LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
Date Issued
2025-08-01
Date Acceptance
2025-06-12
Citation
Nature Metabolism, 2025, 7 (8), pp.1570-1592
ISSN
2522-5812
Publisher
Nature Research
Start Page
1570
End Page
1592
Journal / Book Title
Nature Metabolism
Volume
7
Issue
8
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Identifier
10.1038/s42255-025-01333-7
Publication Status
Published
Date Publish Online
2025-07-21