Abstract
Lithocholic bile acid (LCA) is a potent anti‐aging natural compound that in yeast cultured under longevity‐extending caloric restriction (CR) conditions acts in synergy with CR to enable a significant increase in chronological lifespan. We investigated a mechanism underlying the longevity‐extending effect of LCA under CR. We found that exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane, and also associates with the outer mitochondrial membrane. LCA elicits an age‐related remodeling of phospholipid synthesis and movement within both mitochondrial membranes, thereby altering mitochondrial membrane lipidome and triggering major changes in mitochondrial size, number and morphology. In synergy, these changes in the membrane lipidome and morphology of mitochondria alter the age‐related chronology of mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species homeostasis. The LCA‐driven alterations in these vital mitochondrial processes extend yeast longevity. In sum, our findings suggest a mechanism underlying the ability of LCA to delay chronological aging in yeast by accumulating in both mitochondrial membranes and altering their phospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity. Supported by NSERC of Canada.
Highlights
Growing evidence supports the view that the functional state of mitochondria within eukaryotic cells has a major impact on cellular and organismal aging [1,2,3,4]
If lithocholic acid (LCA) was first dissolved in dimethyl sulfoxide (DMSO) and added to growth medium at a final concentration of 50 μM immediately following cell inoculation into the medium, this bile acid significantly extended the chronological lifespan (CLS) of yeast cells that were cultured under caloric restriction (CR) conditions on 0.2% glucose (Figure 1A; [44])
We found that in yeast cultured with exogenously added LCA in the presence of DMSO (i) LCA was present mostly in the cytosolic (100KgS) fraction; (ii) from 5.2% to 21.6% of LCA was recovered in the 12KgP fraction containing mitochondria, endoplasmic reticulum (ER), Golgi, vacuoles, plasma membrane (PM) and nuclei; and (iii) from 4.2% to 7.1% of LCA was associated with cell surface, as it was recovered in the 1KgP fraction known to consist of unspheroplasted cells and cell debris (Figure 1E)
Summary
Growing evidence supports the view that the functional state of mitochondria within eukaryotic cells has a major impact on cellular and organismal aging [1,2,3,4]. The preservation of a healthy population of functional mitochondria competent at performing the abovementioned three types of longevity-defining processes is under stringent surveillance by an intricate network of mitochondrial quality control pathways These pathways include: (i) the repair of mtDNA; (ii) the proper folding and proteolytic processing of newly imported mitochondrial proteins; (iii) the repair and refolding of unfolded and misfolded mitochondrial proteins; (iv) the degradation of irreversibly damaged proteins within mitochondria; (v) the global hyperacetylation of mitochondrial proteins; (vi) deacetylation, demalonylation, desuccinylation and hyperoxidation of some mitochondrial proteins; (vii) the mitochondrial retrograde signaling, back-signaling and unfolded protein response pathways of mitochondria-to-nucleus communications; (viii) mitochondrial fusion and fission; (ix) the contact-dependent and -independent communications of mitochondria with other cellular organelles; and (x) mitophagy, a process responsible for the selective macroautophagic degradation of aged, dysfunctional, damaged or excessive mitochondria [4, 24,25,26,27,28,29,30,31,32,33,34,35,36,37]
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