Mechanisms Underlying the Essential Role of Mitochondrial Membrane Lipids in Yeast Chronological Aging

Abstract

The functional state of mitochondria is vital to cellular and organismal aging in eukaryotes across phyla. Studies in the yeast Saccharomyces cerevisiae have provided evidence that age-related changes in some aspects of mitochondrial functionality can create certain molecular signals. These signals can then define the rate of cellular aging by altering unidirectional and bidirectional communications between mitochondria and other organelles. Several aspects of mitochondrial functionality are known to impact the replicative and/or chronological modes of yeast aging. They include mitochondrial electron transport, membrane potential, reactive oxygen species, and protein synthesis and proteostasis, as well as mitochondrial synthesis of iron-sulfur clusters, amino acids, and NADPH. Our recent findings have revealed that the composition of mitochondrial membrane lipids is one of the key aspects of mitochondrial functionality affecting yeast chronological aging. We demonstrated that exogenously added lithocholic bile acid can delay chronological aging in yeast because it elicits specific changes in mitochondrial membrane lipids. These changes allow mitochondria to operate as signaling platforms that delay yeast chronological aging by orchestrating an institution and maintenance of a distinct cellular pattern. In this review, we discuss molecular and cellular mechanisms underlying the essential role of mitochondrial membrane lipids in yeast chronological aging.

Figure 1

Processes that define the relative concentrations of different phospholipid classes in both membranes of yeast mitochondria. These processes are facilitated by proteins that reside in the IMM, IMS, OMM, and ER. Only proteins facilitating these processes in the IMM, IMS, and OMM are shown. A T bar denotes a CL-dependent inhibition of PA transfer from the OMM to the IMM. See text for more details. CDP-DAG: cytidine diphosphate-diacylglycerol; CL: cardiolipin; DAG: diacylglycerol; ER: endoplasmic reticulum; IMM: inner mitochondrial membrane; IMS: intermembrane space; MAM: mitochondria-associated membrane domain of the ER; MICOS: mitochondrial contact site protein complex; MLCL: monolysocardiolipin; OMM: outer mitochondrial membrane; PA: phosphatidic acid; PC: phosphatidylcholine; PG: phosphatidylglycerol; PGP: phosphatidylglycerol-phosphate; PI: phosphatidylinositol; PS: phosphatidylserine.

Figure 2

LCA exhibits differential effects on the relative concentrations of various phospholipid classes in mitochondrial membranes of yeast exposed to this bile acid. Arrows next to the names of individual phospholipids indicate phospholipid classes whose concentrations are increased (red arrows) or decreased (blue arrows) in cells cultured with exogenous LCA and therefore accumulating this bile acid in the IMM and OMM. See text for more details. Abbreviations are as provided in the legend for Figure 1.

Figure 3

LCA increases mitochondrial size, reduces mitochondrial number, and elevates the abundance of mitochondrial cristae. Many mitochondrial cristae accumulate in the mitochondrial matrix because they are detached from the IMM. See text for more details. Abbreviations are as provided in the legend for Figure 1.

Figure 4

A model for how LCA-driven changes in different aspects of mitochondrial functionality modulate activities of a discrete set of transcription factors that are integrated into the partial mitochondrial dysfunction (PMD) and oxidative stress (OS) signaling pathways. These factors then orchestrate an establishment of an antiaging transcriptional program for numerous nuclear genes. These genes encode various cellular proteins that play essential roles in regulating longevity of chronologically aging yeast. See text for more details. ΔΨ: the mitochondrial membrane potential. Other abbreviations are provided in the legend for Table 1.

Figure 5

LCA causes specific changes in the relative concentrations of different classes of membrane lipids in mitochondria of chronologically aging yeast. Such LCA-dependent remodeling of mitochondrial lipidome triggers a cascade of consecutive events that establish an aging-delaying cellular pattern. See text for more details.