Amino Acid Starvation Has Opposite Effects on Mitochondrial and Cytosolic Protein Synthesis

Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation.

氨基酸对于细胞生长与增殖至关重要，它们不仅可作为蛋白质合成的先导物质，还能在核苷酸与脂肪生物合成过程中被重新塑形，亦或作为燃料被消耗。线粒体作为能量产生的重要细胞器，同时在氨基酸稳态维持中扮演核心角色。当细胞缺乏外源性氨基酸供应时，人们可能会预期线粒体代谢将侧重于氨基酸的生产与保存。然而，我们发现人类细胞对氨基酸饥饿的反应是通过上调线粒体内的呼吸、蛋白质合成和氨基酸分解代谢过程来消耗氨基酸。这种在细胞器中对营养物质的增加利用并非主要由能量需求驱动，正如葡萄糖充足时发生的那样。相反，有观点认为，线粒体代谢的变化与细胞质蛋白质合成的抑制相辅相成，以限制氨基酸限制条件下的细胞生长与增殖。因此，刺激线粒体功能可能为抑制驱动细胞增殖的营养需求性合成代谢提供一种途径。