ArticleNature metabolism2025
LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Diabetic β-Cell Apoptosis and Dedifferentiation by Delivering miR-4436.Tissue engineering and regenerative medicine · 2026Article
- Pancreatic β-cell aging in physiology and diabetes: emerging roles of m6A mRNA methylation.Journal of molecular endocrinology · 2026Review
- Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.Antioxidants (Basel, Switzerland) · 2026Review
- Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects.The EMBO journal · 2026Article
- Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.Acta diabetologica · 2026Review
- Review
- Mitochondria-associated programmed cell death in pancreatic β cell of T2DM.Apoptosis : an international journal on programmed cell death · 2026Review
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.Burns & trauma · 2026Review
- Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.Nature metabolism · 2026Article
- Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.Frontiers in pharmacology · 2026Review
- Glycemic status-dependent proteomic signatures of biological aging for health risk prediction.GeroScience · 2025Article
- CHD3 and CHD4 coordinate gene expression programs to maintain β-cell function and identityResearch square · 2025Article
- Mechanically sensitive MAPK signalling mediates resistance exercise-induced muscle growth.Nature metabolism · 2025Article
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20 authors.
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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.
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