Inhibiting MARSs reduces hyperhomocysteinemia‐associated neural tube and congenital heart defects

• Published in: EMBO molecular medicine 2020-03, Vol.12 (3), p.e9469-n/a
• Main Authors: Mei, Xinyu, Qi, Dashi, Zhang, Ting, Zhao, Ying, Jin, Li, Hou, Junli, Wang, Jianhua, Lin, Yan, Xue, Yu, Zhu, Pingping, Liu, Zexian, Huang, Lei, Nie, Ji, Si, Wen, Ma, Jingyi, Ye, Jianhong, Finnell, Richard H, Saiyin, Hexige, Wang, Hongyan, Zhao, Jianyuan, Zhao, Shimin, Xu, Wei
• Format: Article
• Language: English
• Subjects: acetyl homocysteine thioether; Alzheimer's disease; Animal models; Animals; Apoptosis; Brain; Congenital diseases; Defects; EMBO27; Female; Heart; Heart Defects, Congenital - prevention & control; Homocysteine; Humans; Hyperhomocysteinemia; Hyperhomocysteinemia - genetics; Infant, Newborn; Lysine; Male; Metabolic disorders; Metabolism; Metabolites; Methionine-tRNA Ligase - antagonists & inhibitors; methionyl‐tRNA synthetase; Mice; Mice, Inbred C57BL; Neural tube defects; Neural Tube Defects - prevention & control; N‐homocysteinylation; Oxidative stress; Protein expression; Protein synthesis; Proteins; Rats; Rats, Sprague-Dawley; reactive oxygen species; Retinoic acid; Superoxide; Superoxide dismutase; tRNA; United States; Wnt protein
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201809469

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. Synopsis Reducing homocysteine levels is not always effective against hyperhomocysteinemia‐associated pathologies such as neural tube and congenital heart defects (NTD/CHD). Here, increased MARS/MARS2 copy numbers were associated with NTD and CHD onsets, and targeting MARSs reduced Hcy signals and NTD/CHD. Increased copy numbers of MARS/MARS2‐encoding genes were associated with the onset of CHDs and NTDs MARS over‐expression potentiated Hcy‐induced ROS accumulation, apoptosis, and Wnt signalling deregulation, via regulation of the activity of HTL, N‐Hcy, and SOD1/2. Inhibiting MARSs decreased the onset of NTDs and CHDs in hyperhomocysteinemia related models. Graphical Abstract Reducing homocysteine levels is not always effective against hyperhomocysteinemia‐associated pathologies such as neural tube and congenital heart defects (NTD/CHD). Here, increased MARS/MARS2 copy numbers were associated with NTD and CHD onsets, and targeting MARSs reduced Hcy signals and NTD/CHD.