Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling

Athanasios Metaxakis; Michail Pavlidis; Nektarios Tavernarakis

doi:10.3390/cells12162024

Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling

Cells. 2023 Aug 8;12(16):2024. doi: 10.3390/cells12162024.

Authors

Athanasios Metaxakis¹, Michail Pavlidis², Nektarios Tavernarakis^{1

3}

Affiliations

¹ Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece.
² Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.
³ Department of Basic Sciences, Faculty of Medicine, University of Crete, 71110 Heraklion, Crete, Greece.

Abstract

The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.

Keywords: 5HTR7 receptor; ATG1; ageing; autophagy; behaviour; cAMP/PKA; ecdysone; longevity; mTORC1; metabolism; serotonin transporter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological
Animals
Autophagy
Brain
Drosophila
Synaptic Transmission*
Zebrafish*

Grants and funding

This research was funded by the following grants: A.M. was supported by H2020 FETOPEN project “Dynamic” (EC-GA 863203), a standard Marie Curie intra-European individual fellowship (AGE-MEMORY), a Niarchos Foundation individual fellowship, and the project “BIOIMAGING-GR” (MIS5002755), which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020). Work in the N.T. lab is supported by the European Research Council (GA695190-MANNA).