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PAYWALLED > Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis

mitochondria lysosome vacuole iron aging yeast amino acid cysteine v-atpase

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#1 Engadin

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Posted 24 January 2020 - 10:20 PM


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P A Y W A L L E D    S O U R C E :   Cell

 

 

 

 

 

Highlights
 
  •  Elevated cysteine disrupts mitochondrial respiration in vacuole-impaired cells
 
  •  Cysteine inhibits mitochondrial function by limiting iron bioavailability
 
  •  Vacuoles sequester cysteine to promote efficient mitochondrial respiration
 
  •  Cysteine restriction or iron supplementation sustains mitochondrial health in aging
 
 
Summary
 
Mitochondria and lysosomes are functionally linked, and their interdependent decline is a hallmark of aging and disease. Despite the long-standing connection between these organelles, the function(s) of lysosomes required to sustain mitochondrial health remains unclear. Here, working in yeast, we show that the lysosome-like vacuole maintains mitochondrial respiration by spatially compartmentalizing amino acids. Defects in vacuole function result in a breakdown in intracellular amino acid homeostasis, which drives age-related mitochondrial decline.
 
Among amino acids, we find that cysteine is most toxic for mitochondria and show that elevated non-vacuolar cysteine impairs mitochondrial respiration by limiting intracellular iron availability through an oxidant-based mechanism. Cysteine depletion or iron supplementation restores mitochondrial health in vacuole-impaired cells and prevents mitochondrial decline during aging. These results demonstrate that cysteine toxicity is a major driver of age-related mitochondrial deterioration and identify vacuolar amino acid compartmentation as a cellular strategy to minimize amino acid toxicity.
 
 
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Edited by Engadin, 24 January 2020 - 10:23 PM.

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Also tagged with one or more of these keywords: mitochondria, lysosome, vacuole, iron, aging, yeast, amino acid, cysteine, v-atpase

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