Mitochondrial dysfunction and role in spreading depolarization and seizure

Toglia, Patrick; Ullah, Ghanim

doi:10.1007/s10827-019-00724-6

Cited by 7 publications

(5 citation statements)

References 110 publications

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“…Single neuron-scale models are very diverse and can include very different levels of detail. Some models are highly detailed, taking into account sub-cellular organelles such as mitochondria [9] or the detailed morphology of the dendritic and axonal tree [20,21]. In the latter case, it is necessary to divide the geometry of the neuron into different compartments.…”

Section: Models At the Single Neuron Levelmentioning

confidence: 99%

“…Building on this work, we propose here to highlight some recent works in this field. Numerous approaches emerged, from phenomenological aspects of dynamics to detailed biophysical models, from the subcellular scale to the large scale of whole brain regions [7][8][9][10][11][12]. We discuss the interest of each of these different approaches to show how all contribute to a better understanding of the mechanisms underlying seizures.…”

Section: Introductionmentioning

confidence: 99%

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Modeling seizures: From single neurons to networks

Depannemaecker

Destexhe

Jirsa

et al. 2021

Seizure

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Dynamical systems tools offer a complementary approach to detailed biophysical seizure modeling, with high potential for clinical applications. This review describes the theoretical framework, allowing theorizing certain properties of seizures and their classifications according to their dynamics properties at onset and offset. We describe various modeling approaches spanning different scales, from single neurons to large-scale networks. We try to offer a large accessible overview through nonexhaustive examples of recent important works.

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Section: Models At the Single Neuron Levelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling seizures: From single neurons to networks

Depannemaecker

Destexhe

Jirsa

et al. 2021

Seizure

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show abstract

“…Several models for mitochondrial Ca 2+ signaling have been developed over the past (for example, see [36,38,47,59,[61][62][63][67][68][69][70]). However, they are mostly based on Ca 2+ uptake in permeabilized cell cultures or isolated mitochondria suspended in aqueous solutions.…”

Section: Discussionmentioning

confidence: 99%

“…However, they are mostly based on Ca 2+ uptake in permeabilized cell cultures or isolated mitochondria suspended in aqueous solutions. These models do not properly incorporate the fine details of MCU's gating kinetics, which could lead to erroneous conclusions [70]. The model in [71] links the biophysical properties of MCU activity to the mitochondrial Ca 2+ uptake at the whole-cell level using Michaelis-Menten type relationship, but it does not incorporate the regulation of MCU by MICU1, MICU2, or EMRE.…”

Section: Discussionmentioning

confidence: 99%

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells

Shah

Ullah

2020

Cells

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Mitochondrial Ca2+ ([Ca2+]M) uptake through its Ca2+ uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca2+ signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca2+ influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca2+ ([Ca2+]C), [Ca2+]M, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca2+ buffering proteins, the separation between mitochondrion and Ca2+-releasing stores, and the duration of opening of Ca2+-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU.

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“…Several models for mitochondrial Ca 2+ signaling have been developed over the past (for example, see [35,37,43,55,[57][58][59][62][63][64][65]). However, they are mostly based on Ca 2+ uptake in permeabilized cell cultures or isolated mitochondria suspended in aqueous solutions.…”

Section: Discussionmentioning

confidence: 99%

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells

Ullah¹,

Shah²

2020

Preprint

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Mitochondrial Ca2+ ([Ca2+]M) uptake through Ca2+ uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca2+ signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca2+ influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca2+ ([Ca2+]C), [Ca2+]M, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca2+ buffering proteins, the separation between mitochondrion and Ca2+-releasing stores, and the duration of Ca2+-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU.

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Mitochondrial dysfunction and role in spreading depolarization and seizure

Cited by 7 publications

References 110 publications

Modeling seizures: From single neurons to networks

Modeling seizures: From single neurons to networks

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells

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