Organelle size control systems: From cell geometry to organelle‐directed medicine

Eukaryotic organelles encapsulate defined subsets of cellular biochemical pathways. For example, beta oxidation of fatty acids occurs inside mitochondria while fatty acid chain elongation takes place on the endoplasmic reticulum membrane. Organelle membranes isolate reactions from each other and store intermediates and products, and can thus be viewed as “reaction vessels”, playing roles analogous to the reflux columns and holding tanks of a chemical factory. To develop an effective chemical manufacturing process, it is not enough to focus just on the chemistry, i.e. the reactants and solvents that directly participate in reactions. The size and design of the reaction vessels is of equal importance. Likewise, within a cell, the size of organelles will influence the rates of biochemical pathways contained within them. Organelle surface area can limit the rate of import of substrates and efflux of products, while the volume of the organelle can dictate the quantity of intermediates that can build up (Figure 1). Many key metabolic enzymes are organelle membrane proteins, and in such cases increased surface area could allow larger numbers of molecules into the membrane to increase metabolic flux. Figure 1 Organelles as reaction vessels. Substrate in cytoplasm (Sc) is imported into an organelle through its bounding membrane to provide substrate inside the organelle (So). This organellar substrate is then subjected to several enzymatic steps in the organelle . The influence of organelle size on metabolism is indicated by the fact that in cells specialized for certain pathways, the organelles that contain these pathways are enlarged compared to other cell types. Secretory cells are an obvious example, in which the requirement for a high rate of flux of secreted proteins is met by a massive over proliferation of endoplasmic reticulum and Golgi apparatus. Other examples include enlarged lipid droplets in adipose cells, proliferation of microvilli on the surface of cells lining the intestine, increased surface area and volume of rhodopsin containing vesicles in rods versus cones, and changes in mitochondrial abundance as a function of respiratory state. If, as we hypothesize, organelle size affects metabolism and signaling, then reprogramming of organelle size could be used as a novel strategy for reprogramming cellular state and behavior, with direct applications in medicine and biotechnology. Organelle-directed medicine and biotechnology Cytopathologists diagnose cancer by visual assessment of cell geometry including organelle size. For example, enlarged nuclei in a pap test indicates early stage cervical cancer. Cytopathology texts are full of such examples, but we don’t understand why these changes occur. According to the hypothesis of this review, these changes of cell geometry in cancer arise because cells have adapted to the metabolic alterations that are a hallmark of cancer [1]. Could we attack cancer cells by reprogramming organelle size? We can distinguish two possible reasons for organelle size alteration in cancer cells, which in turn predict two possible ways that organelle targeted therapy could be useful (Figure 2). First, if organelle size is adjusted as a response to pathological alterations in cell metabolism, then if we could reprogram organelle size in a cancer cell using small molecules that target the size control pathway, the cell might die due to a mismatch between organelle size and metabolic state. Alternatively, organelle size alterations might arise from pathological alterations in signaling pathways that impinge on the size control system, and then alterations in cell metabolism or behavior would be a downstream effect of the change to organelle size. In this case, it might be possible to drive the cell back to a less malignant state by driving its organelles towards a more normal size range. Either outcome would be therapeutically useful, but so far this “organelle directed medicine” strategy has not to our knowledge been tested in any cancer model system. Figure 2 Organelle size changes in disease: two strategies for organelle directed medicine. Disease causing mutations (for example, loss of tumor suppressor genes or activation of oncogenes) cause organelle size changes that are observed by the cytopathologist. Reprogramming organelle size would also have applications in metabolic engineering. Increasing the size of organelles that encapsulate key steps of metabolite production, especially those involving toxic intermediates, could greatly enhance metabolite production. For example biodiesel production could be enhanced by targeting genes that control lipid droplet size [2–3] thereby enhancing the ability of the cell to store triglyceride (TG). Before we can implement or test these applications in medicine and biotechnology, we need to obtain mechanistic understanding of how organelle size is regulated.