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

Abstract

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.—Silvander, J. S. G., Kvarnström, S. M., Kumari‐Ilieva, A., Shrestha, A., Alam, C. M., Toivola, D.M. Keratins regulate β‐cell mitochondrial morphology, motility, and homeostasis. FASEB J. 31, 4578–4587 (2017). www.fasebj.org