IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer

Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP3 receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type 2 IP3R is the most effective in delivering calcium to the mitochondria. Thus, these studies reveal a non-canonical, structural role for the IP3Rs and direct attention towards the type 2 IP3R that was previously neglected in the context of ER-mitochondrial calcium signaling

Initial Results from the Nobeyama Molecular Gas Observations of Distant Bright Galaxies

We present initial results from the CO survey toward high redshift galaxies using the Nobeyama 45m telescope. Using the new wide bandwidth spectrometer equipped with a two-beam SIS receiver, we have robust new detections of three high redshift (z=1.6-3.4) submillimeter galaxies (SXDF 1100.001, SDP9, and SDP17), one tentative detection (SDSS J160705+533558), and one non-detection (COSMOS-AzTEC1). The galaxies observed during the commissioning phase are sources with known spectroscopic redshifts from previous optical or from wide-band submm spectroscopy. The derived molecular gas mass and line widths from Gaussian fits are ~10^11 Msun and 430-530 km/s, which are consistent with previous CO observations of distant submm galaxies and quasars. The spectrometer that allows a maximum of 32 GHz instantaneous bandwidth will provide new science capabilities at the Nobeyama 45m telescope, allowing us to determine redshifts of bright submm selected galaxies without any prior redshift information.Comment: 4 pages, 1 figure, PASJ Letter Accepte

Metabolic adaptation to the chronic loss of Ca 2+ signaling induced by KO of IP 3 receptors or the mitochondrial Ca 2+ uniporter

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP3R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely because of adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress