Iron overload-induced calcium signals modulate mitochondrial fragmentation in HT-22 hippocampal neuron cells

Lee, Dong Seok; Park, Junghyung; Lee, Hyun‐Shik; Lee, Sang-Rae

doi:10.1016/j.tox.2016.07.022

Cited by 44 publications

(33 citation statements)

References 40 publications

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“…Cytosolic Ca 2+ has been known to play a role in mitochondrial fragmentation in some studies [56], [57]. We found that phosphorylation at the inhibitory site of DRP1 was decreased in ΔMICU1 cells, indicating increased DRP1 activity.…”

Section: Discussionmentioning

confidence: 50%

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Bhosale

Sharpe

Koh

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Loss of function mutations of the protein MICU1, a regulator of mitochondrial Ca2 + uptake, cause a neuronal and muscular disorder characterised by impaired cognition, muscle weakness and an extrapyramidal motor disorder. We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca2+ concentration ([Ca2 +]m). We now explore the functional consequences of MICU1 mutations in patient derived fibroblasts in order to clarify the underlying pathophysiology of this disorder. We propose that deregulation of mitochondrial Ca2+ uptake through loss of MICU1 raises resting [Ca2+]m, initiating a futile Ca2+ cycle, whereby continuous mitochondrial Ca2+ influx is balanced by Ca2+ efflux through the sodium calcium exchanger (NLCXm). Thus, inhibition of NCLXm by CGP-37157 caused rapid mitochondrial Ca2+ accumulation in patient but not control cells. We suggest that increased NCLX activity will increase sodium/proton exchange, potentially undermining oxidative phosphorylation, although this is balanced by dephosphorylation and activation of pyruvate dehydrogenase (PDH) in response to the increased [Ca2+]m. Consistent with this model, while ATP content in patient derived or control fibroblasts was not different, ATP increased significantly in response to CGP-37157 in the patient but not the control cells. In addition, EMRE expression levels were altered in MICU1 patient cells compared to the controls. The MICU1 mutations were associated with mitochondrial fragmentation which we show is related to altered DRP1 phosphorylation. Thus, MICU1 serves as a signal–noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca2+ signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

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Section: Discussionmentioning

confidence: 50%

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Bhosale

Sharpe

Koh

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Previous studies have indicated that iron acquisition by primary hippocampal neurons generates calcium signals mediated by oxidative stimulation of RyR calcium release channels; the ensuing iron-induced calcium signals stimulate phosphorylation and nuclear translocation of extracellular signal-regulated kinases 1/2 (ERK1/2) [ 21 ], and promote significant neuronal mitochondrial fragmentation [ 22 ]. In agreement with these results, iron overload promotes mitochondrial fragmentation in mouse HT-22 hippocampal neurons via calcineurin-sensitive signals [ 23 ] and increases intracellular free calcium concentration, which leads to calcineurin activation via calcium-dependent pathways engaging calmodulin and calpain [ 24 ]. Hence, non-physiological iron-induced calcium signals, which through calcineurin activation promote mitochondrial fragmentation, are a likely factor in iron-induced neurotoxicity.…”

Section: Introductionmentioning

confidence: 59%

Development of an iron-selective antioxidant probe with protective effects on neuronal function

García‐Beltrán¹,

Mena²,

Aguirre³

et al. 2017

PLoS ONE

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Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer’s diseases, Friedreich ataxia and Huntington’s disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

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“…In our present study, we found that LA not only inhibited the activity of calpain1 but also significantly decreased the calcium content of brain tissue in LA-treated mice. Given that the levels of intracellular calcium were increased by iron overload [57] , the mechanism through which LA overcomes Tau hyperphosphorylation might involve multiple factors, and in particular, inhibiting the hyperactivation of calpains.…”

Section: Discussionmentioning

confidence: 99%

α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice

et al. 2018

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Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurofibrillary tangles (NFTs) composed of Tau protein. α-Lipoic acid (LA) has been found to stabilize the cognitive function of AD patients, and animal study findings have confirmed its anti-amyloidogenic properties. However, the underlying mechanisms remain unclear, especially with respect to the ability of LA to control Tau pathology and neuronal damage. Here, we found that LA supplementation effectively inhibited the hyperphosphorylation of Tau at several AD-related sites, accompanied by reduced cognitive decline in P301S Tau transgenic mice. Furthermore, we found that LA not only inhibited the activity of calpain1, which has been associated with tauopathy development and neurodegeneration via modulating the activity of several kinases, but also significantly decreased the calcium content of brain tissue in LA-treated mice. Next, we screened for various modes of neural cell death in the brain tissue of LA-treated mice. We found that caspase-dependent apoptosis was potently inhibited, whereas autophagy did not show significant changes after LA supplementation. Interestingly, Tau-induced iron overload, lipid peroxidation, and inflammation, which are involved in ferroptosis, were significantly blocked by LA administration. These results provide compelling evidence that LA plays a role in inhibiting Tau hyperphosphorylation and neuronal loss, including ferroptosis, through several pathways, suggesting that LA may be a potential therapy for tauopathies.

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Iron overload-induced calcium signals modulate mitochondrial fragmentation in HT-22 hippocampal neuron cells

Cited by 44 publications

References 40 publications

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Development of an iron-selective antioxidant probe with protective effects on neuronal function

α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice

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