Macromitophagy is a longevity assurance process that in chronologically aging yeast limited in calorie supply sustains functional mitochondria and maintains cellular lipid homeostasis

Abstract

Macromitophagy controls mitochondrial quality and quantity. It involves the sequestration of dysfunctional or excessive mitochondria within double-membrane autophagosomes, which then fuse with the vacuole/lysosome to deliver these mitochondria for degradation. To investigate a physiological role of macromitophagy in yeast, we examined how the atg32Δ-dependent mutational block of this process influences the chronological lifespan of cells grown in a nutrient-rich medium containing low (0.2%) concentration of glucose. Under these longevity-extending conditions of caloric restriction (CR) yeast cells are not starving. We also assessed a role of macromitophagy in lifespan extension by lithocholic acid (LCA), a bile acid that prolongs yeast longevity under CR conditions. Our findings imply that macromitophagy is a longevity assurance process underlying the synergistic beneficial effects of CR and LCA on yeast lifespan. Our analysis of how the atg32Δ mutation influences mitochondrial morphology, composition and function revealed that macromitophagy is required to maintain a network of healthy mitochondria. Our comparative analysis of the membrane lipidomes of organelles purified from wild-type and atg32Δ cells revealed that macromitophagy is required for maintaining cellular lipid homeostasis. We concluded that macromitophagy defines yeast longevity by modulating vital cellular processes inside and outside of mitochondria.

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.…”