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Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors <jats:italic>in vivo<\/jats:italic> to study its role in hepatic steatosis induced by high\u2010fat diet (HFD). <jats:italic>In vitro<\/jats:italic>, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum\u2013mitochondrial linker was adopted to increase mitochondria\u2010associated membranes (MAMs) and MICU1\u2010EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD\u2010induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high\u2010calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD\u2010induced hepatic steatosis. MCU inhibitors (Ru<jats:sub>360<\/jats:sub> and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01\u2010\u03bcM\u00b7kg<jats:sup>\u22121<\/jats:sup> bodyweight) can alleviate HFD\u2010induced hepatic steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15767","type":"journal-article","created":{"date-parts":[[2021,12,4]],"date-time":"2021-12-04T02:20:39Z","timestamp":1638584439000},"page":"2678-2696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Ruthenium 360 and mitoxantrone inhibit mitochondrial calcium uniporter channel to prevent liver steatosis induced by high\u2010fat 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