A novel marine‐derived mitophagy inducer ameliorates mitochondrial dysfunction and thermal hypersensitivity in paclitaxel‐induced peripheral neuropathy

Author:

Im Sangwoo12,Jeong Dae Jin12,Kim Eunmi12,Choi Jae‐Hyeong34,Jang Hye‐Ji12,Kim Young Yeon12,Um Jee‐Hyun12,Lee Jihoon34,Lee Yeon‐Ju34,Lee Kang‐Min12,Choi Dabin5,Yoo Eunhee5,Lee Hyi‐Seung34,Yun Jeanho12

Affiliation:

1. Department of Biochemistry, College of Medicine Dong‐A University Busan Republic of Korea

2. Department of Translational Biomedical Sciences Graduate School of Dong‐A University Busan Republic of Korea

3. Korea Institute of Ocean Science & Technology (KIOST) Busan Republic of Korea

4. Department of Applied Ocean Science University of Science and Technology Daejeon Republic of Korea

5. Altmedical Co., Ltd Seoul Republic of Korea

Abstract

AbstractBackground and PurposeMitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy‐induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy‐inducing activity of 3,5‐dibromo‐2‐(2′,4′‐dibromophenoxy)‐phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model.Experimental ApproachMitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt‐Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH‐SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel‐induced thermal hyperalgesia phenotype in Drosophila larvae.Key ResultsPDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel‐induced mitochondrial dysfunction in both SH‐SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel‐induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction.Conclusion and ImplicationsThis study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy‐inducing compounds.

Funder

National Research Foundation of Korea

Korea Health Industry Development Institute

Ministry of Oceans and Fisheries

Korea Basic Science Institute

Publisher

Wiley

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