Exposure of pancreatic β cells to long-chain saturated fatty acids (SFA) induces a so-called endoplasmic reticulum (ER) stress that can ultimately lead to cell death. This process is believed to participate in insulin deficiency associated with type 2 diabetes, via a decrease in β-cell mass. By contrast, some unsaturated fatty acid species appear less toxic to the cells and can even alleviate SFA-induced ER stress. In the present study, we took advantage of a simple yeast-based model, which brings together most of the trademarks of lipotoxicity in human cells, to screen fatty acids of various structures for their capacity to counter ER stress. Here we demonstrate that the tendency of a free fatty acid (FFA) to reduce SFA toxicity depends on a complex conjunction of parameters, including chain length, level of unsaturation, position of the double bonds and nature of the isomers (cis or trans). Interestingly, potent FFA act as building blocks for phospholipid synthesis and help to restore an optimal membrane organization, compatible with ER function and normal protein trafficking.

Saturated fatty acids (SFA) have been reported to alter organelle integrity and function in many cell types, including muscle and pancreatic β-cells, adipocytes, hepatocytes and cardiomyocytes. SFA accumulation results in increased amounts of ceramides/sphingolipids and saturated phospholipids (PL). In this study, using a yeast-based model that recapitulates most of the trademarks of SFA-induced lipotoxicity in mammalian cells, we demonstrate that these lipid species act at different levels of the secretory pathway. Ceramides mostly appear to modulate the induction of the unfolded protein response and the transcription of nutrient transporters destined to the cell surface. On the other hand, saturated PL, by altering membrane properties, directly impact vesicular budding at later steps in the secretory pathway, i.e. at the trans-Golgi Network level. They appear to do so by increasing lipid order within intracellular membranes which, in turn, alters the recruitment of loose lipid packing-sensing proteins, required for optimal budding, to nascent vesicles. We propose that this latter general mechanism could account for the well-documented deleterious impacts of fatty acids on the last steps of the secretory pathway in several cell types.

The mechanisms of microalgal senescence may play an important role in nutrient recycling and enhanced survival. However, the aging physiology of microalgae is an understudied phenomenon. To investigate the patterns of conditional senescence in Chlamydomonas reinhardtii P. A. Dangeard, we used a cell wall-less strain, transformed with a reporter gene to infer changes in photosynthetic gene expression. We examined plastid ultrastructure, photosynthetic function, and photoprotective mechanisms during aging in batch cultures. LHCII transcription levels decreased before the population entered stationary phase, and the characteristic transcriptional light-shift response was lost. A decline in photosynthetic proteins with a concomitant increase in the photoprotective protein, LHCSR, was observed over time. However, nonphotochemical quenching remained stable during growth and stationary phase, and then declined as alternative quenching mechanisms were up-regulated. Photosynthetic efficiency declined, while Fv/Fm remained stable until the death phases. As the culture progressed through stationary phase, disorganization of the chloroplast was observed along with an increase in cytoplasmic oil bodies. We also observed a partial recovery of function and proteins during the final death phase, and attribute this to the release of nutrients into the medium from cell lysis and/or active secretion while cells were senescing. Allowing open gas exchange resulted in high levels of sustained starch production and maintained maximum cell density, prolonging the stationary phase.