Study On The Regulation Of Branched-chain Amino Acids Metabolism And Their Novel Biological Function

Homeostasis of branched-chain amino acids(BCAA)is critical for development and physiology.PP2Cm,a mitochondrial Ser/Thr protein phosphatase,plays a key role in BCAA catabolism.To get a further understanding of BCAA homeostatic maintenance,we studied the regulatory mechanism of PP2Cm expression at molecular level.Some putative mi RNAs were screened from targetscan database.Dual luciferase reporter assay,site mutagenesis,and cellular studies showed that mi R-204 and mi R-211 could regulate PP2Cm expression through repressing the activity of 3'UTR,leading to a decreased m RNA abundance.We also found that mi R-204 could mediate the deducted expression of PP2Cm in failing heart.In the study of BCAA biological function,we found that BCAA starvation aggravated H₂O₂-induced non-apoptotic cell death.Further,we demonstrated that branched-chain?-keto acids(BCKA),intermediate products of BCAA catabolism,but not BCAA,protected cells from H₂O₂damage.More experiments excluded the invlvoment of certain signaling pathways and protein synthesis.Energy production was affected by BCKA and potentially contributed to the protection.PP2Cm knockout mice with high blood BCKA concentration has less ischemia/reperfusion injury,suggesting that the protection could occur in vivo.