Molecular mechanism of mitoquinol mesylate in mitigating the progression of hepatocellular carcinoma—in silico and in vivo studies

Abstract

The safety and efficacy of mitoquinol mesylate (MitoQ) in attenuating the progression of hepatocellular carcinoma (HCC) in Wistar rats has been reported. However, the binding modes for MitoQ as well as its molecular mechanisms in cirrhosis and liver cancer have not been fully investigated. This study sought to understand the structural and molecular mechanisms of MitoQ in modulating the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) and mitochondrial succinate dehydrogenase (SDH) in cirrhotic‐HCC rats. The research indicates that the upregulated Nrf2 expression in cirrhotic‐HCC rats was significantly (p < 0.05) reduced by MitoQ while the activity of SDH was significantly (p < 0.05) increased. Analysis of binding modes revealed MitoQ interacts with amino acid residues in the active pocket of tramtrack and bric‐a‐brac (BTB) and KELCH domains of KEAP1 with average binding affinities of −66.46 and −74.74 kcal/mol, respectively. Also, MitoQ interacted with the key amino acid residues at the active site of mitochondrial complex II with a higher average binding affinity of −75.76 kcal/mol compared to co‐crystallized ligand of complex II (−62.31 kcal/mol). Molecular dynamics simulations data showed the binding of MitoQ to be stable with low eigenvalues while the quantum mechanics calculations suggest MitoQ to be very reactive with its mechanism of chemical reactivity to be via electrophilic reactions. Thus, MitoQ modulates expression of Nrf2 and enhances activity of mitochondrial SDH in cirrhotic‐HCC rats via its interaction with key amino acid residues in the active pocket of BTB and KELCH domains of KEAP1 as well as amino residues at the active site of SDH. These findings are significant in demonstrating the potential of Nrf2 and SDH as possible biomarkers for the diagnosis and/or prognosis of hepatocellular carcinoma in patients. This study also supports repurposing of mitoQ for the treatment/management of liver cirrhosis and HCC.

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

“…Vitamins like folate, vitamin B6, vitamin B12, vitamin A, and thiamine [351] Minerals (like selenium, zinc, copper, and magnesium [351] Nicotinamide riboside [85] Mitochondria-targeted ubiquinone [52] Silymarin, corilagin, anthocyanins, dihydromyricetin, berberine, hydroxytyrosol, cysteamine, pentoxifylline, avocado oil, and pegbelfermin, mitotherapy, as well as ACC inhibitors, genistein, and aramchol [237] Ursodeoxycholic acid [373] Less caloric diet, anti-diabetic drugs (i.e., elafibranor, liraglutide, metformin, thiazolidinediones, and MSDC 0602 K) [91,375] MitoE [376] Mitoquinol mesylate (Mito-MES) [377] Capsaicin for septic acute liver injury [140] Adequate nutrition and abstinence [372] Predicting its onset and type by measuring hepatic transporter inhibition, mitochondrial toxicity, reactive metabolite formation, hepatocyte cytotoxicity, as well as the dose and physiochemical properties of the drug ingested [372] Melatonin for chemotherapy hepatotoxicity [382] [384] Mitoquinone for acetaminophen hepatotoxicity [280] Oxidative stress…”

“…There are many ways to treat mitochondrial dysfunction liver diseases, including the consumption of a less caloric diet, anti-diabetic drugs (i.e., elafibranor, liraglutide, metformin, thiazolidinediones, MSDC 0602K), bile acid regulators (i.e., obeticholic acid, ursodeoxycholic acid), and antioxidants that act on nuclear receptors or mitochondrial metabolism (i.e., vitamin E, tempol, resveratrol) [91,375]. Other mitochondria-targeted antioxidants, including mitoquinone [280], MitoE [376], mitoquinol mesylate (Mito-MES) [377], mitochondria-targeted ubiquinone [52], and quercetin [378] were reported to affect mitophagy and improve liver conditions. Furthermore, silymarin, corilagin, anthocyanins, dihydromyricetin, berberine, hydroxytyrosol, cysteamine, pentoxifylline, avocado oil, and pegbelfermin, mitotherapy, as well as ACC inhibitors, genistein, and aramchol were reported to improve mitochondrial function in MASLD [237].…”