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

Flavia Giamogante, Lucia Barazzuol, Francesca Maiorca, Elena Poggio, Alessandra Esposito, Anna Masato, Gennaro Napolitano, Alessio Vagnoni, Tito Calì () and Marisa Brini ()
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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)
Anna Masato: University of Padova
Gennaro Napolitano: Telethon Institute of Genetics and Medicine (TIGEM)
Alessio Vagnoni: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
Tito Calì: University of Padova
Marisa Brini: University of Padova

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46007-2

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