MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development

Alison Robert; David Crottès; Jérôme Bourgeais; Naig Gueguen; Arnaud Chevrollier; Jean-François Dumas; Stéphane Servais; Isabelle Domingo; Stéphanie Chadet; Julien Sobilo; Olivier Hérault; Thierry Lecomte; Christophe Vandier; William Raoul; Maxime Guéguinou

doi:10.1371/journal.pbio.3002854

MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development

PLoS Biol. 2024 Oct 28;22(10):e3002854. doi: 10.1371/journal.pbio.3002854. eCollection 2024 Oct.

Authors

Affiliations

¹ UMR Inserm 1069 N2COx « Niche, Nutrition, Cancer et métabolisme Oxydatif », Tours University, Tours, France.
² CNRS UMR 6015, Inserm U1083 MITOVASC, MitoLab team, Angers University, Angers, France.
³ PHENOMIN-TAAM-CNRS UPS44, Orléans, France.

Abstract

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-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 Ca2+ 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.

Copyright: © 2024 Robert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Animals
Calcium / metabolism
Calcium Channels
Calcium-Binding Proteins* / genetics
Calcium-Binding Proteins* / metabolism
Cation Transport Proteins* / genetics
Cation Transport Proteins* / metabolism
Cell Line, Tumor
Cell Proliferation* / genetics
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Female
Gene Expression Regulation, Neoplastic
Glycolysis / genetics
Humans
Metabolic Reprogramming
Mice
Mitochondria* / metabolism
Mitochondrial Membrane Transport Proteins* / genetics
Mitochondrial Membrane Transport Proteins* / metabolism
Neoplasm Invasiveness
Oxidative Phosphorylation
Up-Regulation*

Substances

Calcium-Binding Proteins
Mitochondrial Membrane Transport Proteins
Cation Transport Proteins
MICU2 protein, human
MICU1 protein, human
Calcium
Calcium Channels

Grants and funding

This project was supported by French departmental committees of Ligue Contre le Cancer "Grand-Ouest": 16 (Charente), 37 (Indre-et-Loire), 49 (Maine-et-Loire), 72 (Sarthe) and 85 (Vendée) (to MG and WR), Inserm (to MG), Fondation ARC (to MG), Labex MabImprove (ANR-10-LABX-53-01) (to MG), INCa (INCa-PLBIO 18-151 and 18-145) (to MG, CV and WR), Université de Tours and Région Centre-Val de Loire APR-IA CAMITHERAPAL (to MG). AR received salary from INSERM / Région Centre Val-de-Loire (3 year doctoral grant). DC received one-year salary from Le Studium Loire Valley Institute for Advanced Studies (Smart Loire Valley Fellowship). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.