PUBLICATION
Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy
- Authors
- Bhandari, S., Kim, Y.I., Nam, I.K., Hong, K., Jo, Y., Yoo, K.W., Liao, W., Lim, J.Y., Kim, S.J., Um, J.Y., Kim, P.K., Lee, H.S., Ryu, D., Kim, S.H., Kwak, S., Park, R., Choe, S.K.
- ID
- ZDB-PUB-230224-43
- Date
- 2023
- Source
- Cellular and molecular life sciences : CMLS 80: 6969 (Journal)
- Registered Authors
- Bhandari, Sushil, Choe, Seong-Kyu, Kim, Seok-Hyung, Kim, Yong-Il, Yoo, Kyeong-Won
- Keywords
- Autophagy, Fasting, Mitochondria, Zellweger spectrum disorder, mTOR, pex5
- Datasets
- GEO:GSE205349
- MeSH Terms
-
- Animals
- Autophagy/physiology
- Fasting*
- Humans
- Mechanistic Target of Rapamycin Complex 1/metabolism
- Mitochondria*/metabolism
- Peroxisome-Targeting Signal 1 Receptor*/genetics
- Peroxisome-Targeting Signal 1 Receptor*/metabolism
- Peroxisomes/metabolism
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 36821008 Full text @ Cell. Mol. Life Sci.
Citation
Bhandari, S., Kim, Y.I., Nam, I.K., Hong, K., Jo, Y., Yoo, K.W., Liao, W., Lim, J.Y., Kim, S.J., Um, J.Y., Kim, P.K., Lee, H.S., Ryu, D., Kim, S.H., Kwak, S., Park, R., Choe, S.K. (2023) Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy. Cellular and molecular life sciences : CMLS. 80:6969.
Abstract
Animal models have been utilized to understand the pathogenesis of Zellweger spectrum disorders (ZSDs); however, the link between clinical manifestations and molecular pathways has not yet been clearly established. We generated peroxin 5 homozygous mutant zebrafish (pex5-/-) to gain insight into the molecular pathogenesis of peroxisome dysfunction. pex5-/- display hallmarks of ZSD in humans and die within one month after birth. Fasting rapidly depletes lipids and glycogen in pex5-/- livers and expedites their mortality. Mechanistically, deregulated mitochondria and mechanistic target of rapamycin (mTOR) signaling act together to induce metabolic alterations that deplete hepatic nutrients and accumulate damaged mitochondria. Accordingly, chemical interventions blocking either the mitochondrial function or mTOR complex 1 (mTORC1) or a combination of both improve the metabolic imbalance shown in the fasted pex5-/- livers and extend the survival of animals. In addition, the suppression of oxidative stress by N-acetyl L-cysteine (NAC) treatment rescued the apoptotic cell death and early mortality observed in pex5-/-. Furthermore, an autophagy activator effectively ameliorated the early mortality of fasted pex5-/-. These results suggest that fasting may be detrimental to patients with peroxisome dysfunction, and that modulating the mitochondria, mTORC1, autophagy activities, or oxidative stress may provide a therapeutic option to alleviate the symptoms of peroxisomal diseases associated with metabolic dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping