Lipotoxicty in yeast: a focus on plasma membrane signalling and membrane contact sites

Abstract

Lipotoxicity is a pathophysiological process triggered by lipid overload. In metazoans, lipotoxicity is characterised by the ectopic deposition of lipids on organs other than adipose tissue. This leads to organ dysfunction, cell death, and is intimately linked to lipid-associated diseases such as cardiac dysfunction, atherosclerosis, stroke, hepatosteatosis, cancer and the metabolic syndrome. The molecules involved in eliciting lipotoxicity include FAs and their acyl-CoA derivatives, triacylglycerol (TG), diacylglycerol (DG), ceramides, acyl-carnitines and phospholipids. However, the cellular transport of toxic lipids through membrane contact sites (MCS) and vesicular mechanisms as well as lipid metabolism that progress lipotoxicity to the onset of disease are not entirely understood. Yeast has proven a useful model organism to study the molecular mechanisms of lipotoxicity. Recently, the Rim101 pathway, which senses alkaline pH and the lipid status at the plasmamembrane, has been connected to lipotoxicity. In this review article, we summarise recent research advances on the Rim101 pathway and MCS in the context of lipotoxicity in yeast and present a perspective for future research directions.

Mechanisms by which PE21, an extract from the white willow Salix alba, delays chronological aging in budding yeast

“…This study and previously published findings [52, 55, 56, 150, 151, 154, 155] validate our hypothesis on the existence of three different mechanisms through which PE21 can delay yeast chronological aging and extend yeast longevity. This hypothesis is described in the Results section and schematically depicted in Figure 2.…”

Fungal plasma membrane domains

“…Additionally, the synthesis of specific cell wall components of C. albicans is also under the control of the Pal/RIM pathway and is critical for masking the fungus from the immune response of the host (Sherrington et al 2017). Evidence accumulates that the Pal/RIM pathway additionally senses lipid asymmetry of the PM, and is involved in lipotoxicity [reviewed in (Rockenfeller and Gourlay 2018)]. More specifically, activation of the RIM pathway was shown to occur in the absence of lipid flippases or floppases and their regulators (Ikeda et al 2008;Obara and Kihara 2014;Brown et al 2018), by expression of phospholipase A2 (Mattiazzi et al 2010), or in response to externally supplied excess of palmitoleic acid (Richard et al 2014) or diacylglycerol .…”

“…More specifically, activation of the RIM pathway was shown to occur in the absence of lipid flippases or floppases and their regulators (Ikeda et al 2008;Obara and Kihara 2014;Brown et al 2018), by expression of phospholipase A2 (Mattiazzi et al 2010), or in response to externally supplied excess of palmitoleic acid (Richard et al 2014) or diacylglycerol . The sensing mechanism again relies on Rim21 (see above), as both lipid stress and alkalization of the medium can result in loss of the proton gradient across the PM, and thus affect the conformation of PalH/Rim21 (Nishino, Obara and Kihara 2015;Rockenfeller and Gourlay 2018).…”

Downregulation of sirtuin 3 by palmitic acid increases the oxidative stress, impairment of mitochondrial function, and apoptosis in liver cells

“…However, the exact molecular pathways of PA‐induced cell death are not well understood. Mitochondria have been shown to be the initial target of the toxic effect of PA . In PA exposed cells, the mitochondrial generation of reactive oxygen species (ROS) has been shown to induce programmed cell death .…”