MERCs. The Novel Assistant to Neurotransmission?

Shirokova, Olesya; Pchelin, Pavel; Мухина, И.В.

doi:10.3389/fnins.2020.589319

Cited by 12 publications

(8 citation statements)

References 178 publications

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“…Perturbation of MERCs halts ER-mitochondria Ca 2+ transfer and impairs activity-dependent cytoplasmic Ca 2+ dynamics in neurons 15 . In addition to having multiple contact sites, the ER forms an elaborate network around mitochondria in neuronal processes 66 . MERC distribution and ER topology in dendrites are also implicated in the regulation of mitochondrial dynamics and the formation of a spatially stable mitochondrial pool near active dendritic spines to fuel synaptic plasticity 67 .…”

Section: Discussionmentioning

confidence: 99%

Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

et al. 2021

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Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria (MERCs), which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics.We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.

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Section: Discussionmentioning

confidence: 99%

Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

et al. 2021

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“…Recently, the VAPB and PTPIP51 pair has been found in synapses, and synaptic activity stimulates their interaction, leading to an increase in MERCS [ 47 ]. A recent review was published by Shirokova and colleagues, who extensively describe the role of MERCS in synapses [ 48 ].…”

Section: Mitochondria–er Contact Sites and Mitochondria-associatedmentioning

confidence: 99%

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Leal

Martins

2021

Biomedicines

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The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.

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“…Some of the ER-mitochondrial tethering proteins are Mfn2, VAPB-PTPI51, and PDZ58 [ 86 , 123 ]. ER-MAM in neurons facilitate several processes like mitochondrial fission [ 110 ], calcium signaling, regulation of autophagy [ 192 ], neuronal homeostasis [ 193 ], and have also been speculated to contribute to neurotransmission [ 194 ]. MERCs have been seen to be altered in various neurodegenerative conditions [ 195 ] including Alzheimer’s disease [ 196 ].…”

Section: Er Morphology In Neurons With a Focus On Mature Neuronsmentioning

confidence: 99%

Morphological Heterogeneity of the Endoplasmic Reticulum within Neurons and Its Implications in Neurodegeneration

Sree

Parkkinen

Their

et al. 2021

Cells

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The endoplasmic reticulum (ER) is a multipurpose organelle comprising dynamic structural subdomains, such as ER sheets and tubules, serving to maintain protein, calcium, and lipid homeostasis. In neurons, the single ER is compartmentalized with a careful segregation of the structural subdomains in somatic and neurite (axodendritic) regions. The distribution and arrangement of these ER subdomains varies between different neuronal types. Mutations in ER membrane shaping proteins and morphological changes in the ER are associated with various neurodegenerative diseases implying significance of ER morphology in maintaining neuronal integrity. Specific neurons, such as the highly arborized dopaminergic neurons, are prone to stress and neurodegeneration. Differences in morphology and functionality of ER between the neurons may account for their varied sensitivity to stress and neurodegenerative changes. In this review, we explore the neuronal ER and discuss its distinct morphological attributes and specific functions. We hypothesize that morphological heterogeneity of the ER in neurons is an important factor that accounts for their selective susceptibility to neurodegeneration.

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MERCs. The Novel Assistant to Neurotransmission?

Cited by 12 publications

References 178 publications

Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Morphological Heterogeneity of the Endoplasmic Reticulum within Neurons and Its Implications in Neurodegeneration

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