MCU (mitochondrial Ca2+ uniporter) makes the calcium go round

Walters, Grant C.; Usachev, Yuriy M.

doi:10.1016/j.jbc.2022.101604

Cited by 6 publications

(4 citation statements)

References 9 publications

(14 reference statements)

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“…In mammals, mitochondrial translation occurs in mitoribosomes, and these ribosomes produce proteins that play a part in oxidative phosphorylation [ 48 , 50 , 51 ]. As previously pointed out, there is a relation between SOCE and calcium regulation in mitochondria [ 52 , 53 , 54 , 55 ]. Our pathway enrichment results also support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

Picón-Pagès

Bosch-Morató

Subirana

et al. 2023

IJMS

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Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1–42. We identified 81 mammalian orthologue genes that enhance Aβ1–42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAβ1–42, whereas SURF4 overexpression induced Aβ1–42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ1–42 neurotoxicity by decreasing SOCE activity.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

Picón-Pagès

Bosch-Morató

Subirana

et al. 2023

IJMS

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“…In their work, Yoast et al, found that MCU deletion led to increased Ca 2+ -dependent inactivation of CRAC channels and reduced Ca 2+ currents through the channels. Yet, the net result was an overall amplification of cytosolic Ca 2+ signaling caused by elimination of mitochondrial Ca 2+ buffering in the absence of MCU ( Yoast et al, 2021 ; Walters and Usachev, 2022 ). Although this effect was documented in non-excitable cell lines, given that CRAC channels and MCU are present in the nervous tissues, it is predicted that a similar mechanism could contribute to the regulation of neuronal excitability ( Walters and Usachev, 2022 ).…”

Section: Mitochondrial Ca 2+ Cycling In Neuronal F...mentioning

confidence: 99%

Mitochondrial calcium cycling in neuronal function and neurodegeneration

Walters

Usachev

2023

Front. Cell Dev. Biol.

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Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.

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“…Meanwhile, mCa 2+ in its physiological state is known to activate three major mitochondrial matrix dehydrogenases, namely, pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), and α-KGDH. The regulation of these three key enzymes by Ca 2+ has a strategic task in coordinating cellular workload and ATP generation [ 180 , 181 , 182 ]. Thus, cancer cells meet their energy demands by the activation of TCA cycle dehydrogenases through increased mCa 2+ uptake [ 183 ].…”

Section: Mitochondrial Metabolism and Mirnamentioning

confidence: 99%

MicroRNAs as Regulators of Cancer Cell Energy Metabolism

Muthukumaran

Velusamy

Mercy

et al. 2022

JPM

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To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.

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MCU (mitochondrial Ca2+ uniporter) makes the calcium go round

Cited by 6 publications

References 9 publications

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

Mitochondrial calcium cycling in neuronal function and neurodegeneration

MicroRNAs as Regulators of Cancer Cell Energy Metabolism

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