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

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.