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Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators of the Respirasome and Neurogenesis
Ist Teil von
iScience, 2019-09, Vol.19, p.1114-1132
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2019
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Mitochondrial protein (MP) assemblies undergo alterations during neurogenesis, a complex process vital in brain homeostasis and disease. Yet which MP assemblies remodel during differentiation remains unclear. Here, using mass spectrometry-based co-fractionation profiles and phosphoproteomics, we generated mitochondrial interaction maps of human pluripotent embryonal carcinoma stem cells and differentiated neuronal-like cells, which presented as two discrete cell populations by single-cell RNA sequencing. The resulting networks, encompassing 6,442 high-quality associations among 600 MPs, revealed widespread changes in mitochondrial interactions and site-specific phosphorylation during neuronal differentiation. By leveraging the networks, we show the orphan C20orf24 as a respirasome assembly factor whose disruption markedly reduces respiratory chain activity in patients deficient in complex IV. We also find that a heme-containing neurotrophic factor, neuron-derived neurotrophic factor [NENF], couples with Parkinson disease-related proteins to promote neurotrophic activity. Our results provide insights into the dynamic reorganization of mitochondrial networks during neuronal differentiation and highlights mechanisms for MPs in respirasome, neuronal function, and mitochondrial diseases.
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•Rewiring of mitochondrial (mt) protein interaction network in distinct cell states•Dramatic changes in site-specific phosphorylation during neuronal differentiation•C20orf24 is a respirasome assembly factor depleted in patients deficient in CIV•NENF binding with DJ-1/PINK1 promotes neurotrophic activity and neuronal survival
Biological Sciences; Developmental Neuroscience; Developmental Biology; Proteomics