The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity

Abstract 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. Cystein-rich with EGF-like domain (Creld) are ER-proteins associated with atrioventricular septal defects, but human CRELD1 is also a poorly characterized risk gene for Parkinson’s disease. Here we show that Creld is required for ER-mitochondria communication. Loss of Creld leads to mitochondrial hyperfusion and reduced ROS signaling in Drosophila melanogaster, Xenopus tropicalis and human cells. We found that reduced respiratory complex I activity lowers hydrogen peroxide levels, which disturbs neuronal activity and leads to impaired locomotion in Creld mutants. Our study presents a new paradigm of neuron dysfunction as a result of impaired ER-mitochondria communication and a new model for Parkinson’s disease.