Elevated intracellular calcium causes distinct mitochondrial remodelling and calcineurin-dependent fission in astrocytes

Tan, Andrew R.; Cai, Andrew Yi; Deheshi, Samineh; Rintoul, Gordon L.

doi:10.1016/j.ceca.2010.12.002

Cited by 30 publications

(31 citation statements)

References 32 publications

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“…Loss of the yeast homolog of mammalian Miro1, Gem1p, causes aberrant mitochondrial distribution and morphology (Frederick et al, 2004). Interestingly, cytosolic Ca 2+ -mediated mitochondrial length reduction has been proposed to be Drp1-independent mechanism (Tan et al, 2011). Although these findings support the view of mitochondria as dynamic in nature, the molecular mechanisms that mediate phenotypic changes during pathophysiological conditions remain unknown.…”

Section: Introductionmentioning

confidence: 99%

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

et al. 2018

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SUMMARY Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dys-regulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST.

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Section: Introductionmentioning

confidence: 99%

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

et al. 2018

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“…More recent reports have attributed calcium-dependent changes in mitochondrial morphological shape to processes may be independent of Drp1-mediated mitochondrial fission (187, 188). In cortical astrocytes, treatment with a calcium ionophore, 4Br-A23187, increases intracellular calcium levels and leads to a decrease in mitochondrial length (187).…”

Section: Calcium Regulates Mitochondrial Morphology and Intracellumentioning

confidence: 99%

“…In cortical astrocytes, treatment with a calcium ionophore, 4Br-A23187, increases intracellular calcium levels and leads to a decrease in mitochondrial length (187). Yet, calcineurin inhibitors, CsA and FK506, did not inhibit 4Br-32187-mediated reduction in mitochondrial length (187), indicating a calcineurin-independent mechanism.…”

Section: Calcium Regulates Mitochondrial Morphology and Intracellumentioning

confidence: 99%

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

2016

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Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca2+ transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases.

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“…Importantly, the intracellular environment can have an impact on mitochondrial morphology. Indeed, Tan et al [73] showed that pharmacological Ca 2 + elevations in cultured astrocytes resulted in remodelling or rounding of mitochondria. Similarly, in neurons, influx of Ca 2 + resulting from glutamate treatment also altered mitochondrial morphology [78].…”

Section: Mitochondrial Morphology In Astrocytesmentioning

confidence: 99%

“…Here, mitochondria could be important for local Ca 2 + buffering. Tan et al [73] have shown that with pharmacological elevations of intracellular Ca 2 + , released from internal stores, using 4Br-A23187 in primary cortical astrocytes, mitochondria became shorter with a reduction in motility. Furthermore, Jackson et al [42] revealed that pharmacological inhibition of the NCX increased the percentage of mobile mitochondria in organotypic slice astrocytes.…”

Section: Mitochondrial Trafficking In Astrocytic Processesmentioning

confidence: 99%

Mitochondrial dynamics in astrocytes

Stephen

Gupta‐Agarwal

Kittler

2014

Biochemical Society Transactions

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Astrocytes exhibit cellular excitability through variations in their intracellular calcium (Ca 2 + ) levels in response to synaptic activity. Astrocyte Ca 2 + elevations can trigger the release of neuroactive substances that can modulate synaptic transmission and plasticity, hence promoting bidirectional communication with neurons. Intracellular Ca 2 + dynamics can be regulated by several proteins located in the plasma membrane, within the cytosol and by intracellular organelles such as mitochondria. Spatial dynamics and strategic positioning of mitochondria are important for matching local energy provision and Ca 2 + buffering requirements to the demands of neuronal signalling. Although relatively unresolved in astrocytes, further understanding the role of mitochondria in astrocytes may reveal more about the complex bidirectional relationship between astrocytes and neurons in health and disease. In the present review, we discuss some recent insights regarding mitochondrial function, transport and turnover in astrocytes and highlight some important questions that remain to be answered.

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Elevated intracellular calcium causes distinct mitochondrial remodelling and calcineurin-dependent fission in astrocytes

Cited by 30 publications

References 32 publications

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

Mitochondrial dynamics in astrocytes

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