The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity
Autor(en): | Paradis, Marie Kucharowski, Nicole Faret, Gabriela Edwards Palacios, Santiago Jose Maya Meyer, Christian Stuempges, Birgit Jamitzky, Isabell Kalinowski, Julia Thiele, Christoph Bauer, Reinhard Paululat, Achim Sellin, Julia Buelow, Margret Helene |
Stichwörter: | DYSFUNCTION; EXPRESSION; Multidisciplinary Sciences; PARKINSONS-DISEASE; PATHOLOGY; Science & Technology - Other Topics; SYSTEM | Erscheinungsdatum: | 2022 | Herausgeber: | AMER ASSOC ADVANCEMENT SCIENCE | Enthalten in: | SCIENCE ADVANCES | Band: | 8 | Ausgabe: | 29 | Zusammenfassung: | 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 mitochondria! 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 Drosophila melanogaster, Xenopus tropicalis, 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. |
ISSN: | 2375-2548 | DOI: | 10.1126/sciadv.abo0155 |
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geprüft am 07.06.2024