AI Article Synopsis
- Mitochondrial disease, particularly the MELAS phenotype linked to the m.3243A>G genotype, presents significant treatment challenges.
- Research revealed that serine catabolism pathways were notably upregulated in MELAS patients' muscle tissue, with a significant increase in the protein SHMT2.
- Inhibiting SHMT2 with the compound SHIN1 improved cell viability and the NAD/NADH ratio in MELAS muscle cells, suggesting a promising therapeutic approach.
Article Abstract
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.
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| http://dx.doi.org/10.1096/fj.202302286RRR | DOI Listing |
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