Ruthenium 360 and mitoxantrone inhibit mitochondrial calcium uniporter channel to prevent liver steatosis induced by high-fat diet.

Abstract

BACKGROUND AND PURPOSE:

Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis.

EXPERIMENTAL APPROACH:

In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high-fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum-mitochondrial linker was adopted to increase mitochondria-associated membranes (MAMs) and MICU1-EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel.

KEY RESULTS:

Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD-induced 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-calcium 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-induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01-μM·kg-1 bodyweight) can alleviate HFD-induced hepatic steatosis.

CONCLUSION AND IMPLICATIONS:

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.

• Authors: Zhiwang Zhang, Zupeng Luo, Lin Yu, Yang Xiao, Siqi Liu, Zhier ALuo, Zeqiang Ma, Liang Huang, Lianggui Xiao, Mengting Jia, Ziyi Song, Haojie Zhang, Yixing Li, Lei Zhou
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 11 Pg. 2678-2696 (06 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34862596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

• Calcium Channels
• Calcium-Binding Proteins
• MICU1 protein, mouse
• Mitochondrial Membrane Transport Proteins
• mitochondrial calcium uniporter
• Ruthenium
• Mitoxantrone
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels
• Calcium-Binding Proteins (genetics)
• Diet, High-Fat (adverse effects)
• Fatty Liver (prevention & control)
• Humans
• Mice
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitoxantrone
• Ruthenium