Mitochondrial ion channels in pancreatic β‐cells: Novel pharmacological targets for the treatment of Type 2 diabetes

Marchi, Umberto De; Fernandez-Martinez, Silvia; Fuente, Sergio de la; Wiederkehr, Andreas; Santo‐Domingo, Jaime

doi:10.1111/bph.15018

Cited by 17 publications

(12 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…pro-inflammatory mediators (e.g., cytokines) [71], proinsulin misfolding [72,73], human islet amyloid polypeptide misfolding [74], as well as endoplasmic reticulum stress [75], which these sequential events initiate apoptosis, increase β-cell workload and stress, culminate in exhaustion, and finally β-cell death [76][77][78][79][80]. Therefore, creating a successful treatment for T2D will need to specifically include targeting insulin resistance, regenerating β-cell mass, and restoring appropriate insulin release by recovery and increase of β-cell function.…”

Section: Discussionmentioning

confidence: 99%

The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on $\textrm{Ca}^{2+}$ dynamics

Saadati,

Jamali

2020

Preprint

View full text Add to dashboard Cite

ABSTRCT: Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of β-cell mass via progressive programmed cell death and alteration of β-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in β-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of β-cell mass to β-cell function in T2D, we make use of a comprehensive electrophysiological model from human β-cell clusters. We find that defect in β-cell mass causes a functional decline in single β-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular Ca 2+ concentration, which can lead to changes in insulin secretion dynamics and in insulin levels. The model demonstrates good correspondence between suppression of synchronizing electrical activity and pulsatile insulin release, and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both β-cell synchronization and metabolic coupling in the behavior of Ca 2+ concentration dynamics within human islets. Our results indicate that inter-β-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D.We further predict that varying the conductance gating of delayed rectifier K + channels modifies oscillatory activity patterns of β-cell population lacking intercellular coupling, which significantly affect Ca 2+ concentration and insulin secretion.

show abstract

Section: Discussionmentioning

confidence: 99%

The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on $\textrm{Ca}^{2+}$ dynamics

Saadati,

Jamali

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…VDAC1 plays a central role in many cellular processes ranging from energy metabolism to the triggering of mitochondria-mediated apoptosis [8,9]. For these reasons, VDAC1 is often regarded as a promising target for the treatment of metabolic disorders [10] as well as cancer [11,12] and neurogenerative diseases [13,14] where pro-and anti-apoptotic action are required, respectively. At the molecular level, VDAC1 regulation is characterized by the ability of the channel to switch or "gate" between a high-conducting open state, which is permeable to most ions and metabolites, and multiple low-conducting closed states, which display a reduced ion conductance and are impermeable to large metabolites [6,15].…”

Section: Introductionmentioning

confidence: 99%

A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States

Preto

Gorny

Krimm

2022

IJMS

View full text Add to dashboard Cite

The voltage-dependent anion channel 1 (VDAC1) is a crucial mitochondrial transporter that controls the flow of ions and respiratory metabolites entering or exiting mitochondria. As a voltage-gated channel, VDAC1 can switch between a high-conducting “open” state and a low-conducting “closed” state emerging at high transmembrane (TM) potentials. Although cell homeostasis depends on channel gating to regulate the transport of ions and metabolites, structural hallmarks characterizing the closed states remain unknown. Here, we performed microsecond accelerated molecular dynamics to highlight a vast region of VDAC1 conformational landscape accessible at typical voltages known to promote closure. Conformers exhibiting durable subconducting properties inherent to closed states were identified. In all cases, the low conductance was due to the particular positioning of an unfolded part of the N-terminus, which obstructed the channel pore. While the N-terminal tail was found to be sensitive to voltage orientation, our models suggest that stable low-conducting states of VDAC1 predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. In addition, our results were consistent with conductance jumps observed experimentally and corroborated a recent study describing entropy as a key factor for VDAC gating.

show abstract

“…Mitochondria have a double membrane structure, namely mitochondrial inner membrane (MIM) and mitochondrial outer membrane (MOM), both of which contain selective and nonselective ion channels and transporters [ 6 , 7 ]. The MOM with a simple structure is a permeable membrane for small molecules and ions, while the MIM is highly impermeable and its passive transport mode is usually driven by electrochemistry [ 8 , 9 ]. The recently discovered mitochondrial metal ion channels/transporters are mainly located on these mitochondrial membranes, especially the MIM.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

Wang

et al. 2021

IJMS

View full text Add to dashboard Cite

Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases.

show abstract

Mitochondrial ion channels in pancreatic β‐cells: Novel pharmacological targets for the treatment of Type 2 diabetes

Cited by 17 publications

References 155 publications

The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on $\textrm{Ca}^{2+}$ dynamics

The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on $\textrm{Ca}^{2+}$ dynamics

A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

Contact Info

Product

Resources

About