PXD039478-2

PXD039478 is an original dataset announced via ProteomeXchange.

Title	Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:47:11.254.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD039478
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Byung-gyu kim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-16 08:29:48	ID requested
1	2023-05-10 13:59:57	announced
⏵ 2	2023-11-14 08:47:12	announced	2023-11-14: Updated project metadata.

Thoudam T, Chanda D, Lee JY, Jung MK, Sinam IS, Kim BG, Park BY, Kwon WH, Kim HJ, Kim M, Lim CW, Lee H, Huh YH, Miller CA, Saxena R, Skill NJ, Huda N, Kusumanchi P, Ma J, Yang Z, Kim MJ, Mun JY, Harris RA, Jeon JH, Liangpunsakul S, Lee IK, -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease. Nat Commun, 14(1):1703(2023) [pubmed]

10.6019/PXD039478;

submitter keyword: PTM, mitochondrial dysfunction,PDK4, GRP75, LC-MS/MS, alcohol-associated liver disease

In-Kyu Lee
contact affiliation	Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
contact email	leei@knu.ac.kr
lab head
Byung-gyu kim
contact affiliation	Center for genomic integrity (CGI), Institute of basic science (IBS), UNIST, Ulsan, 44919, Republic of Korea
contact email	goldenlion@ibs.re.kr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD039478

PRIDE project URI

• PRIDE
  1. PXD039478
     1. Label: PRIDE project
     2. Name: Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease