Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Straße 31, 53115 Bonn, Germany.
VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
Sci Adv. 2022 Jul 22;8(29):eabo0155. doi: 10.1126/sciadv.abo0155.
Dynamic contacts are formed between endoplasmic reticulum (ER) and mitochondria that enable the exchange of calcium and phospholipids. Disturbed contacts between ER and mitochondria impair mitochondrial dynamics and are a molecular hallmark of Parkinson's disease, which is also characterized by impaired complex I activity and dopaminergic neuron degeneration. Here, we analyzed the role of cysteine-rich with EGF-like domain (Creld), a poorly characterized risk gene for Parkinson's disease, in the regulation of mitochondrial dynamics and function. We found that loss of Creld leads to mitochondrial hyperfusion and reduced ROS signaling in , , and human cells. Creld fly mutants show differences in ER-mitochondria contacts and reduced respiratory complex I activity. The resulting low-hydrogen peroxide levels are linked to disturbed neuronal activity and lead to impaired locomotion, but not neurodegeneration, in Creld mutants. We conclude that Creld regulates ER-mitochondria communication and thereby hydrogen peroxide formation, which is required for normal neuron function.
内质网（ER）和线粒体之间形成动态接触，使钙和磷脂交换成为可能。ER 和线粒体之间接触的紊乱会损害线粒体的动态平衡，这也是帕金森病的一个分子标志，帕金森病还伴有复合物 I 活性降低和多巴胺能神经元变性。在这里，我们分析了富含半胱氨酸的表皮生长因子样域（Creld）在调节线粒体动态平衡和功能中的作用，Creld 是帕金森病的一个特征不明显的风险基因。我们发现 Creld 的缺失会导致 、 和人细胞中线粒体过度融合和 ROS 信号降低。Creld 果蝇突变体在 ER-线粒体接触和呼吸复合物 I 活性降低方面存在差异。由此产生的低过氧化氢水平与神经元活动紊乱有关，导致 Creld 突变体运动能力受损，但不会导致神经退行性变。我们的结论是，Creld 调节 ER-线粒体通讯，从而调节过氧化氢的形成，这对于正常神经元功能是必需的。
