Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.

Abstract

Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.

• Authors: Xinyu Mei, Dashi Qi, Ting Zhang, Ying Zhao, Li Jin, Junli Hou, Jianhua Wang, Yan Lin, Yu Xue, Pingping Zhu, Zexian Liu, Lei Huang, Ji Nie, Wen Si, Jingyi Ma, Jianhong Ye, Richard H Finnell, Hexige Saiyin, Hongyan Wang, Jianyuan Zhao, Shimin Zhao, Wei Xu
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 12 Issue 3 Pg. e9469 (03 06 2020) ISSN: 1757-4684 [Electronic] England
• PMID: 32003121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Homocysteine
• Methionine-tRNA Ligase

Topics

• Animals
• Female
• Heart Defects, Congenital (prevention & control)
• Homocysteine
• Humans
• Hyperhomocysteinemia (genetics)
• Infant, Newborn
• Male
• Methionine-tRNA Ligase (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Neural Tube Defects (prevention & control)
• Rats
• Rats, Sprague-Dawley
• United States