MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development
Résumé
The mitochondrial Ca 2+ uniporter (MCU) plays crucial role in intramitochondrial Ca 2+ uptake, allowing Ca 2+ -dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and invasion using in vitro and in vivo models of human colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca 2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming.
Mots clés
ADP, adenosine diphosphate BN-PAGE, blue native polyacrylamide gel electrophoresis BSA, bovine serum albumin CRC, colorectal cancer CS, citrate synthase DEA, differential expression analysis DMEM, Dulbecco's Modified Eagle Medium ER, endoplasmic reticulum FBS, fetal bovine serum GSEA, gene set enrichment analysis IMM, inner mitochondrial membrane KO, knockout LDH, lactate dehydrogenase LPA, lysophosphatidic acid MCU, mitochondrial calcium uniporter OCR, oxygen consumption rate PBS, phosphate-buffered saline PCR, polymerase chain reaction PSS, physiological saline solution ROS, reactive oxygen species SOCE, store-operated calcium entry TCA, tricarboxylic acid VDAC, voltage-dependent anionselective channel
ADP, adenosine diphosphate
BN-PAGE, blue native polyacrylamide gel electrophoresis
BSA, bovine serum albumin
CRC, colorectal cancer
CS, citrate synthase
DEA, differential expression analysis
DMEM, Dulbecco's Modified Eagle Medium
ER, endoplasmic reticulum
FBS, fetal bovine serum
GSEA, gene set enrichment analysis
IMM, inner mitochondrial membrane
KO, knockout
LDH, lactate dehydrogenase
LPA, lysophosphatidic acid
MCU, mitochondrial calcium uniporter
OCR, oxygen consumption rate
PBS, phosphate-buffered saline
PCR, polymerase chain reaction
PSS, physiological saline solution
ROS, reactive oxygen species
SOCE, store-operated calcium entry
TCA, tricarboxylic acid
VDAC, voltage-dependent anionselective channel
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