Research Paper Volume 5, Issue 7 pp 551—574

Figure 10. A model for a mechanism underlying the ability of LCA to extend yeast longevity by accumulating in mitochondria, altering mitochondrial membrane lipidome, and affecting mitochondrial morphology and function.

Exogenously added LCA enters yeast cells and accumulates mainly in the inner mitochondrial membrane (IMM). A smaller portion of LCA also associates with the outer mitochondrial membrane (OMM). The accumulated within mitochondrial membranes LCA alters their lipidomes by remodeling glycerophospholipid synthesis within the IMM, attenuating the cardiolipin (CL)-dependent inhibition of phosphatidic acid (PA) transport from the OMM to the IMM and accelerating PA movement from the mitochondria-associated membrane (MAM) domain of the ER to the OMM via mitochondria-ER junctions. The LCA-driven progressive remodeling of mitochondrial membrane lipidomes with the chronological age of a yeast cell causes major changes in mitochondrial size, number and morphology. The elicited by LCA substantial changes in mitochondrial membrane lipidome and the resulting major changes in mitochondrial morphology act in synergy to alter the age-related chronology of mitochondrial respiration, electrochemical membrane potential, ATP synthesis and ROS homeostasis. Because of these LCA-dependent changes in the age-related dynamics of the four longevity-defining processes confined to mitochondria, chronologically “old” cells cultured with exogenous LCA exhibit higher (as compared to age-matched cells cultured without LCA) mitochondrial respiration, electrochemical membrane potential, ATP level and ROS concentration. This increases their long-term viability and stress resistance and, thus, extends their longevity. Arrows next to the names of lipid species denote those of them whose concentrations are elevated (red arrows) or reduced (blue arrows) in cells cultured with exogenous LCA and therefore accumulating this bile acid in the IMM and OMM. Activation arrows and inhibition bars displayed in red color denote anti-aging processes. See text for details. Abbreviations: CDP-DAG, cytidine diphosphate-diacylglycerol; MLCL, monolysocardiolipin; PC, phosphatidylcholine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine.