Downregulation of the Mitochondrial Calcium Uniporter by Cancer-Related miR-25

Section of General Pathology, Department of Morphology, Surgery and Experimental Medicine, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
Current biology: CB (Impact Factor: 9.57). 12/2012; 23(1). DOI: 10.1016/j.cub.2012.11.026
Source: PubMed


The recently discovered mitochondrial calcium uniporter (MCU) promotes Ca(2+) accumulation into the mitochondrial matrix [1, 2]. We identified in silico miR-25 as a cancer-related MCU-targeting microRNA family and demonstrate that its overexpression in HeLa cells drastically reduces MCU levels and mitochondrial Ca(2+) uptake, while leaving other mitochondrial parameters and cytosolic Ca(2+) signals unaffected. In human colon cancers and cancer-derived cells, miR-25 is overexpressed and MCU accordingly silenced. miR-25-dependent reduction of mitochondrial Ca(2+) uptake correlates with resistance to apoptotic challenges and can be reversed by anti-miR-25 overexpression. Overall, the data demonstrate that microRNA targeting of mitochondrial Ca(2+) signaling favors cancer cell survival, thus providing mechanistic insight into the role of mitochondria in tumorigenesis and identifying a novel therapeutic target in neoplasia.

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Available from: Paolo Pinton, Jan 10, 2014
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    • "The cancer-related miRNA miR-25 is up-regulated in various human cancers, including prostate and colon carcinomas. Indeed, colon adenocarcinoma samples with high miR-25 levels display low MCU expression (Marchi et al. 2013). "
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    • "The cancer-related miRNA miR-25 is up-regulated in various human cancers, including prostate and colon carcinomas. Indeed, colon adenocarcinoma samples with high miR-25 levels display low MCU expression (Marchi et al. 2013). "
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    ABSTRACT: Although it has long been known that mitochondria take up Ca(2+), the molecular identities of the channels and transporters involved in this process were revealed only recently. Here, we discuss the recent work that has led to the characterization of the mitochondrial calcium uniporter complex, which includes the channel-forming subunit MCU (mitochondrial calcium uniporter) and its regulators MICU1, MICU2, MCUb, EMRE, MCUR1 and miR-25. We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca(2+) uptake but also their implications in different physiopathological contexts.
    The Journal of Physiology 12/2013; 592(5). DOI:10.1113/jphysiol.2013.268235 · 5.04 Impact Factor
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    • "The correlation between low mtDNA copy number and how that may benefit cancer cell survival remains to be elucidated. More recent research into mitochondria in cancer cells has identified other variations in mitochondrial function, such as the inhibition of mitochondrial calcium uptake to promote cancer cell survival [102]. Recently it was reported that mitochondrial miRNAs may also play a role in modulating mitochondrial function and energetic in cancer situations, in which miRNA regulation is altered [103,104]. "
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