Mitochondrial calcium uniporter complex modulation in cancerogenesis

Marchi, Saverio; Vitto, Veronica Angela Maria; Danese, Alberto; Wieckowski, Mariusz R.; Giorgi, Carlotta; Pinton, Paolo

doi:10.1080/15384101.2019.1612698

Cited by 38 publications

(32 citation statements)

References 118 publications

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“…Previous studies on the mitochondrial Ca 2+ uniporter (MCU) complex indicated that the level of mtCa 2+ is an important determinant in the progression of different cancer types ( Marchi et al, 2019a ; Marchi et al, 2013 ; Marchi et al, 2019b ; Tosatto et al, 2016 ). The downregulation of MCU and subsequent reduction of mtCa 2+ uptake correlated with resistance to apoptosis of colorectal cancer cell lines ( Marchi et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Pathak

Guéguinou

Walter

et al. 2020

eLife

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Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Pathak

Guéguinou

Walter

et al. 2020

eLife

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“…However, the few studies that have directly assessed the intrinsic role of mitochondrial Ca 2+ in the regulation of the cancer cell energetic status have depicted a complex scenario that mainly involves aberrant expression or function of the mitochondrial calcium uniporter (MCU) complex [59] ( Fig. 4 ).…”

Section: Mitochondria-dependent Regulation Of Malignant Energetic Stamentioning

confidence: 99%

Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours

et al. 2020

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Mitochondria are dynamic organelles that have essential metabolic activity and are regarded as signalling hubs with biosynthetic, bioenergetics and signalling functions that orchestrate key biological pathways. However, mitochondria can influence all processes linked to oncogenesis, starting from malignant transformation to metastatic dissemination. In this review, we describe how alterations in the mitochondrial metabolic status contribute to the acquisition of typical malignant traits, discussing the most recent discoveries and the many unanswered questions. We also highlight that expanding our understanding of mitochondrial regulation and function mechanisms in the context of cancer cell metabolism could be an important task in biomedical research, thus offering the possibility of targeting mitochondria for the treatment of cancer.

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“…Mitochondrial calcium homeostasis is essential for cell survival and metabolic regulation [60,61]. Therefore, mitochondria play a dual role in death and survival, and dysregulation of mitochondrial Ca 2+ -homeostasis is associated with various diseases including cancer [62]. Importantly, mitochondrial calcium uniporter (MCU) is the channel enabling accumulation of Ca 2+ in the matrix [62].…”

Section: [Ca2+]i -Signaling In Cell Proliferation and Apoptosismentioning

confidence: 99%

“…Therefore, mitochondria play a dual role in death and survival, and dysregulation of mitochondrial Ca 2+ -homeostasis is associated with various diseases including cancer [62]. Importantly, mitochondrial calcium uniporter (MCU) is the channel enabling accumulation of Ca 2+ in the matrix [62]. Aberrant expression or functioning of MCU complex contributes to cancer [62].…”

Section: [Ca2+]i -Signaling In Cell Proliferation and Apoptosismentioning

confidence: 99%

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

Varghese

Samuel

Sadiq

et al. 2019

IJMS

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Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis.

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Mitochondrial calcium uniporter complex modulation in cancerogenesis

Cited by 38 publications

References 118 publications

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

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