Cell Rep. 10, 694–701 (2015)

Credit: ANJALI NATH

Model organisms such as zebrafish offer unique advantages for chemical screening in terms of cost and ease of screening. Nath et al. wanted to validate the use of zebrafish larvae as a model system for small-molecule screening to identify regulators of glucose metabolism. As expected, treatment of larvae with anti-diabetic drugs such as insulin and pioglitazone decreased glucose levels. In addition, ablation of liver cells using a tissue-specific nitroreductase transgenic system decreased glucose levels, while similar ablation of pancreatic β cells increased glucose levels. With this validation in place, the authors then treated larvae with a library of 13,120 small-molecule compounds to identify those that lowered systemic glucose levels. One of the most effective candidates was alexidine, a known mitochondrial phosphatase PTPMT1 inhibitor. Treatment of larvae with additional, structurally distinct PTPMT1 inhibitors and development of a TALEN-generated ptpmt1 knockout also yielded reduced glucose levels. Alexidine treatment was ineffective in ptpmt1 mutants, confirming that PTPMT1 is the compound's target. To determine the potential substrates of PTPMT1 activity in the mitochondria, Nath et al. analyzed phosphotyrosine- and phosphoserine-modified proteins that were differentially expressed between wild-type and ptpmt1-heterozygous larvae. They found that the succinate dehydrogenase (SDH) subunit SDHA, which is involved in TCA and electron transport chain metabolism, was hyperphosphorylated in ptpmt1 mutants. Considering that FGR kinase phosphorylates SDHA, the authors thought that PTPMT1 might reduce SDHA phosphorylation. As expected, PTPMT1 decreased FGR-mediated phosphorylation of SDHA, resulting in diminished SDH activity. Finally, given that alexidine was unable to lower glucose in larvae lacking insulin-producing beta cells, it is possible that PTPMT1 regulation of SDH activity may lower glucose levels by stimulating increased insulin secretion.