Dynamic lipidomics of the nucleus

Abstract

Once nuclear envelope membranes have been removed from isolated nuclei, around 6% of mammalian cell phospholipid is retained within the nuclear matrix, which calculations suggest may occupy 10% of the volume of this subcellular compartment. It is now acknowledged that endonuclear phospholipid, largely ignored for the past 40 years, provides substrate for lipid-mediated signaling events. However, given its abundance, it likely also has other as yet incompletely defined roles. Endonuclear phosphatidylcholine is the predominant phospholipid comprising distinct and highly saturated molecular species compared with that of the whole cell. Moreover, this unusual composition is subject to tight homeostatic maintenance even under conditions of extreme dietary manipulation, presumably reflecting a functional requirement for highly saturated endonuclear phosphatidylcholine. Recent application of new lipidomic technologies exploiting tandem electrospray ionization mass spectrometry in conjunction with deuterium stable isotope labeling have permitted us to probe not just molecular species compositions but endonuclear phospholipid acquisition and turnover with unparalleled sensitivity and specificity. What emerges is a picture of a dynamic pool of endonuclear phospholipid subject to autonomous regulation with respect to bulk cellular phospholipid metabolism. Compartmental biosynthesis de novo of endonuclear phosphatidylcholine contrasts with import of phosphatidylinositol synthesized elsewhere. However, irrespective of the precise temporal-spatial-dynamic relationships underpinning phospholipid acquisition, derangement of endonuclear lipid-mediated signaling from these parental phospholipids halts cell growth and division indicating a pivotal control point. This in turn defines the manipulation of compartmentalized endonuclear phospholipid acquisition and metabolism as intriguing potential targets for the development of future antiproliferative strategies.