species (ROS) donors. The plasma SOD level was significantly increased in patients with ALF compared with those with cirrhosis (444.4 ± 23.58 vs. 170.07 ± 3.52 U/ml, P < 0.01) and was positively correlated with the Model for End-Stage Liver Disease-Na score ( R = 0.4720, P < 0.01). In vivo observations revealed that SOD2 immunostaining was increased in ALF patients and mice models, and in vitro experiments demonstrated that LPS/ROS promoted inflammation via inhibiting mitophagy. Moreover, the regulation of inflammation was apoptosis independent in HSCs. LPS-induced increases in oxidative stress promote inflammation through inhibiting mitophagy in HSCs during the process of ALF, providing a novel strategy for the treatment of patients with ALF. NEW & NOTEWORTHY Here we demonstrate that the serum superoxide dismutase (SOD) level is significantly increased in patients with acute liver failure (ALF), and, correlated with the Model for End-Stage Liver Disease-Na score, SOD level dropped in the remission stage of ALF. We identify that, in liver tissue from ALF patients and mice models, manganese-dependent SOD was overexpressed, and show lipopolysaccharide/HO inhibits mitophagy via reactive oxygen species in hepatic stellate cells (HSCs). We show that inhibited mitophagy promotes inflammation in HSCs, whereas mitophagy inducer rescues HSCs from lipopolysaccharide-induced inflammation.

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…Studies have revealed an OS microenvironment in the femoral-head necrotic area in which transplanted BMSCs incur a great deal of stress apoptosis and aging, which seriously limits transplantation effectiveness [11][12][13] . More and more studies have shown that mitochondrial dysfunction and damaged-mitochondria accumulation occur before cell stress apoptosis and senescence [19][20][21][22] . In this study, we preliminarily confirmed that the accumulation of damaged mitochondria was an important cause of BMSCs stress apoptosis and aging.…”

“…Under OS, mitochondria suffer functional damage and accumulate in cells, releasing excessive ROS and apoptosis-inducing factors, which not only oxidatively damage DNA, protein, lipid, and other biological macromolecules, but also activate c-Jun N-terminal kinase (JNK), P38MAPK, DDR, and P53 pathways, ultimately leading to cell stress apoptosis and senescence 21,22,[49][50][51] . Therefore, accumulation of damaged mitochondria is an important cause of stress apoptosis and aging in BMSCs 52 .…”

“…Stress-induced apoptosis and senescence in BMSCs are related to the accumulation of damaged mitochondria in cells [20][21][22]36 . Could enhancing mitophagy to clear these accumulated mitochondria effectively resist BMSCs stress-induced apoptosis and senescence?…”

“…Therefore, normal mitophagy is essential for maintaining cell redox homeostasis and promoting cell survival under OS conditions. However, under such conditions the level of mitophagy is always decreased, causing massive accumulation of damaged mitochondria and leading to stress-induced apoptosis and senescence in cells [20][21][22] .…”

Roles of hepatic stellate cells in acute liver failure: From the perspective of inflammation and fibrosis

“…Our recent work showed that during the pathogenesis of ALF, reactive oxygen species activate the NLRP3 inflammasome and promote inflammation in HSCs. We also revealed that LPS treatment induced reactive oxygen species generation in HSCs via mitophagy inhibition[51]. Studies have suggested that in hepatocytes, reactive oxygen species play important roles in the pathophysiology of diseases, including ALF.…”