The mitochondrial calcium uniporter regulates breast cancer progression via HIF ‐1α

Abstract

Triple‐negative breast cancer (TNBC) represents the most aggressive breast tumor subtype. However, the molecular determinants responsible for the metastatic TNBC phenotype are only partially understood. We here show that expression of the mitochondrial calcium uniporter (MCU), the selective channel responsible for mitochondrial Ca2+ uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca2+ uptake might be instrumental for tumor growth and metastatic formation. Accordingly, MCU downregulation hampered cell motility and invasiveness and reduced tumor growth, lymph node infiltration, and lung metastasis in TNBC xenografts. In MCU‐silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia‐inducible factor‐1α (HIF‐1α) is reduced, suggesting a signaling role for mROS and HIF‐1α, downstream of mitochondrial Ca2+. Finally, in breast cancer mRNA samples, a positive correlation of MCU expression with HIF‐1α signaling route is present. Our results indicate that MCU plays a central role in TNBC growth and metastasis formation and suggest that mitochondrial Ca2+ uptake is a potential novel therapeutic target for clinical intervention.

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

“…The following plasmids were used and are described elsewhere: 2mtGCaMP6m 29,61, 4mtGCaMP6f 62, mtAeq 63, MICU1-HA 29, MICU1-Flag 29, MICU2-Flag 29, MICU1 C465A -HA 29, MCU-Flag 15, GCaMP6f, a kind gift from Douglas Kim (Addgene plasmid # 40755) and R-GECO1, a kind gift from Robert Campbell (Addgene plasmid # 32444)64. The MICU3-myc chimera was produced by gene synthesis (ThermoFisher Scientific) using the coding sequence derived from NM_030110, and cloned into pcDNA3.1.…”

Mitochondrial Ca2+ uptake controls actin cytoskeleton dynamics during cell migration

“…Subsequent studies on MCU and MICU1 in mammalian cells showed an evolutionarily conserved contribution of the mitochondrial Ca 2+ uptake machinery in cell migration. Indeed, in endothelial36 or breast37 and cervical cancer38 cells, alteration of the mitochondrial Ca 2+ uptake led to similar defects in migration abilities. Finally, computed data from clinical studies suggested that mcu -overexpression and micu1 -under expression were associated with poor prognosis for breast cancer patients3839.…”

RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2+ Uptake and Promotes Colorectal Oncogenesis

“…However, there is no direct evidence associating MCU downregulation with carcinogenesis. On the contrary, studies have shown that expression of MCU correlates positively with tumor size and lymph node infiltration in triple-negative breast cancer, demonstrating that mitochondrial Ca 2þ uptake is important for tumor growth and metastasis (44). Other experiments demonstrated that MCU is important for survival and migration of breast carcinoma cells (25,27).…”