Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy
Sushil Bhandari, Yong‐Il Kim, In-Koo Nam, KwangHeum Hong, Yunju Jo, Kyeong‐Won Yoo, Weifang Liao, Jae‐Young Lim, Seong‐Jin Kim, Jae‐Young Um, Peter K. Kim, Ho Sub Lee, Dongryeol Ryu, Seok-Hyung Kim, SeongAe Kwak, Raekil Park, Seong‐Kyu Choe
Abstract
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.