Mitochondrial Ca2+ in neurodegenerative disorders

Abeti, Rosella; Abramov, Andrey Y.

doi:10.1016/j.phrs.2015.05.007

Cited by 94 publications

(76 citation statements)

References 78 publications

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“…Finally, there is increasing realization that mitochondrial calcium overload might be a final common pathway in a multitude of disease conditions including various myopathies, certain neurodegenerative diseases, models of heart failure, and ischemic tissue injury (Abeti and Abramov, 2015; Bhosale et al, 2015; Martin and McGee, 2014; Santulli et al, 2015; Vallejo-Illarramendi et al, 2014). As such, strategies that modulate mitochondrial calcium uptake might have wide therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

“…These entities are often accompanied by mitochondrial dysfunction and damage. Indeed, mitochondrial calcium overload is being increasingly viewed as a common final pathway for a wide range of human pathologies (Abeti and Abramov, 2015; Bhosale et al, 2015; Martin and McGee, 2014; Santulli et al, 2015; Vallejo-Illarramendi et al, 2014). Most of these conditions, like MICU1 deficiency, have few therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

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MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

et al. 2016

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MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1−/− mitochondria demonstrate altered calcium uptake and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1−/− mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1−/− mice show marked, spontaneous improvement, coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1−/− mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

et al. 2016

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“…On a broader scale, therapeutic treatment with C-R(7) may have the potential to minimize mitochondrially induced damage resulting from stroke or traumatic brain injury (55,68) and possibly serve to ameliorate slow progressive neurodegenerative disorders such as multiple sclerosis and Parkinson disease (69). Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of N-Methyl-d-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential

Marshall

Wong

Rupasinghe

et al. 2015

Journal of Biological Chemistry

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Background: NMDA receptor hyperactivity results in mitochondrial dysfunction in neurons promoting neurodegenerative disorders. Results: Short polyarginine peptides target mitochondria to promote neuronal survival. Conclusion: Short polyarginine peptides reduce mitochondrial respiration, membrane hyperpolarization, and generation of reactive oxygen species. Significance: Treatment with polyarginine has the potential to minimize neuronal damage resulting from stroke or traumatic brain injury and may be therapeutic to ameliorate multiple sclerosis and Parkinson disease.

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“…Mitochondria are one of the main buffers of cytosolic calcium, taking up calcium predominantly through the mitochondrial calcium uniporter [75]. Calcium uptake by mitochondria activates mitochondrial respiratory chain function and can increase mitochondrial ATP (and free radical) production through activation of calcium-dependent NADH dehydrogenases [75].…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

104

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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Mitochondrial Ca2+ in neurodegenerative disorders

Cited by 94 publications

References 78 publications

MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

Inhibition of N-Methyl-d-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential

Pathophysiology of status epilepticus

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