Li Jin, Deng Yamei, Gasser Marie, Zhu Jie, Walker Emily M, Sidarala Vaibhav, Reck Emma C, Hubers Dre L, Pasmooij Mabelle B, Shin Chun-Shik, Bandesh Khushdeep, Motakis Eftyhmios, Nargund Siddhi, Kursawe Romy, Basrur Venkatesha, Nesvizhskii Alexey I, Stitzel Michael L, Chan David C, Rutter Guy A, Soleimanpour Scott A
Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Nat Metab. 2025 Jul 21. doi: 10.1038/s42255-025-01333-7.
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.
蛋白质错误折叠是2型糖尿病（T2D）发病的一个促成因素，但蛋白质稳态受损的具体作用尚不清楚。在这里，我们展示了T2D患者人类胰岛线粒体中错误折叠蛋白的大量积累，并阐明了其通过线粒体基质蛋白酶LONP1对β细胞活力的影响。对蛋白质聚集体的定量蛋白质组学研究表明，T2D供体的胰岛具有类似于线粒体而非内质网蛋白质错误折叠的特征。LONP1是线粒体蛋白质稳态机制的重要组成部分，在T2D供体的β细胞中表达降低，其缺失会导致线粒体蛋白质错误折叠和呼吸功能降低，从而导致β细胞凋亡和高血糖。LONP1功能增强可改善线粒体蛋白质错误折叠，并通过一种不依赖蛋白酶的效应恢复糖脂毒性后人β细胞的存活，该效应需要LONP1-线粒体HSP70伴侣活性。因此，LONP1通过促进线粒体蛋白质折叠来促进β细胞存活并预防高血糖。这些观察结果为在T2D发病机制中促进β细胞丢失的蛋白质毒性本质提供了见解，这可被视为未来的治疗靶点。
