Temporal proteomics during neurogenesis reveals large-scale proteome and organelle remodeling via selective autophagy

Alban Ordureau, Felix Kraus, Jiuchun Zhang, Heeseon An, Sookhee Park, Tim Ahfeldt, Joao A. Paulo, J. Wade Harper

    Research output: Contribution to journalArticlepeer-review

    44 Scopus citations

    Abstract

    Cell state changes are associated with proteome remodeling to serve newly emergent cell functions. Here, we show that NGN2-driven conversion of human embryonic stem cells to induced neurons (iNeurons) is associated with increased PINK1-independent mitophagic flux that is temporally correlated with metabolic reprogramming to support oxidative phosphorylation. Global multiplex proteomics during neurogenesis revealed large-scale remodeling of functional modules linked with pluripotency, mitochondrial metabolism, and proteostasis. Differentiation-dependent mitophagic flux required BNIP3L and its LC3-interacting region (LIR) motif, and BNIP3L also promoted mitophagy in dopaminergic neurons. Proteomic analysis of ATG12−/− iNeurons revealed accumulation of endoplasmic reticulum, Golgi, and mitochondria during differentiation, indicative of widespread organelle remodeling during neurogenesis. This work reveals broad organelle remodeling of membrane-bound organelles during NGN2-driven neurogenesis via autophagy, identifies BNIP3L's central role in programmed mitophagic flux, and provides a proteomic resource for elucidating how organelle remodeling and autophagy alter the proteome during changes in cell state.

    Original languageEnglish
    Pages (from-to)5082-5098.e11
    JournalMolecular Cell
    Volume81
    Issue number24
    DOIs
    StatePublished - 16 Dec 2021

    Keywords

    • autophagy
    • iNeurons
    • mitophagy
    • proteomics

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