Enhanced Ca²⁺-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.

ABSTRACT: Ca²⁺ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca²⁺ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca²⁺-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphor

SUBMITTER: Thoudam T 

PROVIDER: S-EPMC10042999 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature