The alpha subunit of HIF-1 can be suppressed by two types of oxygen-dependent hydroxylases: PHDs and FIH-1. Depletion of HIF-1α affects ATP production in macrophages under normoxic conditions, indicating that HIF-1α is necessary for macrophages to produce ATP via glycolysis even in the presence of oxygen. Consequently, there must be a mechanism that maintains HIF-1 activity in macrophages in the presence of normal oxygen levels. In this review we introduce Mint3, which activates HIF-1 transcriptional activity in limited cell types, including macrophages, under normoxic conditions. Mint3-deficient mice show no apparent abnormality, but macrophages from these mice have defective ATP production via glycolysis under normal oxygen conditions, similar to those from HIF-1α defi cient mice. Due to the defects in glycolysis and other HIF-1 target gene expression, macrophage hyperactivation is suppressed in Mint3-deficient mice and these mice are also resistant to acute inflammation, such as lipopolysaccharide (LPS)induced endotoxic shock and acute infl uenza pneumonia. Additionally, Mint3 depletion promotes pyroptosis in Listeria monocytogenes-infected macrophages, thereby attenuating Listeria proliferation and listeriosis. In the context of cancer, Mint3 depletion affects glycolysis and VEGFA production in inflammatory monocytes, resulting in reduced metastasis. Administration of naphthofluorescein which inhibits Mint3-mediated HIF-1 activation can also suppress cancer metastasis and LPS-induced septic shock in mice. Thus, Mint3 is an essential regulator of HIF-1 activity in macrophages under normoxic conditions and may be a good target for macrophage-involved cancer and infl ammatory disease treatment. Oxygen availability affects energy production and HIF-1 plays an essential role in adaptation to hypoxic conditions.

In mammalian cells, the plasma membrane is composed of various lipids such as phospholipids, glycolipids, and cholesterol, with most of them being asymmetrically positioned between the lipid bilayer. Typically, phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) are localized in the inner leafl et, while phosphatidylcholine (PtdCho) and sphingomyelin (SM) are enriched in the outer leaflet. ATP11A and ATP11C are phospholipid flippases at the plasma membrane that specifi cally translocate PtdSer and PtdEtn from the outer to the inner leafl et, maintaining their asymmetry. Dysfunction of these fl ippases, such as impairment of the fl ippase activity and alteration of their substrate specifi city, results in improper distribution of phospholipids in the plasma membrane. As a result, mutations in ATP11A and ATP11C genes cause various diseases, such as B-cell lymphopenia, cholestasis, anemia, developmental disorder, hearing loss, and neurological deterioration in mice and humans. These fi ndings indicate that ATP11A and ATP11C are essential for maintaining the lipid organization of the plasma membrane and the homeostasis of mammals.

Breast cancer incidence has increased significantly worldwide, and in Japan, one out of every nine women may experience this disease during their lifetime. Despite recent advances in diagnostic and therapeutic strategies, some patients experience relapse several years after treatment and have a poor prognosis. Therefore, it is essential to develop effective treatment strategies to prevent relapse. Recent evidence suggests that subpopulations of cancer stem cells are highly resistant to chemotherapy and radiotherapy, allowing them to survive after treatment. These cancer stem cells were fi rst discovered in breast cancer in 2003. Scientists around the world have made efforts to elucidate the molecular mechanisms of these cells, and it is now believed that they survive in a “cancer stem cell niche” in the tumor microenvironment, among other cells such as cancer-associated fibroblasts and immune cells, by interacting with multiple cytokines and growth factors. Recent cutting-edge single-cell technologies have allowed for the elucidation of the molecular mechanisms of these therapy-resistant cancer stem cells. These efforts in basic science may pave the way for the development of effective treatment strategies to target these cells and prevent relapse, ultimately leading to a signifi cant improvement in the prognosis of breast cancer patients.