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 theatg32Δ-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.
Highlights
Mitophagy is a key mechanism of mitochondrial quality and quantity control responsible for the autophagic degradation of aged, dysfunctional, damaged or excessive mitochondria [1,2,3]
Our findings provide evidence that macromitophagy defines longevity of chronologically aging yeast limited in calorie supply, underlies the synergistic beneficial effects of caloric restriction (CR) and lithocholic acid (LCA) on lifespan, modulates a compendium of vital processes confined to mitochondria, and maintains cellular lipid homeostasis
As a first step towards addressing a role of selective macroautophagic mitochondrial removal in sustaining essential biological processes in yeast, we evaluated the importance of macromitophagy in longevity assurance
Summary
Mitophagy is a key mechanism of mitochondrial quality and quantity control responsible for the autophagic degradation of aged, dysfunctional, damaged or excessive mitochondria [1,2,3]. A micromitophagic mode of mitophagy involves the engulfment of such mitochondria through direct invagination of the vacuolar/lysosomal boundary membrane [4, 5], whereas its macromitophagic mode refers to the sequestration of targeted mitochondria into double-membrane-bounded structures known as autophagosomes [2, 5]. Following fusion of these autophagosomes with the vacuole/ lysosome, sequestered mitochondria are degraded by acid hydrolases [1, 6]. AGING, April 2013, Vol. No.4 mammalian cells is known to play essential roles in several vital biological processes underlying organismal aging, development and differentiation, including (i) selective degradation of depolarized mitochondria in dopaminergic neurons in the substantia nigra, a PINK1/Parkin-dependent process impaired in autosomal recessive forms of Parkinson’s disease; (ii) massive elimination of mitochondria driven by Nix, a protein in the outer mitochondrial membrane, during reticulocyteto-erythrocyte maturation; and (iii) selective clearance of surplus mitochondria during white adipose tissue differentiation in an Atg5/Atg7-dependent manner [2, 3, 7,8,9]
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