Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive... Show moreBeta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors. Show less
Spits, M.; Heesterbeek, I.T.; Voortman, L.M.; Akkermans, J.J.; Wijdeven, R.H.; Cabukusta, B.; Neefjes, J. 2021
The endoplasmic reticulum (ER) is the largest organelle contacting virtually every other organelle for information exchange and control of processes such as transport, fusion, and fission. Here, we... Show moreThe endoplasmic reticulum (ER) is the largest organelle contacting virtually every other organelle for information exchange and control of processes such as transport, fusion, and fission. Here, we studied the role of the other organelles on ER network architecture in the cell periphery. We show that the co-migration of the ER with other organelles, called ER hitchhiking facilitated by late endosomes and lysosomes is a major mechanism controlling ER network architecture. When hitchhiking occurs, emerging ER structures may fuse with the existing ER tubules to alter the local ER architecture. This couples late endosomal/lysosomal positioning and mobility to ER network architecture. Conditions restricting late endosomal movement-including cell starvation-or the depletion of tether proteins that link the ER to late endosomes reduce ER dynamics and limit the complexity of the peripheral ER network architecture. This indicates that among many factors, the ER is controlled by late endosomal movement resulting in an alteration of the ER network architecture. Show less
