PUBLICATION
Low phosphorus causes hepatic energy metabolism disorder through Dynamin-related protein 1-mediated mitochondrial fission in fish
- Authors
- Lin, J., Li, X., Lu, K., Song, K., Wang, L., Dai, W., Mohamed, M., Zhang, C.
- ID
- ZDB-PUB-241104-15
- Date
- 2024
- Source
- The Journal of nutrition 155(1): 132-152 (Journal)
- Registered Authors
- Keywords
- Drp1, Glycolipid metabolism, Mitochondrial dynamic, Phosphorus deficiency, cAMP/PKA signaling pathway
- MeSH Terms
-
- Energy Metabolism*/drug effects
- Dynamins*/genetics
- Dynamins*/metabolism
- Liver*/drug effects
- Liver*/metabolism
- Hepatocytes/drug effects
- Hepatocytes/metabolism
- Mitochondrial Dynamics*/drug effects
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Animals
- Diet/veterinary
- Phosphorus/metabolism
- Zebrafish*
- PubMed
- 39491675 Full text @ J. Nutr.
Citation
Lin, J., Li, X., Lu, K., Song, K., Wang, L., Dai, W., Mohamed, M., Zhang, C. (2024) Low phosphorus causes hepatic energy metabolism disorder through Dynamin-related protein 1-mediated mitochondrial fission in fish. The Journal of nutrition. 155(1):132-152.
Abstract
Background Low phosphorus (LP) diets perturb hepatic energy metabolism homeostasis in fish. However, the specific mechanisms in LP-induced hepatic energy metabolism disorders remain to be fully elucidated.
Objectives This study sought to elucidate the underlying mechanisms of mitochondria involved in LP-induced energy metabolism disorders.
Methods Spotted seabass were fed diets with 0.72% (S-AP, control) or 0.36% (S-LP) available phosphorus for 10 weeks. Drp1 was knocked down or protein kinase A (PKA) was activated using 8Br-cAMP (5 μM, a PKA activator) in spotted seabass hepatocytes under LP medium. Zebrafish were fed Z-LP diets (0.30% available phosphorus) containing Mdivi-1 (5 mg/kg, a Drp1 inhibitor) or 8Br-cAMP (0.5 mg/kg) for 6 weeks. Biochemical and molecular parameters, along with transmission electron microscopy and immunofluorescence, were used to assess hepatic glycolipid metabolism, mitochondrial function and morphology.
Results Spotted seabass fed S-LP diets showed reduced ATP (0.52-fold) and cyclic adenosine monophosphate (cAMP) (0.52-fold) levels, along with reduced Drp1 (s582) (0.38-fold) and PKA (0.61-fold) phosphorylation levels in the liver compared with those fed S-AP diets (P < 0.05). Drp1 knockdown elevated ATP levels (1.99-fold), decreased mitochondrial DRP1 protein levels (0.45-fold), and increased mitochondrial aspect ratio (1.82-fold) in LP-treated hepatocytes (P < 0.05). Furthermore, 8Br-cAMP-treated hepatocytes exhibited higher PKA phosphorylation (2.85-fold), ATP levels (1.60-fold), and mitochondrial aspect ratio (2.00-fold), along with decreased mitochondrial DRP1 protein levels (0.29-fold) under LP medium (P < 0.05). However, mutating s582 to alanine mimic Drp1 dephosphorylation decreased ATP levels (0.63-fold) and mitochondrial aspect ratio (0.53-fold) in 8Br-cAMP-treated hepatocytes (P < 0.05). In addition, zebrafish were fed Z-LP diets containing Mdivi-1 or 8Br-cAMP had higher ATP levels (3.44-fold or 1.98-fold) than that fed Z-LP diets (P < 0.05).
Conclusions These findings provide a potential mechanistic elucidation for LP-induced energy metabolism disorders through the cAMP/PKA/Drp1-mediated mitochondrial fission signaling pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping