Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) governs rhythmic mitochondrial lysine-malonylation and daily hepatic metabolism
Abstract
Hepatic daily rhythms are coordinated by feeding and the molecular circadian clock, ensuring metabolic homeostasis. Disrupted feeding schedules promote circadian misalignment and metabolic diseases but the underlying mechanisms remain scarce. Post-translational modifications have emerged as key regulators of circadian metabolic outputs. Here, we show that the mitochondrial enzyme Acyl-CoA synthetase family member 3 (ACSF3) oscillates in phase with different feeding schedules to drive rhythmic lysine-malonylation and coordinate daily hepatic metabolism. Hepatic Acsf3 knockdown drastically affected lysine-malonylation rhythms, decreased fasting glycemia, insulin sensitivity, and AKT phosphorylation, indicative of perturbed glucose homeostasis. Concomitantly, Acsf3 knockdown shifted lipid oxidation from mitochondria to peroxisomes, enhanced lipogenesis and triglyceride synthesis, while increasing diurnal autophagy. Multi-omics profiling uncovered specific lysine-malonylation targets in glycolysis, the tricarboxylic acid (TCA) cycle, fatty-acid oxidation and autophagy. Our findings uncover hepatic ACSF3 as a pivotal molecular nexus that integrates feeding time with dynamic protein lysine-malonylation and orchestrates the diurnal rhythm of liver metabolism.
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BibTeX
@article{questel2026diurnal,
title = {{Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) governs rhythmic mitochondrial lysine-malonylation and daily hepatic metabolism}},
author = {Enora Le Questel and Charlène Besnard and Florian Atger and Yolène Foucher and Alwéna Tollec and Victoria Pakulska and Arsênio Rodrigues Oliveira and Chloé Cloteau and Mathilde Gourdel and Ivan Nemazanyy and Amélie Thouzeau and Cédric Le May and Mikaël Croyal and Yohann Couté and David Jacobi and Bertrand Cariou and Daniel Mauvoisin},
journal = {Cell Reports},
year = {2026},
month = aug,
doi = {10.1016/j.celrep.2026.117774},
url = {https://hal.science/hal-05715771v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) governs rhythmic mitochondrial lysine-malonylation and daily hepatic metabolism
AU - Enora Le Questel
AU - Charlène Besnard
AU - Florian Atger
AU - Yolène Foucher
AU - Alwéna Tollec
AU - Victoria Pakulska
AU - Arsênio Rodrigues Oliveira
AU - Chloé Cloteau
AU - Mathilde Gourdel
AU - Ivan Nemazanyy
AU - Amélie Thouzeau
AU - Cédric Le May
AU - Mikaël Croyal
AU - Yohann Couté
AU - David Jacobi
AU - Bertrand Cariou
AU - Daniel Mauvoisin
PY - 2026
DA - 2026/08/07
JO - Cell Reports
DO - 10.1016/j.celrep.2026.117774
UR - https://hal.science/hal-05715771v1
AB - Hepatic daily rhythms are coordinated by feeding and the molecular circadian clock, ensuring metabolic homeostasis. Disrupted feeding schedules promote circadian misalignment and metabolic diseases but the underlying mechanisms remain scarce. Post-translational modifications have emerged as key regulators of circadian metabolic outputs. Here, we show that the mitochondrial enzyme Acyl-CoA synthetase family member 3 (ACSF3) oscillates in phase with different feeding schedules to drive rhythmic lysine-malonylation and coordinate daily hepatic metabolism. Hepatic Acsf3 knockdown drastically affected lysine-malonylation rhythms, decreased fasting glycemia, insulin sensitivity, and AKT phosphorylation, indicative of perturbed glucose homeostasis. Concomitantly, Acsf3 knockdown shifted lipid oxidation from mitochondria to peroxisomes, enhanced lipogenesis and triglyceride synthesis, while increasing diurnal autophagy. Multi-omics profiling uncovered specific lysine-malonylation targets in glycolysis, the tricarboxylic acid (TCA) cycle, fatty-acid oxidation and autophagy. Our findings uncover hepatic ACSF3 as a pivotal molecular nexus that integrates feeding time with dynamic protein lysine-malonylation and orchestrates the diurnal rhythm of liver metabolism.
SN - 2211-1247
SN - 2211-1247
ER -