Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan

Li, Jun; Huang, Xinhe; Withers, Bradley R.; Blalock, Eric M.; Liu, Ke; Dickson, Robert C.

doi:10.1111/acel.12107

Cited by 66 publications

(78 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…30 By contrast with csg2Δ cells in which Snf1 activity is impaired in conjunction with IPC accumulation, inhibiting sphingolipid synthesis (with myriocin) has been reported to induce Snf1 activity, resulting in upregulation of genes involved in oxidative phosphorylation. 12 ROS proliferation is a cellular phenotype shared by csg2Δ cells and human sphingolipidoses, diseases in which sphingolipids build-up abnormally. 15 Significantly, our work highlights mitochondria and associated metabolic pathways as targets of lipid toxicity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

View full text Add to dashboard Cite

Sphingolipids are structural components of cell membranes that have signaling roles to regulate many activities, including mitochondrial function and cell death. Sphingolipid metabolism is integrated with numerous metabolic networks, and dysregulated sphingolipid metabolism is associated with disease. Here, we describe a monogenic yeast model for sphingolipid accumulation. A csg2Δ mutant cannot readily metabolize and accumulates the complex sphingolipid inositol phosphorylceramide (IPC). In these cells, aberrant activation of Ras GTPase is IPC-dependent, and accompanied by increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial mass. Survival or death of csg2Δ cells depends on nutritional status. Abnormal Ras activation in csg2Δ cells is associated with impaired Snf1/AMPK protein kinase, a key regulator of energy homeostasis. csg2Δ cells are rescued from ROS production and death by overexpression of mitochondrial catalase Cta1, abrogation of Ras hyperactivity or genetic activation of Snf1/AMPK. These results suggest that sphingolipid dysregulation compromises metabolic integrity via Ras and Snf1/AMPK pathways.Sphingolipids are critical structural molecules in cell membranes, forming membrane microdomains by associating with cholesterol and specific proteins.1 Sphingolipid metabolites are also important signaling molecules linked to multiple other metabolic pathways with kinases and phosphatases as regulatory targets.2,3 Sphingolipids have roles in numerous cell processes, including regulation of mitochondrial function, cell death and aging.2,4 Cellular sphingolipid homeostasis is maintained by control of synthesis, breakdown and interorganellar transport of sphingolipid metabolites.1 The importance of sphingolipids is underscored by several lysosomal storage disorders, including Tay Sachs, Gaucher and Nieman-Pick diseases, which are attributable to defective sphingolipid breakdown; similarly, a hereditary sensory neuropathy is caused by accumulation of abnormal sphingolipid metabolites.

show abstract

Section: Discussionmentioning

confidence: 99%

“…11 Recent work shows that Snf1/AMPK, a key regulator of energy metabolism, responds to changes in sphingolipid homeostasis. 12,13 These pathways involved in regulating and responding to sphingolipids are evolutionarily conserved.…”

mentioning

confidence: 99%

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It is known that a defect in sphingolipid synthesis, as mediated by pharmacological inhibition or down-regulating expression of serine palmitoyltransferase (the first enzyme in the sphingolipid synthesis pathway (86)), extends chronological life span in yeast (118). This process involves the down-regulation of the Pkh1/2-Sch9 signaling pathway (118), which in turn activates the Snf1/AMP kinase signaling pathway and down-regulates the protein kinase A and target of rapamycin complex 1 signaling pathways (119). Because PI, one of the major phospholipids that is elevated in the pah1⌬ mutant (35), is the direct precursor for the synthesis of inositolphosphoceramide and mannose (inositol-P) 2 -ceramide (85, 86), we considered the hypothesis that the reduced chronological life span in the pah1⌬ mutant might also be ascribed to an increase in membrane sphingolipids.…”

Section: Discussionmentioning

confidence: 99%

Altered Lipid Synthesis by Lack of Yeast Pah1 Phosphatidate Phosphatase Reduces Chronological Life Span

Park

Han

Mileykovskaya

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Pah1 phosphatidate phosphatase regulates the synthesis of triacylglycerol and membrane phospholipids. Results: The lack of Pah1 causes increases in phospholipid synthesis, ATP consumption, and oxidative stress and a decrease in chronological life span. Conclusion: Pah1 plays a role in chronological life span by regulating lipid synthesis. Significance: Pah1-mediated regulation of triacylglycerol and phospholipid syntheses is important for chronological life span.

show abstract

“…A comparison of the genetic determinants of lifespan extension in the worm induced by various cytotoxic agents prominently featured ceramide and its metabolism. This is not surprising, as it is known that sphingolipids impact virtually every signaling pathway in the yeast cell that is relevant for longevity (Huang, et al, 2013, Liu, et al, 2013). This includes the various pathways and cellular processes with which the retrograde response cross-talks.…”

Section: Retrograde Signaling Is a Response To Cytotoxic Stressmentioning

confidence: 94%

Mitochondria to nucleus signaling and the role of ceramide in its integration into the suite of cell quality control processes during aging

Jazwinski

2015

Ageing Research Reviews

View full text Add to dashboard Cite

Mitochondria to nucleus signaling has been the most extensively studied mode of inter-organelle communication. The first signaling pathway in this category of information transfer to be discovered was the retrograde response, with its own set of signal transduction proteins. The finding that this pathway compensates for mitochondrial dysfunction to extend the replicative lifespan of yeast cells has generated additional impetus for its study. This research has demonstrated crosstalk between the retrograde response and the target of rapamycin (TOR), small GTPase RAS, and high-osmolarity glycerol (HOG) pathways in yeast, all of which are key players in replicative lifespan. More recently, the retrograde response has been implicated in the diauxic shift and survival in stationary phase, extending its operation to the yeast chronological lifespan as well. In this capacity, the retrograde response may cooperate with other, related mitochondria to nucleus signaling pathways. Counterparts of the retrograde response are found in the roundworm, the fruit fly, the mouse, and even in human cells in tissue culture. The exciting realization that the retrograde response is embedded in the network of cellular quality control processes has emerged over the past few years. Most strikingly, it is closely integrated with autophagy and the selective brand of this quality control process, mitophagy. This coordination depends on TOR, and it engages ceramide/sphingolipid signaling. The yeast LAG1 ceramide synthase gene was the first longevity gene cloned as such, and its orthologs hyl-1 and hyl-2 determine worm lifespan. Thus, the involvement of ceramide signaling in quality control gives these findings cellular context. The retrograde response and ceramide are essential components of a lifespan maintenance process that likely evolved as a cytoprotective mechanism to defend the organism from diverse stressors.

show abstract

Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan

Cited by 66 publications

References 45 publications

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

Altered Lipid Synthesis by Lack of Yeast Pah1 Phosphatidate Phosphatase Reduces Chronological Life Span

Mitochondria to nucleus signaling and the role of ceramide in its integration into the suite of cell quality control processes during aging

Contact Info

Product

Resources

About