Yeast Cells Exposed to Exogenous Palmitoleic Acid Either Adapt to Stress and Survive or Commit to Regulated Liponecrosis and Die

Abstract

A disturbed homeostasis of cellular lipids and the resulting lipotoxicity are considered to be key contributors to many human pathologies, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer. The yeast Saccharomyces cerevisiae has been successfully used for uncovering molecular mechanisms through which impaired lipid metabolism causes lipotoxicity and elicits different forms of regulated cell death. Here, we discuss mechanisms of the “liponecrotic” mode of regulated cell death in S. cerevisiae. This mode of regulated cell death can be initiated in response to a brief treatment of yeast with exogenous palmitoleic acid. Such treatment prompts the incorporation of exogenously added palmitoleic acid into phospholipids and neutral lipids. This orchestrates a global remodeling of lipid metabolism and transfer in the endoplasmic reticulum, mitochondria, lipid droplets, and the plasma membrane. Certain features of such remodeling play essential roles either in committing yeast to liponecrosis or in executing this mode of regulated cell death. We also outline four processes through which yeast cells actively resist liponecrosis by adapting to the cellular stress imposed by palmitoleic acid and maintaining viability. These prosurvival cellular processes are confined in the endoplasmic reticulum, lipid droplets, peroxisomes, autophagosomes, vacuoles, and the cytosol.

Mechanisms through which lithocholic acid delays yeast chronological aging under caloric restriction conditions

“…Altogether, the above findings and our previously published data [ 76 – 79 ] indicate that the efficiency of decreasing the risk of age-related liponecrotic RCD by LCA inversely correlates with the intracellular concentration of FFA. Thus, in support of our hypothesis proposed at the end of the previous section, LCA delays yeast chronological aging under CR conditions in part by decreasing the risk of liponecrotic RCD during PD and ST phases and actively increasing the chance of cell survival during these phases.…”

“…We then examined if LCA influences the susceptibility of calorically restricted WT cells to liponecrotic RCD; this mode of age-related RCD can be triggered by a short-term treatment of yeast with FFA [ 36 , 76 – 79 ]. We found that in WT yeast cultured under CR conditions, LCA significantly increases clonogenic survival of cells briefly (for 2 h) treated with palmitoleic acid (POA; a monounsaturated form of FFA) if these cells were recovered during PD or ST phase of culturing (Figure 6C ).…”

“…It needs to be noted that the age-related onset of liponecrotic RCD and the rate of its progression in the above experiments were monitored in the absence of endogenous POA (a monounsaturated form of FFA), whereas cell susceptibility to liponecrotic RCD in these experiments was measured in yeast exposed to exogenous POA. Our previous studies have revealed that the buildup of POA-containing phospholipids in the PM and the excessive accumulation of POA-containing phospholipids in both mitochondrial membranes are direct pro-death processes in yeast treated with POA, whereas the assimilation of POA into TAG in the ER and the ensuing buildup of POA-containing TAG in LD are direct pro-survival processes in this yeast [ 76 – 79 ]. We have also previously demonstrated that the dga1Δ and are2Δ mutations, both of which decelerate the synthesis of TAG from FFA in the ER ( Supplementary Figure 3 ) and decrease the incorporation of POA into TAG, increase cell susceptibility to liponecrotic RCD [ 76 , 77 ].…”

Some Metabolites Act as Second Messengers in Yeast Chronological Aging

“…In chronologically “old” yeast, the ethanol-dependent suppression of peroxisomal β-oxidation of fatty acids leads to the excessive accumulation of free (non-esterified) fatty acids (FFA) [ 3 , 21 , 37 ]. Such build-up of FFA accelerates yeast chronological aging by increasing the risk of an age-related mode of regulated cell death (RCD) called “liponecrosis” ( Figure 1 K) [ 3 , 98 , 99 , 100 ].…”

“…The ethanol-driven excessive accumulation of unoxidized FFA in yeast peroxisomes (see Section 2.10 ) elicits several negative-feedback loops whose action causes a buildup of FFA and DAG in the ER and lipid droplets (LD) [ 3 , 100 , 101 ]. This buildup of FFA and DAG accelerates the onset of the liponecrotic mode of RCD, thereby increasing the risk of death and accelerating yeast chronological aging ( Figure 1 L) [ 3 , 21 , 98 , 99 , 100 ]. Thus, both FFA and DAG are pro-aging metabolites that shorten yeast CLS.…”