ABSTRACT
Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson's disease, suggesting that it might play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.
Footnotes
Author contributions
Conceptualization: D.T., M.M., N.T.; Formal analysis: D.T.; Funding acquisition: N.T.; Investigation: D.T., M.M., N.T.; Methodology: D.T., M.M., N.T.; Resources: D.T., M.M., N.T.; Supervision: M.M., N.T.; Validation: D.T., N.T.; Visualization: D.T., N.T.; Writing – original draft: D.T., M.M.; Writing – review & editing: D.T., M.M., N.T.
Funding
Work in the authors’ laboratory is funded by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the ‘1st Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment’ (Project Number: HFRI–FM17C3-0869, NeuroMitophagy), the General Secretariat for Research and Innovation of the Greek Ministry of Development, the European Union – NextGenerationEU (project code: TAEDR-0535850, Acronym: BrainPrecision) in the framework of the Action ‘Flagship Actions in Interdisciplinary Scientific Areas with Special Interest in Connection to the Productive Fabric’, under the National Recovery and Resilience Plan ‘Greece 2.0’ and the European Commission Research Executive Agency Excellence Hub ‘CHAngeing’ (GA-101087071). D.T. is supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) (Scholarship Code: 11403).
Data and resource availability
All relevant data can be found within the article and its supplementary information.
Special Issue
This article is part of the Special Issue ‘Cell Biology of Mitochondria’, guest edited by Ana J. Garcia-Saez and Heidi McBride. See related articles at https://journals.biologists.com/jcs/issue/138/9.
