Keratins regulate β‐cell mitochondrial morphology, motility, and homeostasis

Silvander, Jonas S. G.; Kvarnström, Sofie M.; Kumari‐Ilieva, Angeli; Shrestha, Anup; Alam, Catharina M.; Toivola, Diana M.

Abstract

Loss of the epithelial intermediate filament protein keratin 8 (K8) in murine β cells leads to irregular insulin vesicles and decreased insulin levels. Because mitochondria are central in glucose-stimulated insulin secretion, the relationship between keratins and β-cell mitochondrial function and morphology was investigated. β cells in murine K8-knockout (K8−/−) islets of Langerhans have increased numbers of mitochondria, which are rounder and have diffuse cristae, as seen by electron microscopy. The mitochondrial network in primary cultured K8−/− β cells is more fragmented compared with K8+/+ mitochondria, correlating with decreased levels of mitofusin 2 and the mitofusin 2- and keratin-binding protein trichoplein. K8−/− β-cell mitochondria have decreased levels of total and mitochondrial cytochrome c, which correlates with a reduction in electron transport complexes I and IV. This provokes loss of mitochondrial membrane potential and reduction of ATP and insulin amount, as seen in K8−/− β cells. Mitochondria in K8 wild-type β cells and MIN6 insulinoma cells overexpressing K8 and 18 are more stationary compared with mitochondria in keratin-deficient cells. In conclusion, keratins, likely through trichoplein-mitofusin interactions, regulate both structural and dynamic functions of β-cell mitochondria, which could have implications for downstream insulin secretion.

• Journal Article Type: Article
• Acceptance Date: Jun 19, 2017
• Online Publication Date: Sep 19, 2017
• Publication Date: 2017-10
• Deposit Date: Nov 14, 2022
• Journal: The FASEB Journal
• Print ISSN: 0892-6638
• Electronic ISSN: 1530-6860
• Publisher: Federation of American Society of Experimental Biology
• Peer Reviewed: Peer Reviewed
• Volume: 31
• Issue: 10
• Pages: 4578-4587
• DOI: https://doi.org/10.1096/fj.201700095r
• Keywords: TEM, insulin secretion, islets, K8-null mice, fusion
• Public URL: http://researchrepository.napier.ac.uk/Output/2957226