DISC1通过双重核质机制在糖尿病性脑病中诱导线粒体钙超载

Abstract

Hyperglycemia-driven mitochondrial dysfunction is a primary driver of diabetic encephalopathy (DE). Here, we identify a novel nucleocytoplasmic “dual effect” of DISC1 that coordinates mitochondrial Ca2+overload under high-glucose conditions. Using nucleocytoplasmic fractionation and mass spectrometry, we demonstrate that high glucose triggers PAK2-mediated phosphorylation of DISC1, necessitating its nuclear translocation. In the nucleus, DISC1 acts as a coactivator for the transcription factor RFX1 to induce Grp75, a critical tethering protein of the GRP75/IP3R1/VDAC1 complex that facilitates Ca2+transfer from the endoplasmic reticulum to mitochondria. Conversely, we find that cytoplasmic DISC1 physically sequesters GRP75, hindering the assembly of the Ca2+conduction complex. Enhanced nuclear translocation of DISC1 results in reduced cytoplasmic DISC1 levels. This depletion removes the “molecular brake” on Ca2+influx, synergizing with the nuclear signaling pathway to drive mitochondrial Ca2+overload. Together, our findings suggest that high glucose hijacks DISC1 through a bipartite mechanism: the upregulation of Ca2+conduction and the concurrent loss of cytoplasmic inhibition. Targeting DISC1 may represent a potential therapeutic strategy for mitigating neurodegeneration in DE.