A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity
- 1Foundation for Research and Technology - Hellas
Abstract
Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a central regulator of lipid metabolism and a critical mediator of neuroprotection, yet the mechanisms linking these functions remain unclear. Here, we identify the Caenorhabditis elegans nuclear receptor SEX-1 as a functional PPAR{gamma}-like regulator and define a pathway that coordinates lipid metabolism with mitochondrial homeostasis to preserve neuronal function. Integrating comparative genomics, multi-omics profiling, meta-analysis, and experimental validation, we show that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet (LD) dynamics, and mitochondrial quality control through interconnected lipogenic and autophagic programs. Loss of sex-1 disrupts this metabolic network, resulting in aberrant LD accumulation, mitochondrial dysfunction, and widespread alterations in sphingolipid metabolism. These defects compromise the structural integrity and thermosensory function of amphid neurons during early adulthood, while the capacity of SEX-1 to restrict neuronal lipid droplet accumulation declines with age. Notably, genetic modulation of sphingolipid metabolic pathways rescues neuronal defects, establishing a causal link between lipid metabolic homeostasis and neuronal maintenance. Together, our findings identify a PPAR{gamma}-like signalling axis that integrates sphingolipid metabolism, organelle quality control, and neuronal homeostasis, providing a mechanistic framework for understanding how metabolic regulation promotes neuroprotection.
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BibTeX
@misc{tsagkari2026pparγlike,
title = {{A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity}},
author = {D. Tsagkari and M. Markaki and T. Zhang and E. Nollen and N. Tavernarakis},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755091},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755091v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity
AU - D. Tsagkari
AU - M. Markaki
AU - T. Zhang
AU - E. Nollen
AU - N. Tavernarakis
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755091
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755091v1
AB - Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a central regulator of lipid metabolism and a critical mediator of neuroprotection, yet the mechanisms linking these functions remain unclear. Here, we identify the Caenorhabditis elegans nuclear receptor SEX-1 as a functional PPAR{gamma}-like regulator and define a pathway that coordinates lipid metabolism with mitochondrial homeostasis to preserve neuronal function. Integrating comparative genomics, multi-omics profiling, meta-analysis, and experimental validation, we show that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet (LD) dynamics, and mitochondrial quality control through interconnected lipogenic and autophagic programs. Loss of sex-1 disrupts this metabolic network, resulting in aberrant LD accumulation, mitochondrial dysfunction, and widespread alterations in sphingolipid metabolism. These defects compromise the structural integrity and thermosensory function of amphid neurons during early adulthood, while the capacity of SEX-1 to restrict neuronal lipid droplet accumulation declines with age. Notably, genetic modulation of sphingolipid metabolic pathways rescues neuronal defects, establishing a causal link between lipid metabolic homeostasis and neuronal maintenance. Together, our findings identify a PPAR{gamma}-like signalling axis that integrates sphingolipid metabolism, organelle quality control, and neuronal homeostasis, providing a mechanistic framework for understanding how metabolic regulation promotes neuroprotection.
ER -