Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis
Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis
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DOI：
10.1016/j.cell.2019.12.035
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发表时间：
2020-01-23
期刊：
影响因子：
64.5
通讯作者：
Hughes, Adam L.
中科院分区：
文献类型：
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作者：
Hughes, Casey E.;Coody, Troy K.;Hughes, Adam L.
线粒体和溶酶体在功能上是相互联系的，它们相互依赖的下降是衰老和疾病的标志。尽管这些细胞器之间存在长期联系，但维持线粒体健康所需的溶酶体功能仍不清楚。在这里，在酵母中工作，我们表明，溶酶体样空泡维持线粒体呼吸空间区隔氨基酸。空泡功能的缺陷导致细胞内氨基酸稳态的破坏，这驱动了与年龄相关的线粒体衰退。在氨基酸中，我们发现半胱氨酸对线粒体的毒性最大，并且表明升高的非空泡半胱氨酸通过基于氧化剂的机制限制细胞内铁的可用性来损害线粒体呼吸。半胱氨酸耗竭或铁补充可恢复空泡受损细胞中的线粒体健康，并防止衰老过程中的线粒体衰退。这些结果表明，半胱氨酸毒性是与年龄相关的线粒体退化的主要驱动因素，并确定液泡氨基酸区室化是最大限度地减少氨基酸毒性的细胞策略。
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.