Proteomics

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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 mitochondria-associated ER membranes (MAMs) mediates Ca2+ accumulation-induced mitochondrial dysfunction in ALD via the formation of glucose-regulated protein 75 (GRP75)-mediated MAM Ca2+-channeling (MCC) complex. Unbiased transcriptomic analysis reveals pyruvate dehydrogenase kinase 4 (PDK4) as a prominently inducible MAM kinase in ALD. Additional mass spectrometry analysis unveils the critical role of PDK4 in promoting alcohol-induced MCC complex formation and mitochondrial dysfunction by phosphorylating GRP75. Non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced mitochondrial Ca2+ accumulation and dysfunction. Conversely, ectopic induction of MAM formation in PDK4-deficient mice abrogate the protective effect in alcohol-induced liver injury. Together, our study defines the mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Byung-gyu kim  

LAB HEAD: In-Kyu Lee

PROVIDER: PXD039478 | Pride | 2023-05-10

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
GRP75_1.raw Raw
GRP75_2.raw Raw
Mudpit_GRP75_1__GRP75_1.mzid.gz Mzid
Mudpit_GRP75_1__GRP75_1.mzid_Mudpit_GRP75_1__GRP75_1.MGF Mzid
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Publications


Ca<sup>2+</sup> 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 Ca<sup>2+</sup> accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca<sup>2+</sup>-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mo  ...[more]

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