Giamogante, Flavia;
Barazzuol, Lucia;
Maiorca, Francesca;
Poggio, Elena;
Esposito, Alessandra;
Masato, Anna;
Napolitano, Gennaro;
... Brini, Marisa; + view all
(2024)
A SPLICS reporter reveals
-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
Nature Communications
, 15
, Article 1516. 10.1038/s41467-024-46007-2.
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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.
| Type: | Article |
|---|---|
| Title: | A SPLICS reporter reveals -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-024-46007-2 |
| Publisher version: | https://doi.org/10.1038/s41467-024-46007-2 |
| Language: | English |
| Additional information: | © The Author(s), 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Intracellular signalling peptides and proteins, Molecular medicine, Neurological disorders, Organelles |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10187721 |
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