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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