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A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation

Author

Listed:
  • Flavia Giamogante

    (University of Padova)

  • Lucia Barazzuol

    (University of Padova)

  • Francesca Maiorca

    (University of Padova)

  • Elena Poggio

    (University of Padova)

  • Alessandra Esposito

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Anna Masato

    (University of Padova
    University College London)

  • Gennaro Napolitano

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Alessio Vagnoni

    (Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London)

  • Tito Calì

    (University of Padova
    University of Padova
    University of Padova)

  • Marisa Brini

    (University of Padova
    University of Padova
    University of Padova)

Abstract

Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca2+ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca2+ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues.

Suggested Citation

  • Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46007-2
    DOI: 10.1038/s41467-024-46007-2
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    References listed on IDEAS

    as
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    2. Gennaro Napolitano & Chiara Di Malta & Alessandra Esposito & Mariana E. G. de Araujo & Salvatore Pece & Giovanni Bertalot & Maria Matarese & Valerio Benedetti & Angela Zampelli & Taras Stasyk & Dilett, 2020. "A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome," Nature, Nature, vol. 585(7826), pages 597-602, September.
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