LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes
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.
Authors
- Romy Kursawe (ORCID: https://orcid.org/0000-0001-6509-1917)
- Guy A. Rutter (ORCID: https://orcid.org/0000-0001-6360-0343)
- Emily M. Walker (ORCID: https://orcid.org/0000-0001-8394-1567)
- Venkatesha Basrur
- Vaibhav Sidarala (ORCID: https://orcid.org/0000-0002-8010-3418)
- Jie Zhu (ORCID: https://orcid.org/0000-0001-7941-4166)
- Scott A. Soleimanpour (ORCID: https://orcid.org/0000-0001-6777-4498)
- David C. Chan (ORCID: https://orcid.org/0000-0002-0191-2154)
- Chun-Shik Shin (ORCID: https://orcid.org/0000-0002-1382-9876)
- Marie Gasser (ORCID: https://orcid.org/0000-0002-7242-1141)
- Khushdeep Bandesh (ORCID: https://orcid.org/0000-0002-5057-7313)
- Yamei Deng (ORCID: https://orcid.org/0000-0002-3680-5930)
- Jin Li (ORCID: https://orcid.org/0000-0002-5743-696X)
- Michael L. Stitzel (ORCID: https://orcid.org/0000-0001-5630-559X)
- Emma C. Reck (ORCID: https://orcid.org/0009-0003-0784-1312)
- Alexey I. Nesvizhskii (ORCID: https://orcid.org/0000-0002-2806-7819)
- Dre L. Hubers
- Eftyhmios Motakis
- Siddhi Nargund
- Mabelle B. Pasmooij
Institutions
- California Institute of Technology (US)
- Nanyang Technological University (SG)
- University of Michigan (US)
- Hammersmith Hospital (GB)
- McGill University Health Centre (CA)
- VA Ann Arbor Healthcare System (US)
- Michigan Medicine (US)
- Jackson Laboratory (US)
- Université de Montréal (CA)
- UConn Health (US)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1038/s42255-025-01333-7
- Citations
- 10
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- American Diabetes Association
- U.S. Department of Veterans Affairs
- Wellcome
- Juvenile Diabetes Research Foundation United States of America
- Innovation, Science and Economic Development Canada
- Diabetes UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases
- CIHR Skin Research Training Centre