The mitochondrial respiratory chain is essential for oxidative phosphorylation and comprises multiple complexes, including cytochrome c oxidase, assembled in macromolecular supercomplexes. Little is known about factors that contribute to supercomplex organization. Here we identify COX7RP as a factor that promotes supercomplex assembly. Cox7rp-knockout mice exhibit decreased muscular activity and heat production failure in the cold due to reduced COX activity. In contrast, COX7RP-transgenic mice exhibit increased exercise performance with increased cytochrome c oxidase activity. Two-dimensional blue native electrophoresis reveals that COX7RP is a key molecule that promotes assembly of the III 2 /IV n supercomplex with complex I. Our study identified COX7RP as a protein that functions in I/III 2 /IV n supercomplex assembly and is required for full activity of mitochondrial respiration.

Vitamin K is a fat-soluble vitamin that is necessary for blood coagulation. In addition, it has bone-protective effects. Vitamin K functions as a cofactor of g-glutamyl carboxylase (GGCX), which activates its substrates by carboxylation. These substrates are found throughout the body and examples include hepatic blood coagulation factors. Furthermore, vitamin K functions as a ligand of the nuclear receptor known as steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR). We have previously reported on the bone-protective role of SXR/PXR signaling by demonstrating that systemic Pxr-knockout mice displayed osteopenia. Because systemic Ggcx-knockout mice die shortly after birth from severe hemorrhage, the GGCX-mediated effect of vitamin K on bone metabolism has been difficult to evaluate. In this work, we utilized Ggcx-floxed mice to generate osteoblastspecific GGCX-deficient (Ggcx Dobl/Dobl ) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of Ggcx Dobl/Dobl mice was significantly higher than that of control Col1-Cre (Ggcx +/+ ) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in Ggcx Dobl/Dobl mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in Ggcx Dobl/Dobl mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in Ggcx Dobl/Dobl mice. The mechanical properties of bones from Ggcx Dobl/Dobl mice tended to be stronger than those from control Ggcx +/+ mice. These results suggest that GGCX in osteoblasts functions to prevent abnormal mineralization in bone formation, although this function may not be a prerequisite for the bone-protective effect of vitamin K.

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Low-grade and early-stage endometrial cancer usually has a favorable prognosis, whereas recurrent or metastatic disease is often difficult to cure. Thus, the molecular mechanisms underlying advanced pathophysiology remain to be elucidated. From the perspective of the origin of advanced endometrial cancer, the characterization of cancer stem-like cells (CSCs) will be the first step toward the development of clinical management. We established long-term culturable patient-derived cancer cells (PDCs) from patient endometrial tumors by spheroid cell culture, which is favorable for the enrichment of CSCs. PDC-derived xenograft tumors were generated in immunodeficient NOD/Shi-scid, IL-2RγKO Jic mice. Morphologically, PDCs derived from three distinct patient samples and their xenograft tumors recapitulated the corresponding original patient tumors. Of note, CSC-related genes including ALDH1A1 were upregulated in all of these PDCs, and the therapeutic potentiality of aldehyde dehydrogenase inhibitors was demonstrated. In addition, these PDCs and their patient-derived xenograft (PDX) models exhibited distinct characteristics on the basis of their hormone responsiveness and metastatic features. Interestingly, genes associated with inflammation and tumor immunity were upregulated by 17β-estradiol in PDC lines with high estrogen receptor expression and were also overexpressed in secondary PDCs obtained from metastatic tumor models. These results suggest that PDC and PDX models from endometrial cancer specimens would be useful to elucidate CSC traits and to develop alternative diagnostic and therapeutic options for advanced disease.