Protective Effect of Mitophagy Regulated by mTOR Signaling Pathway in Liver Fibrosis Associated with Selenium

Abstract

Background: As a central organ of energy metabolism, the liver is closely related to selenium for its normal function and disease development. However, the underlying roles of mitochondrial energy metabolism and mitophagy in liver fibrosis associated with selenium remain unclear. Methods: 28 rats were randomly divided into normal, low-selenium, nano-selenium supplement-1, and supplement-2 groups for a 12-week intervention. We observed pathological and ultrastructural changes in the liver and analyzed the effects of selenium deficiency and nano-selenium supplementation on liver metabolic activities and crucial proteins expression of mammalian target of the rapamycin (mTOR) signaling pathway. Results: Selenium deficiency caused liver pathological damage and fibrosis with the occurrence of mitophagy by disrupting normal metabolic activities; meanwhile, the mTOR signaling pathway was up-regulated to enhance mitophagy to clear damaged mitochondria. Furthermore, nano-selenium supplements could reduce the severity of pathological damage and fibrosis in livers and maintain normal energy metabolic activity. With the increased concentrations of nano-selenium supplement, swelling mitochondria and mitophagy gradually decreased, accompanied by the higher expression of mTOR and phosphorylation-modified mTOR proteins and lower expression of unc-51 like autophagy activating kinase 1 (ULK1) and phosphorylation-modified ULK1 proteins. Conclusions: Mitophagy regulated by the mTOR signaling pathway plays a dual protective role on low-selenium inducing liver fibrosis and nano-selenium supplements preventing liver fibrosis. Mitochondrial energy metabolism plays an important role in these processes as well.

Novel Therapeutic Approaches to Liver Fibrosis Based on Targeting Oxidative Stress

“…Importantly, deficient mitophagy in hepatocytes has been associated with the development of liver disease, so targeting mitophagy presents itself as a promising therapeutic target. A protective effect of mitophagy—regulated by the mTOR signaling pathway—has been described in a rat model of liver fibrosis associated with selenium deficiency [ 108 ]. Similarly, melatonin was seen to enhance mitophagy and mitochondrial biogenesis while diminishing liver fibrosis in rats [ 109 ].…”

“…In this regard, it has recently been demonstrated that mito-DAMP released from injured mitochondria in hepatocytes directly activate HSC in a liver fibrosis resistant/susceptible mouse strain system. In addition, circulating mito-DAMP were markedly increased in two cohorts of patients with NASH and liver fibrosis; the majority of them had active NASH, defined histopathologically as NAFLD activity score (NAS) ≥ 4, and various degrees of fibrosis ranging from F0 (no fibrosis) to F4 (cirrhosis) [ 108 ]. Of note, circulating mtDNA levels were increased in patients with active NASH (NAS score 4–8, versus NAS score 0–3) and particularly in those with significant histological signs of fibrosis (F2–4) on biopsy, compared to patients with minimal/no fibrosis [ 112 ].…”

Omics insights into the responses to dietary selenium

“…Untargeted metabolomic analysis after Se supplementation have been performed using mice models [47,73,[85][86][87][88][89][90][91][92][93][94][95][96][97][98], pigs [99][100][101][102], broilers [103], cells [104], rats [105][106][107], gazelle [108], zebra fish [109], humans [110], donkeys [111], salmon [112], and catfish [113]. These studies reported a wide range of altered metabolites after Se supplementation focused on liver [73, 91, 94-96, 100-102, 105, 112] and plasma/serum metabolism [73,92,96,101,105,108,110], but also in muscle [99,103], kidneys [73,93], testes [73], lungs [73,90], spleen [96], blood…”

“…A summary of the metabolomics studies reported after Se supplementation using different analytical platforms is shown in Table 2. As can be seen, metabolomics is usually combined with transcriptomics [47,90,94,99,101,103,109,111], histopathology [98,103,106,109], metallomics [73,90,91,98,99,105,107], proteomics [96,101], enzymatic activities [91,97,98], or targeted metabolomics [100,109]. Several studies focused on metataxonomics and gut metabolomics [95,96,101,106,113].…”

“…Untargeted metabolomic analysis after Se supplementation have been performed using mice models [47, 73, 85–98], pigs [99–102], broilers [103], cells [104], rats [105–107], gazelle [108], zebra fish [109], humans [110], donkeys [111], salmon [112], and catfish [113]. These studies reported a wide range of altered metabolites after Se supplementation focused on liver [73, 91, 94–96, 100–102, 105, 112] and plasma/serum metabolism [73, 92, 96, 101, 105, 108, 110], but also in muscle [99, 103], kidneys [73, 93], testes [73], lungs [73, 90], spleen [96], blood [97, 102, 106, 113], urine [107], feces or fecal/gut content [47, 96, 106], semen [106], follicular fluid [111], brain [47, 73, 93, 97, 109], and brain sections [98]. A summary of the metabolomics studies reported after Se supplementation using different analytical platforms is shown in Table 2.…”