Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Paolo Pinton, Jan 10, 2014
    • "The Ca 2+ uptake by the mitochondria determines cell susceptibility to apoptotic stimuli. For example, reduced ER Ca 2+ flux toward mitochondria results in resistance to apoptosis (Pinton et al., 2011; Marchi et al., 2012, 2013; Bononi et al., 2013; Giorgi et al., 2015; Patergnani et al., 2015), inhibiting the mitochondrial Ca 2+ overload required for permeability transition pore opening (Bonora et al., 2013a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Bcl-2 (B-cell lymphoma-2) family proteins are critical regulators of apoptosis and consist of both pro- and anti-apoptotic factors. Within this family, the myeloid cell leukemia factor 1 (Mcl-1) protein exists in two forms as the result of alternative splicing. The long variant (Mcl-1L) acts as an anti-apoptotic factor, whereas the short isoform (Mcl-1S) displays pro-apoptotic activity. In this study, using splice-switching antisense oligonucleotides (ASOs), we increased the synthesis of Mcl-1S, which induced a concurrent reduction of Mcl-1L, thus resulting in the increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial calcium (Ca2+) accumulation. The high Mcl-1S/L ratio was correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a Dynamin-related protein (Drp1)-dependent manner. Our data indicate that the balance between the long and short variants of the Mcl-1 gene represents a key aspect of the regulation of mitochondrial physiology. Moreover, we propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery.
    No preview · Article · Oct 2015 · Molecular biology of the cell
  • Source
    • "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). "

    Full-text · Dataset · Jan 2014
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2013 · The Journal of Physiology
Show more