Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure

Lombardi, Angela; Trimarco, Bruno; Iaccarino, Guido; Santulli, Gaetano

doi:10.1186/s12964-017-0203-0

Cited by 42 publications

(29 citation statements)

References 59 publications

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“…It is also important to note the important role that pancreatic β cell mitochondria play in facilitating insulin secretion and that mitochondrial dysfunction in β cells is associated with beta cell failure and thus dysregulation of glucagon ( 94 – 96 ). This principle has been further substantiated recently in a study illustrating the deleterious effect of tacrolimus on β cell mitochondria and subsequent β cell failure ( 97 ). It is interesting to speculate that the mitochondrial impairment noted in aging and diabetes could deleteriously impact the metabolic flexibility needed for the mitochondria to adapt to an exercise challenge and further interfere with the acute adaptive response of the islet to an exercise bout.…”

Section: Pancreatic Dysfunctionmentioning

confidence: 81%

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review

et al. 2018

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The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches.

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Section: Pancreatic Dysfunctionmentioning

confidence: 81%

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review

et al. 2018

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“…Calstabin1 and calstabin2 preferentially bind RyR1 and RyR2, respectively, and help to stabilize the closed state of the channel (Santulli and Marks 2015). Calstabins are the cytosolic targets for the immunosuppressant drugs rapamycin and FK506 (Lombardi et al 2017a, 2017b). Rapamycin (or sirolimus) coated on coronary artery stents is used to prevent restenosis by inhibiting vascular smooth muscle migration and proliferation (Santulli 2015; Marks 2003; Santulli and Totary-Jain 2013; Santulli et al 2014).…”

Section: 7 Modulation Of Ryr Dynamics and Gatingmentioning

confidence: 99%

Ryanodine Receptor Structure and Function in Health and Disease

Santulli

Lewis

Georges

et al. 2018

Subcellular Biochemistry

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117

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Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca2+) release channels required for the function of many organs including heart and skeletal muscle, synaptic transmission in the brain, pancreatic beta cell function, and vascular tone. In disease, defective function of RyRs due either to stress (hyperadrenergic and/or oxidative overload) or genetic mutations can render the channels leaky to Ca2+ and promote defective disease-causing signals as observed in heat failure, muscular dystrophy, diabetes mellitus, and neurodegerative disease. RyRs are massive structures comprising the largest known ion channel-bearing macromolecular complex and exceeding 3 million Daltons in molecular weight. RyRs mediate the rapid release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) to stimulate cellular functions through Ca2+-dependent processes. Recent advances in single-particle cryogenic electron microscopy (cryo-EM) have enabled the determination of atomic-level structures for RyR for the first time. These structures have illuminated the mechanisms by which these critical ion channels function and interact with regulatory ligands. In the present chapter we discuss the structure, functional elements, gating and activation mechanisms of RyRs in normal and disease states.

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“…The calcineurin inhibitors, particularly tacrolimus, are commonly used as part of the immunosuppressive regimen post lung transplantation 47 48. Tacrolimus alters mitochondrial calcium uptake and uncouples oxidative phosphorylation 49–51. The combination of altered mitochondrial function secondary to the downregulated CFTR protein and the effect of calcineurin inhibitors on an organ with high oxidative demands such as the brain, could explain the increased neurological events in these patients.…”

Section: Discussionmentioning

confidence: 99%

CNS imaging studies in cystic fibrosis patients presenting with sudden neurological events

Ellis

Rang

Kotsimbos³

et al. 2019

BMJ Open Resp Res

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BackgroundAcute neurological events may present as an extrapulmonary complication in patients with cystic fibrosis (CF). These events can be secondary to a range of different aetiologies.MethodsA retrospective analysis of 476 medical records of CF patients attending a large teaching hospital between 2000 and 2018 was performed. Patients presenting with acute neurological events who had MRI brain imaging were evaluated. Patients who had headaches without associated neurological symptoms were excluded from this analysis.ResultsAcute neurological presentations, excluding headaches without associated neurological symptoms, were reported in 27 index patients out of the 476 patients. Of these, 16 patients had MRI brain imaging for review. Three patients suffered pathology secondary to vascular events, both ischaemic and haemorrhagic; four patients had evidence of ischaemia or infarction not consistent with a vascular territory stroke and the remaining patients experienced a range of different neurological events. The most common presentation among these patients was seizure activity, followed by a transient motor or sensory deficit.ConclusionsNeurological complications are recognised among individuals with CF. Although rare, they can be secondary to a range of different aetiologies, including dysfunctional cell energetics. Additional studies are required to further evaluate this association.

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Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure

Cited by 42 publications

References 59 publications

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review

Ryanodine Receptor Structure and Function in Health and Disease

CNS imaging studies in cystic fibrosis patients presenting with sudden neurological events

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