Department of Molecular, Cellular & Developmental Biology, University of Michigan,1105 North University, Ann Arbor, Michigan 48109, USA.
J Cell Sci. 2022 Dec 1;135(1). doi: 10.1242/jcs.259254. Epub 2022 Jan 10.
Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS responses, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation. We now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1Δ cells, which are defective in peroxisomal β-oxidation of fatty acids, the respiratory response to ERS is impaired and ROS accrues. However, the respiratory response to ERS is rescued and ROS production is mitigated in pox1Δ cells overexpressing Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the tricarboxylic acid cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation upon ERS to remodel the respiratory machinery. The abundance of several peroxisome-based proteins was also increased, corroborating the role of peroxisomes in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher-order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.
内质网应激（ERS）发生在细胞对蛋白质折叠的需求超过细胞器的能力时。为了适应 ERS，细胞需要线粒体和过氧化物酶体的关键贡献。在 ERS 反应期间，线粒体呼吸增加以减轻活性氧（ROS）的积累。我们现在在酵母中表明，过氧化物酶体的丰度也会增加，以促进适应性反应。在过氧化物酶体脂肪酸β-氧化缺陷的 pox1Δ 细胞中，ERS 引起的呼吸反应受损，ROS 积累。然而，在过氧化物酶体脂肪酸β-氧化缺陷的 pox1Δ 细胞中过度表达 Mpc1（提供另一种乙酰辅酶 A 来源以支持三羧酸循环和氧化磷酸化的线粒体丙酮酸载体）可挽救 ERS 引起的呼吸反应并减轻 ROS 的产生。使用蛋白质组学，鉴定了几种在 ERS 下上调的线粒体蛋白，以重塑呼吸机制。几种基于过氧化物酶体的蛋白质的丰度也增加了，这证实了过氧化物酶体在 ERS 适应中的作用。最后，ERS 刺激呼吸复合物组装成更高阶的超复合物，从而提高电子转移效率。我们的结果强调了过氧化物酶体和线粒体对 ERS 适应的支持，以促进细胞存活。
