Multiomics analysis reveals serine catabolism as a potential therapeutic target for MELAS.

Autor: Liufu T; Department of Neurology, Peking University First Hospital, Beijing, China., Zhao X; Department of Neurology, Peking University First Hospital, Beijing, China., Yu M; Department of Neurology, Peking University First Hospital, Beijing, China., Xie Z; Department of Neurology, Peking University First Hospital, Beijing, China., Meng L; Department of Neurology, Peking University First Hospital, Beijing, China., Lv H; Department of Neurology, Peking University First Hospital, Beijing, China., Zhang W; Department of Neurology, Peking University First Hospital, Beijing, China., Yuan Y; Department of Neurology, Peking University First Hospital, Beijing, China.; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China., Xing G; Neuroscience Research Institute, Peking University, Beijing, China., Deng J; Department of Neurology, Peking University First Hospital, Beijing, China.; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China.; Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, China., Wang Z; Department of Neurology, Peking University First Hospital, Beijing, China.; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Jun 30; Vol. 38 (12), pp. e23742.
DOI: 10.1096/fj.202302286RRR
Abstrakt: Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G being the most common phenotype and genotype, respectively. The treatment for MELAS patients is still less effective. Here, we performed transcriptomic and proteomic analysis in muscle tissue of MELAS patients, and discovered that the expression of molecules involved in serine catabolism were significantly upregulated, and serine hydroxymethyltransferase 2 (SHMT2) increased significantly in both the mRNA and protein levels. The SHMT2 protein level was also increased in myoblasts with m.3243A>G mutation, which was transdifferentiated from patients derived fibroblasts, accompanying with the decreased nicotinamide adenine dinucleotide (NAD + )/reduced NAD + (NADH) ratio and cell viability. After treating with SHMT2 inhibitor (SHIN1), the NAD + /NADH ratio and cell viability in MELAS myoblasts increased significantly. Taken together, our study indicates that enhanced serine catabolism plays an important role in the pathogenesis of MELAS and that SHIN1 can be a potential small molecule for the treatment of this disease.
(© 2024 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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