ABSTRACT

Temperature variations induce stressful conditions that challenge the ability of organisms to maintain cell homeostasis. The intensity and duration of heat stress affect cell response very differently, ranging from a beneficial effect – hormesis – to necrotic cell death. There is a strong interplay between the cell response to heat shock and macroautophagy/autophagy, which is induced to cope with stress. Using Caenorhabditis elegans, we developed a new paradigm to study adaptation to acute non-lethal heat-stress (aHS) during development. We found that aHS results in transient fragmentation of mitochondria, decreased cellular respiration, and delayed development. Moreover, an active autophagy flux associated with mitophagy events is triggered in many tissues, enables the rebuilding of the mitochondrial network and modulates the adaptive plasticity of the development, showing that the autophagic response is protective for C. elegans. Using genetic and cellular approaches, we showed that mitochondria are a major site for autophagosome biogenesis in the epidermis, under both standard and heat-stress conditions. We determined that DRP-1 (Dynamin-Related Protein 1) involved in mitochondrial fission, is an important player for the autophagy process and the adaptation to aHS. Our study suggests that DRP-1 is involved in coordinating mitochondrial fission and autophagosome biogenesis during stress.

摘要

温度变化会引发压力条件，挑战生物体维持细胞稳态的能力。热应激的强度和持续时间对细胞反应的影响非常不同，从有益作用（兴奋作用）到坏死细胞死亡。细胞对热休克的反应和巨自噬/自噬之间存在强烈的相互作用，后者被诱导以应对压力。使用秀丽隐杆线虫，我们开发了一种新的范式来研究在发育过程中对急性非致命热应激 (aHS) 的适应。我们发现 aHS 会导致线粒体短暂断裂、细胞呼吸减少和发育延迟。此外，与线粒体自噬事件相关的主动自噬通量在许多组织中被触发，能够重建线粒体网络并调节发育的适应性可塑性，表明自噬反应对秀丽隐杆线虫具有保护作用. 使用遗传和细胞方法，我们发现线粒体是表皮中自噬体生物发生的主要位点，在标准和热应激条件下。我们确定参与线粒体裂变的 DRP-1（动力相关蛋白 1）是自噬过程和适应 aHS 的重要参与者。我们的研究表明，DRP-1 在应激过程中参与协调线粒体裂变和自噬体的生物发生。