Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy.

Autor: Bhandari S; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea., Kim YI; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea., Nam IK; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea.; Institute of Brain Science, Wonkwang University, Iksan, 54538, South Korea., Hong K; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea.; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea., Jo Y; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea.; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea., Yoo KW; Department of Microbiology, Wonkwang University School of Medicine, Iksan, 54538, South Korea., Liao W; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea.; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea., Lim JY; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea., Kim SJ; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea.; Department of Biomedical Science, Graduate School, Wonkwang University, Iksan, 54538, South Korea., Um JY; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, South Korea., Kim PK; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada., Lee HS; Hanbang Cardio-Renal Research Center, Wonkwang University, Iksan, 54538, South Korea., Ryu D; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea.; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea., Kim SH; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea., Kwak S; Hanbang Cardio-Renal Research Center, Wonkwang University, Iksan, 54538, South Korea., Park R; Department of Biomedical Science and Engineering, Institute of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea., Choe SK; Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr.; Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr.; Department of Microbiology, Wonkwang University School of Medicine, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr.; Department of Biomedical Science, Graduate School, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr.; Institute of Wonkwang Medical Science, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2023 Feb 23; Vol. 80 (3), pp. 69. Date of Electronic Publication: 2023 Feb 23.
DOI: 10.1007/s00018-023-04700-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: