PMID- 36821008 OWN - NLM STAT- MEDLINE DCOM- 20230227 LR - 20230315 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 80 IP - 3 DP - 2023 Feb 23 TI - Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy. PG - 69 LID - 10.1007/s00018-023-04700-3 [doi] LID - 69 AB - 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. CI - (c) 2023. The Author(s). FAU - Bhandari, Sushil AU - Bhandari S AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. FAU - Kim, Yong-Il AU - Kim YI AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. FAU - Nam, In-Koo AU - Nam IK AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. AD - Institute of Brain Science, Wonkwang University, Iksan, 54538, South Korea. FAU - Hong, KwangHeum AU - Hong K AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. FAU - Jo, Yunju AU - Jo Y AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. AD - Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea. FAU - Yoo, Kyeong-Won AU - Yoo KW AD - Department of Microbiology, Wonkwang University School of Medicine, Iksan, 54538, South Korea. FAU - Liao, Weifang AU - Liao W AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. FAU - Lim, Jae-Young AU - Lim JY AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. FAU - Kim, Seong-Jin AU - Kim SJ AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. AD - Department of Biomedical Science, Graduate School, Wonkwang University, Iksan, 54538, South Korea. FAU - Um, Jae-Young AU - Um JY AD - Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, South Korea. FAU - Kim, Peter K AU - Kim PK AD - Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada. FAU - Lee, Ho Sub AU - Lee HS AD - Hanbang Cardio-Renal Research Center, Wonkwang University, Iksan, 54538, South Korea. FAU - Ryu, Dongryeol AU - Ryu D AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. AD - Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea. FAU - Kim, Seok-Hyung AU - Kim SH AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. FAU - Kwak, SeongAe AU - Kwak S AD - Hanbang Cardio-Renal Research Center, Wonkwang University, Iksan, 54538, South Korea. FAU - Park, Raekil AU - Park R AD - Department of Biomedical Science and Engineering, Institute of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea. FAU - Choe, Seong-Kyu AU - Choe SK AUID- ORCID: 0000-0002-2102-973X AD - Department of Medicine, Graduate School, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr. AD - Sarcopenia Total Solution Center, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr. AD - Department of Microbiology, Wonkwang University School of Medicine, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr. AD - Department of Biomedical Science, Graduate School, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr. AD - Institute of Wonkwang Medical Science, Wonkwang University, Iksan, 54538, South Korea. seongkyu642@wku.ac.kr. LA - eng GR - 2021R1A5A8029876/National Research Foundation of Korea/ GR - MOF-No. 20180430/Korea Institute of Marine Science and Technology promotion/ GR - 2019R1I1A3A01061491/National Research Foundation of Korea/ GR - 2017R1A5A2015805/National Research Foundation of Korea/ GR - 2022R1A2C2005930/National Research Foundation of Korea/ PT - Journal Article DEP - 20230223 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Peroxisome-Targeting Signal 1 Receptor) SB - IM MH - Animals MH - Humans MH - Autophagy/physiology MH - *Fasting MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - *Mitochondria/metabolism MH - Peroxisomes/metabolism MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - *Zebrafish/genetics/metabolism MH - *Peroxisome-Targeting Signal 1 Receptor/genetics/metabolism PMC - PMC9950184 OTO - NOTNLM OT - Autophagy OT - Fasting OT - Mitochondria OT - Zellweger spectrum disorder OT - mTOR OT - pex5 COIS- The authors declare no relevant financial or non-financial interest to disclose. EDAT- 2023/02/24 06:00 MHDA- 2023/03/03 06:00 PMCR- 2023/02/23 CRDT- 2023/02/23 11:31 PHST- 2021/11/23 00:00 [received] PHST- 2023/01/09 00:00 [accepted] PHST- 2022/12/30 00:00 [revised] PHST- 2023/02/23 11:31 [entrez] PHST- 2023/02/24 06:00 [pubmed] PHST- 2023/03/03 06:00 [medline] PHST- 2023/02/23 00:00 [pmc-release] AID - 10.1007/s00018-023-04700-3 [pii] AID - 4700 [pii] AID - 10.1007/s00018-023-04700-3 [doi] PST - epublish SO - Cell Mol Life Sci. 2023 Feb 23;80(3):69. doi: 10.1007/s00018-023-04700-3.