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Molecular and Cellular Biochemistry

  • KUGE Osamu, Professor
  • OGISHIMA Tadashi, Associate Professor
  • TANI Motohiro, Associate Professor
  • MIYATA Non, Assistant Professor
Our group conducts basic research examining the molecular and cell biology of lipids related to the problems of membrane and organelle biogenesis and intra- and inter-cellular signalings in eukaryotic cells. Other areas of investigation include physiological roles of local steroid hormones synthesized in the pancreas. We are currently working on (1) the mechanisms of interorganelle and intramitochondria transport of phospholipids, (2) the biological roles of complex sphingolipids, and (3) effects of nonsystemic or local steroids on the survival of ER-stressed pancreatic cells.

1. The Mechanisms of Interorganelle and Intramitochondria Transport of Phospholipids

Phospholipid bilayers provide the basic structure of all biological membranes that play many essential roles in the maintenance of cell life and functions. However, in studies on the biogenesis of the phospholipid bilayer, there are two fundamental questions unresolved. One is what mechanisms regulate the composition and total content of phospholipids in biological membranes. Another question is how phospholipids move between two biological membranes and different monolayers of lipid bilayers. Because phospholipid synthesis occurs in limited organelles, such as the endoplasmic reticulum (ER) and mitochondria, many biological membranes are incapable of producing their own phospholipids. Therefore, the intracellular transport of phospholipids from the sites of synthesis to their final location is an essential event in the biogenesis of functional biological membranes. Several mechanisms have been proposed for phospholipid transport, including ones involving soluble carrier proteins, transport vesicles, and contact zones between donor and acceptor membranes. However, the importance of the proposed mechanisms for membrane biogenesis remains unclear, and phospholipid transport processes are poorly understood.

Mitochondria are double membrane-bound organelles with a distinctive phospholipid composition rich in cardiolipin (CL) and phosphatidylethanolamine (PE). The mitochondrial inner membrane (MIM) of the yeast Saccharomyces cerevisiae contain a set of enzymes required for CL and PE biosynthesis; however, since phosphatidic acid (PA) and phosphatidylserine (PS), which are the starting material for CL biosynthesis and a precursor of PE, respectively, are synthesized in the ER, PA and PS should be transported from the ER to the MIM to synthesize CL and PE in mitochondria. Accordingly, phospholipid traffic between the ER and MIM across the mitochondrial outer membrane is a crucial process for phospholipid homeostasis. However, the molecular mechanisms of this traffic remain to be elucidated. To address this issue, we are making the genetic and biochemical study of phospholipid in the yeast S. cerevisiae.

Major phospholipid biosynthetic phathways in yeast.
Possible pathway of transport of phospholipids to the mitochondrial inner membrane.

2. The biological roles of complex sphingolipids

Complex sphingolipids had long been thought to function exclusively as one of the structural constituents of eukaryotic plasma membranes; however, in the past two decades research into the complex sphingolipids has progressed along two areas. First, complex sphingolipids dynamically cluster with sterols to form lipid microdomains, which function as platforms for effective signal transduction and localization of membrane proteins. Second, the metabolites of complex sphingolipids, such as ceramide, have emerged as a new class of lipid mediators that regulate various signal transduction systems. In mammals, the number of molecular species of complex sphingolipid is over thousands, and this structural diversity is thought to attribute to the multiple biological functions of complex sphingolipids. The structural diversity of complex sphingolipid in the yeast Saccharomcyes cerevisiae is relatively simple as compared with that in mammalian cells, making yeast a useful model for investigating the physiological significance of the structural complexity of sphingolipid. The aim of our research is to understand the relationship between structural diversity and multifunctional role of complex sphingolipids in the yeast Saccharomyces cerevisiae. Current projects include: 1) physiological function of specific complex sphingolipid (MIPC) in various stress responses, 2) physiological significance and mechanism of regulation of complex sphingolipid composition, 3) molecular mechanism of ceramide-mediated signal transduction systems.

3. Nonsystemic or local steroidogensis in pancreatic β-cells

In succession to our recent discovery of cytochrome P45017α,lyase in pancreatic β-cells, we detected expression of mRNAs of almost all species of steroidogenic cytochrome P450s therein. Thus, numerous species of steroids including progestogens, glucocorticoids and estrogens in addition to androgens are producible in β-cells, and they are believed to affect only the steroidgenic cells themselves or the peripheral cells as autocrine and paracrine. To elucidate roles of the pancreatic nonsystemic steroids, we treated rat β-cell-derived INS-1 cells with thapsigargin, which dames β-cells though ER-stress leading to type-2 diabetes, and found that the cells could resist the stress by producing steroids.