PXD060404

PXD060404 is an original dataset announced via ProteomeXchange.

Title	LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes
Description	Protein 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.
HostingRepository	PRIDE
AnnounceDate	2025-06-05
AnnouncementXML	Submission_2025-06-05_06:40:54.101.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yamei Deng
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-31 10:25:27	ID requested
⏵ 1	2025-06-05 06:40:54	announced

Dataset with its publication pending

submitter keyword: Diabetes

apoptosis

mitochondrial protein folding

LONP1

Scott A.
contact affiliation	Division of Metabolism, Endocriology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA
contact email	ssol@med.umich.edu
lab head
Yamei Deng
contact affiliation	University of Michigan
contact email	dengya@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060404
     1. Label: PRIDE project
     2. Name: LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes