Phosphatase activity-based PPM1K: a key player in the regulation of mitochondrial function and its multifaceted impact in diseases.

Abstract

PPM1K is a significant metal-dependent phosphatase predominantly located in the mitochondrial matrix, where it plays a crucial role in the metabolism of branched-chain amino acids (BCAAs). It is implicated in cellular function and development across various tissues and is associated with diseases like Alzheimer's, cardiomyopathy, and maple syrup urine disease (MSUD). This article reviews PPM1K's impact on mitochondrial function and cellular metabolism, as well as its role in disease progression. The regulation of PPM1K expression and activity by various factors is complex and highlights its therapeutic potential. PPM1K's dysfunction can lead to the accumulation of BCAAs and the excessive opening of the mitochondrial permeability transition pore (MPTP), disrupting physiological metabolism and function. It also regulates the degradation of BCAAs by acting as a specific phosphatase for the E1α subunit of the BCKD complex. Outside the mitochondria, PPM1K suppresses de novo fatty acid synthesis and promotes fatty acid oxidation by dephosphorylating ACL. Furthermore, PPM1K has anti-inflammatory effects and modulates immune cell infiltration in tumor tissues. The expression and activity of PPM1K are influenced by factors such as BCAA concentration, fructose intake, and drug treatments, making it a promising target for therapeutic applications and further basic research.