Phospholipids are the core building blocks of most cellular membranes, without which cells themselves would not exist. The plasma membrane defines the outer-most boundary for the chemistry of life and the inner membrane systems or organelles provide an organisational framework to compartmentalise the chemical reactions that we know as cellular metabolism. And it is the combination of these activities, membrane biogenesis and energy metabolism, that enable cells to grow and multiply. It seems rather obvious then, that cells need to co-ordinate membrane biogenesis with basic metabolism to ensure successful replication and the passing-on of their genes. This is especially true for single-celled organisms that are, by nature, at the mercy of the elements and must respond to environmental changes quickly and efficiently, but is also tremendously important during embryo-genesis in metazoans, in which a single cell gives rise to a complex multicellular organism.
How then do cells co-ordinate membrane production with metabolism? To begin to answer this question we will turn to a simple model eukaryotic cell, the budding yeast Saccharomyces cerevisiae
. Yeast, because it is single-celled, has evolved elaborate and dynamic ways to control membrane synthesis in response to its environment. In the past three decades, tremendous progress has been made in defining the fundamental metabolic pathways that contribute to phospholipid synthesis and turnover as well as defining many of the regulatory mechanisms. Much of this foundation has arisen from genetic and biochemical characterisation of yeast mutants from a small group of key labs (for extensive reviews see [1
]). Their work has paved the way for recent studies that, in large part through the use of new cell and systems biology approaches, are uncovering surprising links between membrane biogenesis and the cell cycle.
This article will discuss the pivotal role for the lipid phosphatidic acid as a signaling hub for the integration of metabolic signals with membrane biogenesis. But why phosphatidic acid? The reason is that phosphatidic acid is a key metabolic precursor in the synthesis of both phospholipids (which make up membranes) and neutral lipids (such as triacylglycerol that is stored in cytoplasmic lipid droplets) and therefore sits at the crossroads between membrane biogenesis and lipid storage (see ). What better a lipid to sense the levels of then? We will discuss the effects of key nutrients - inositol, zinc and glucose - on regulation of lipid metabolism, emphasising how these affect the signaling activity of phosphatidic acid to couple membrane biogenesis to metabolism.
Coupling membrane biogenesis to metabolism and the cell cycle