Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
Mol Cell. 2019 Jun 6;74(5):877-890.e6. doi: 10.1016/j.molcel.2019.03.031. Epub 2019 Apr 22.
Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.
内质网（ER）应激和未折叠蛋白反应在营养应激条件下是能量消耗很大的过程。然而，控制营养和 ER 应激下能量需求的调节机制在很大程度上尚不清楚。在这里，我们表明 ER 应激和葡萄糖剥夺通过蛋白激酶 R 样内质网激酶（PERK）刺激线粒体生物能学和呼吸超复合体（SCs）的形成。PERK 的遗传缺失或药理学抑制可抑制营养和 ER 应激介导的 SC 水平增加，并降低氧化磷酸化依赖性 ATP 产生。相反，PERK 的激活增强了呼吸超复合体。PERK-eIF2α-ATF4 轴增加超复合体组装因子 1（SCAF1 或 COX7A2L），促进 SCs 和增强的线粒体呼吸。PERK 的激活足以挽救源自线粒体疾病患者的复合物 I 错义突变引起的生物能量缺陷。这些研究确定了 ER 和线粒体之间的能量通讯，这与细胞存活和与线粒体功能障碍相关的疾病有关。
