Drosophila Tweety Facilitates Autophagy to Regulate Mitochondrial Homeostasis and Bioenergetics in Glia

Authors

Ho Hang Leung
Christina Mansour
Morgan Rousseau
Anwar Nakhla
Kirill Kiselyov
Kartik Venkatachalam
Ching-On Wong

Publication Date

2-1-2024

Journal

Glia

Abstract

Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected. Here, we identify an endolysosomal membrane protein that facilitates autophagy to regulate ATP production in glia. We determined that Drosophila tweety (tty) is highly expressed in glia and localized to endolysosomes. Diminished fusion between autophagosomes and endolysosomes in tty-deficient glia was rescued by expressing the human Tweety Homolog 1 (TTYH1). Loss of tty in glia attenuated mitochondrial turnover, elevated mitochondrial oxidative stress, and impaired locomotor functions. The cellular and organismal defects were partially reversed by antioxidant treatment. We performed live-cell imaging of genetically encoded metabolite sensors to determine the impact of tty and autophagy deficiencies on glial bioenergetics. We found that tty-deficient glia exhibited reduced mitochondrial pyruvate consumption accompanied by a shift toward glycolysis for ATP production. Likewise, genetic inhibition of autophagy in glia resulted in a similar glycolytic shift in bioenergetics. Furthermore, the survival of mutant flies became more sensitive to starvation, underlining the significance of tty in the crosstalk between autophagy and bioenergetics. Together, our findings uncover the role for tty in mitochondrial homeostasis via facilitating autophagy, which determines bioenergetic balance in glia.

Keywords

Animals, Humans, Adenosine Triphosphate, Autophagy, Drosophila, Energy Metabolism, Homeostasis, Mitochondria, Neuroglia, Membrane Proteins, Drosophila Proteins, Endolysosomes, Autophagy, Mitochondria, Bioenergetics, Tweety homologs, Drosophila

DOI

10.1002/glia.24484

PMID

37870193

PMCID

PMC10842981

PubMedCentral® Posted Date

2-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes