Reduction of endoplasmic reticulum- mitochondria interactions in beta cells from patients with type 2 diabetes

Thivolet, Charles; Vial, Guillaume; Cassel, R.; Rieusset, Jennifer; Madec, Anne-Marie

doi:10.1371/journal.pone.0182027

Cited by 77 publications

(71 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The direct modulation of intracellular Ca 2+ release channels on the ER offers a novel mechanistic insight on the diabetogenic effect of sirolimus. Intriguingly, the upregulation of IP3R observed in pancreatic β cells following sirolimus treatment is consistent with the recent observation that IP3R levels are increased in islets from diabetic patients, mirrored by a reduced number of interactions between ER and mitochondria 64 . Additionally, Madec and colleagues had shown that exposing pancreatic islets to high glucose concentrations led to increased levels of IP3R 65 .…”

Section: Discussionsupporting

confidence: 90%

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Lombardi

Gambardella

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal β cells in a dose- and time-dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca2+) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca2+ uptake. Crucially, the reduced mitochondrial Ca2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug.

show abstract

Section: Discussionsupporting

confidence: 90%

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Lombardi

Gambardella

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This glucose-dependent regulation of ER-mitochondria MCSs is defective in the liver of insulin-resistant obese mice (Theurey et al, 2016), which show increased ER-mitochondria MCSs, causing mitochondrial dysfunction through mitochondrial Ca 2+ overload (Arruda et al, 2014). Pancreatic beta-cells from patients with type 2 diabetes show reduced ER-mitochondria MCSs, and a similar effect is observed after fatty acid overload (Thivolet et al, 2017). Interestingly, ER-mitochondria MCSs are reduced in pro-opiomelanocortin neurons of diabetic mice, and reduction of ER-mitochondria MCSs in the same neurons, via ablation of MFN2, induces leptin resistance and obesity (Schneeberger et al, 2013).…”

Section: Peripheral Neuropathies and Ermentioning

confidence: 99%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

View full text Add to dashboard Cite

The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca 2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca 2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.

show abstract

“…Studies in beta‐cells also indicate the existence of alterations in response to metabolic stress. Thivolet et al reported an increased IP3R2 and decreased VDAC1 expression, accompanied by reduced mitochondria–ER contact sites in beta‐cells from type 2 diabetic patients. In addition, Min6‐B1 beta‐cells exposed to palmitate show ER stress, reduced mitochondria–ER contacts, and impaired insulin secretion .…”

Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 99%

“…Thivolet et al reported an increased IP3R2 and decreased VDAC1 expression, accompanied by reduced mitochondria–ER contact sites in beta‐cells from type 2 diabetic patients. In addition, Min6‐B1 beta‐cells exposed to palmitate show ER stress, reduced mitochondria–ER contacts, and impaired insulin secretion . Zhang et al reported increased VDAC1 abundance accompanied by mislocalization of part of VDAC1 to the plasma membrane.…”

Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 99%

Metabolic implications of organelle–mitochondria communication

2019

View full text Add to dashboard Cite

Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.

show abstract

Reduction of endoplasmic reticulum- mitochondria interactions in beta cells from patients with type 2 diabetes

Cited by 77 publications

References 31 publications

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

Metabolic implications of organelle–mitochondria communication

Contact Info

Product

Resources

About