Creld mediates ER-mitochondria communication to enable the formation of H₂O₂, a prerequisite for neuron function
Creld in HeLa cells
Creld in dopaminergic neurons of Drosophila
In our study, we set out to understand how the communication between the endoplasmic reticulum (ER) and mitochondria affects neuronal function. We focused on dopaminergic neurons, which are central to movement control and are impaired in Parkinson’s disease. We investigated the role of Cystein-rich with EGF-like domain (Creld), an ER protein previously implicated in developmental processes, and discovered a surprising new role: it regulates the production of hydrogen peroxide (H₂O₂) in mitochondria, which in turn is critical for maintaining dopaminergic neuron activity.
Using Drosophila melanogaster as a model, we found that loss of Creld function led to movement deficits reminiscent of Parkinson-like symptoms. Strikingly, these flies didn't show signs of dopaminergic neuron degeneration. Instead, the neurons were inactive. Their morphology was intact, but their function was impaired.
We traced this dysfunction back to a disturbed lipid exchange at the ER-mitochondria contact sites. At these contact sites, specific phospholipids are exchanged between the compartments. In the absence of Creld, this transfer is disrupted, leading to a shortage of these lipids in mitochondria. As a result, respiratory complex I, a key component of mitochondrial energy production, becomes inactive, and the generation of H₂O₂, a signaling molecule required for dopaminergic neuron activity, is impaired.
Importantly, when we restored H₂O₂ production genetically in the dopaminergic neurons of Creld mutants, their movement improved significantly. This demonstrated a direct link between lipid exchange, mitochondrial function, and neuron activity.
We also showed that this mechanism is evolutionarily conserved. In Xenopus tropicalis and human cell models, disruption of Creld caused similar mitochondrial abnormalities, elongated, hyperfused mitochondria, as we observed in our fly model. Our work shows how a subcellular process, the interplay between ER and mitochondria, shapes neuron function.