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PXD060404

PXD060404 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes
DescriptionProtein misfolding is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether impaired proteostasis in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability. Quantitative proteomics studies of protein aggregates surprisingly reveal that islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. Loss of the matrix protease LONP1, a vital component of the mitochondrial proteostatic machinery whose expression is reduced in β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to β cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations open novel insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D that could be considered as future therapeutic targets.
HostingRepositoryPRIDE
AnnounceDate2025-06-05
AnnouncementXMLSubmission_2025-06-05_06:40:54.101.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterYamei Deng
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02025-01-31 10:25:27ID requested
12025-06-05 06:40:54announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Diabetes
apoptosis
mitochondrial protein folding
LONP1
Contact List
Scott A.
contact affiliationDivision of Metabolism, Endocriology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA
contact emailssol@med.umich.edu
lab head
Yamei Deng
contact affiliationUniversity of Michigan
contact emaildengya@umich.edu
dataset submitter
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Dataset FTP location
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PRIDE project URI
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