ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Wilson, Emily; Metzakopian, Emmanouil

doi:10.1038/s41418-020-00705-8

Cited by 80 publications

(76 citation statements)

References 133 publications

(176 reference statements)

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“…In mammalian cells, multiple tethering molecules have been suggested to act at contact sites between the ER and mitochondria [82]. For example, a single recent split proximity labeling approach proposed that 30 proteins are enriched in ER mitochondrial contact zones [83], but the individual functions of these factors still need to be elucidated; however, there is no doubt that these contacts are highly important for cellular functionality [84,85]. Thus, the ER and mitochondria form entangled intracellular networks that are connected by several specific tethering complexes.…”

Section: Contact Sites Of the Er And Mitochondriamentioning

confidence: 99%

“…tact zones [83], but the individual functions of these factors still need to be elucidated; however, there is no doubt that these contacts are highly important for cellular functionality [84,85]. Thus, the ER and mitochondria form entangled intracellular networks that are connected by several specific tethering complexes.…”

Section: Destructive Targeting Via Erad and Madmentioning

confidence: 99%

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ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Koch

Schuldiner

Herrmann

2021

IJMS

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Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins.

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Section: Contact Sites Of the Er And Mitochondriamentioning

confidence: 99%

Section: Destructive Targeting Via Erad and Madmentioning

confidence: 99%

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Koch

Schuldiner

Herrmann

2021

IJMS

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“…Over the last two decades, specialized structures called mitochondria-ER contact sites (MERCS) have been identified as critical regulators of cellular homeostasis by controlling tethering dynamics and Ca 2+ transfer between the two organelles [ 4 , 9 ]. Under physiological conditions, regulated Ca 2+ transfer from ER to mitochondria promotes oxidative phosphorylation (OXPHOS) and sustains mitochondrial bioenergetics by stimulating the synthesis of ATP [ 10 , 11 ]. Under pathological conditions, however, abnormal mitochondrial calcium overload induces the opening of the mitochondrial permeability transition pore (mPTP), a mitochondria-regulated cell death pathway [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact

Liu

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.

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“…Accumulating evidence indicates that ER-Mito dysfunction contributes to a variety of neurodegenerative diseases (4, 44). In Parkinson’s disease models, β2-AR agonists have been documented to be beneficial (45).…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled receptor signaling regulates ER-mitochondria contacts

Lim

Cho

Rennke

et al. 2020

Preprint

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Endoplasmic reticulum-mitochondrial (ER-Mito) contacts are crucial for many cellular functions. Their dysregulation has been implicated in many disorders including neurodegenerative, cardiovascular and metabolic diseases, and cancer. However, little is known about the regulatory pathways of ER-Mito contacts. To uncover such pathways, we screened a drug library for the ER-Mito contact modulators using a split-luciferase reassembly assay. We identified multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (b-ARs) in particular, in our screen. Using multiple independent assays, we validated that these drugs enhance the physical and functional interactions between ER and mitochondria. Our data provide evidence that cytoplasmic calcium plays a role in drug-induced ER-Mito coupling.Together our study identifies GPCR activation as a novel regulatory mechanism of ER-Mito contacts and highlights the role of these contacts in responding to physiological demands or stresses. Furthermore, our findings reveal a new mechanism of action for b-AR agonists in multiple diseases.

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ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Cited by 80 publications

References 133 publications

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact

G protein-coupled receptor signaling regulates ER-mitochondria contacts

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