김용일 (원광대학교, 현 University of Colorado Anschutz Medical Campus) | 한빛사논문 > 한빛사

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원광대학교, 현 University of Colorado Anschutz Medical Campus

Cell. Mol. Life Sci., 2023 Feb 23;80(3):69 | https://doi.org/10.1007/s00018-023-04700-3 Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy

Sushil Bhandari¹ · Yong‑Il Kim¹ · In‑Koo Nam^2,3 · KwangHeum Hong^1,2 · Yunju Jo^2,4 · Kyeong‑Won Yoo⁵ · Weifang Liao^1,2 · Jae‑Young Lim¹ · Seong‑Jin Kim^2,6 · Jae‑Young Um⁷ · Peter K. Kim⁸ · Ho Sub Lee⁹ · Dongryeol Ryu^2,4 · Seok‑Hyung Kim² · SeongAe Kwak⁹ · Raekil Park¹⁰ · Seong‑Kyu Choe^1,2,5,6,11

¹ Department of Medicine, Graduate School, Wonkwang University, Iksan 54538, South Korea
² Sarcopenia Total Solution Center, Wonkwang University, Iksan 54538, South Korea
³ Institute of Brain Science, Wonkwang University, Iksan 54538, South Korea
⁴ Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
⁵ Department of Microbiology, Wonkwang University School of Medicine, Iksan 54538, South Korea
⁶ Department of Biomedical Science, Graduate School, Wonkwang University, Iksan 54538, South Korea
⁷ Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, South Korea
⁸ Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
⁹ Hanbang Cardio-Renal Research Center, Wonkwang University, Iksan 54538, South Korea
¹⁰ Department of Biomedical Science and Engineering, Institute of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju 61005, South Korea
¹¹ Institute of Wonkwang Medical Science, Wonkwang University, Iksan 54538, South Korea

Sushil Bhandari, Yong-Il Kim and In-Koo Nam contributed equally as frst authors.
Corresponding author : Correspondence to Seong-Kyu Choe.

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.

논문정보

형식Research article
게재일2023년 02월 (BRIC 등록일 2023-03-07)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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