Mitochondrial membrane lipidome defines yeast longevity

Abstract

Our studies revealed that lithocholic acid (LCA), a bile acid, 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 further increase in chronological lifespan. Here, we investigate a mechanism underlying this robust 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 glycerophospholipid synthesis and movement within both mitochondrial membranes, thereby causing substantial changes in 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 the age-related dynamics of 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 glycerophospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity.

Mechanism of liponecrosis, a distinct mode of programmed cell death

“…S3). [7][8][9][10][11][12][13][14][15] Other PL classes (such as PE and CL) are known to be formed only in the inner mitochondrial membrane (IMM); PE is then transported from mitochondria to the ER via mitochondria-ER junctions and from the ER to the PM via PM-ER junctions (Fig. S3).…”

“…1 To further verify our hypothesis, we examined how various single-gene-deletion mutations (each eliminating an enzyme involved in POA transport to the ER or in POA incorporation into PL and/or NL within the ER; see refs. [7][8][9][10][11][12][13][14][15][16][17][18] and Fig. S3) influence the susceptibility of yeast to POA-induced liponecrotic PCD.…”

“…S3). [9][10][11][12][13]15 Furthermore, although PE resides in all cellular membranes, it is known to be synthesized only in the IMM from PS that is formed exclusively in the ER membrane and delivered to mitochondria via mitochondria-ER junctions (Fig. S3).…”

“…S3). [9][10][11][12][13]15 Moreover, the relative levels of other PL classes in both mitochondrial membranes are known to be defined by a bidirectional exchange of PL between the mitochondrial and ER membranes; such exchange integrates lipid dynamics within these organellar membranes into an intricate network (Fig. S3).…”

“…S3). [7][8][9][10][11][12][13][14][15][16][17][18] It is conceivable therefore that: (1) POA-containing species of PA, PS, PE, PC and PI could amass within the PM bilayer of yeast treated with POA; and (2) such buildup of POA-containing species of PL within the PM could alter the proper PL asymmetry in the PM bilayer and, thus, could induce the alkaline-pH-and lipid-asymmetryresponsive Rim101 signaling pathway.…”