Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Sci Rep. 2024 Apr 3;14(1):7877. doi: 10.1038/s41598-024-58656-w.
Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.
复制压力是肿瘤发生的主要原因，因为它通过重组事件提供了染色体重排的来源。PARK2 编码 parkin，是线粒体动态平衡的调节剂，位于常见的脆性位点之一，容易受到复制压力的重排影响，这表明复制压力可能会潜在地影响线粒体动态平衡。在这里，我们显示慢性低剂量复制压力导致 parkin 表达固定减少，这与线粒体功能障碍有关，表现为 mtROS 增加。与 parkin 在自噬中的主要作用一致，parkin 蛋白表达的减少与自噬略有减少和线粒体形态的变化有关。相比之下，即使在慢性复制压力下，表达异位 PARK2 基因的细胞也不会出现 mtROS 增加和线粒体形态的变化，这表明与 parkin 减少相关的 PARK2 基因座的内在脆弱性是由慢性复制压力引起的线粒体功能障碍的原因。由于内源性复制压力和线粒体功能障碍都涉及多种病理生理学，我们的数据支持在人类保健中恢复 parkin 表达的治疗性开发。
