A research group led by Graduate Student Yojiro Hoshikawa Graduate School of Agricultural and Life Sciences, the University of Tokyo, (Hiroshima University at the time of the research), Graduate Student Natsuho Shirota and Professor Shinichi Nishimura from the Graduate School of Integrated Sciences for Life, Hiroshima University, and Visiting Researcher Hiroshi Tsugawa (Professor, Tokyo University of Agriculture and Technology) from the RIKEN Center for Integrative Medical Sciences announced that they have clarified that when 15-carbon saturated fatty acid (pentadecanoic acid) accumulates in fission yeast, a type of fungi, the shape of the endoplasmic reticulum changes, leading to cell death. Applications to pharmaceuticals and agricultural chemicals for stopping the growth of pathogenic fungi are expected. Their results were published in the May 28 issue of Proceedings of the National Academy of Sciences: PNAS.
Fatty acids are molecules with a hydrocarbon chain and a terminal carboxyl group, with those lacking double or triple bonds called saturated fatty acids and those possessing them called unsaturated fatty acids. They are major components for producing "lipids," one of the three major nutrients. Biological membranes that envelop the cells constituting the body are composed of lipids. It is known that excessive intake of saturated fatty acids causes a phenomenon called lipotoxicity which causes various problems in cells and organs. However, the mechanism behind it was not well understood.
In this study, the research group discovered that pentadecanoic acid, a type of saturated fatty acid with 15 carbons, inhibits the growth of fission yeast during the process of searching for antifungal compounds targeting biological membranes from marine microorganism cultures, and investigated its molecular mechanism. Generally, fatty acids are synthesized from 2-carbon materials and are therefore even-chain, but it was known that odd-chain fatty acids also exist in trace amounts in living organisms.
When pentadecanoic acid was added to cells and observed under a microscope, the structure of the endoplasmic reticulum changed dramatically. The group discovered that the endoplasmic reticulum transformed into a giant sheet structure which they named "giant ER sheets." Further analysis revealed that the formation of giant ER sheets makes cell division control incomplete and that giant ER sheets get caught in the cell division site, preventing cell division.
Investigation of the molecular mechanism of this phenomenon revealed that pentadecanoic acid was excessively incorporated into glycerophospholipids (a group of lipid molecular species) that constitute cell membranes, increasing the proportion of saturated fatty acids.
In mutant strains with modified cellular lipid metabolism, the effects shown by pentadecanoic acid were also observed with the addition of commonly found even-carbon saturated fatty acids. Furthermore, this effect was also confirmed with the addition of common even-carbon saturated fatty acids.
From these findings, it became clear that when lipotoxicity is induced in fission yeast, giant ER sheets are formed, which then inhibits cell division. The reason pentadecanoic acid more strongly induces lipotoxicity is believed to be because it is less susceptible to metabolic conversion within fission yeast. The formation and disappearance of giant ER sheets is expected to become an analytical approach for elucidating organelle function.
Nishimura commented: "In the process of searching for therapeutic drug candidates for fungal infections, we found that a substance called pentadecanoic acid suppresses the growth of fission yeast, and as a result, we were able to clarify that an unusual structure called giant ER sheets inhibits cell proliferation. However, at the beginning of our research, we never imagined that such a simple fatty acid as pentadecanoic acid would have such unique effects. Since it is a very common substance, we would be pleased if cell biology using this substance develops worldwide (although this would increase our competitors). At the same time, we would like to explore the potential of pentadecanoic acid as a therapeutic agent."
Journal Information
Publication: PNAS
Title: Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast
DOI: /10.1073/pnas.2422126122
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