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Theranostics 2024; 14(1):56-74. doi:10.7150/thno.88718 This issue Cite

Research Paper

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models

Jee-Hyun Um1,2*, Dong Jin Shin1,2,3*, Se Myeong Choi4*, Alen Benhur Pravin Nathan5*, Young Yeon Kim1,2,3, Da Ye Lee1,2,3, Dae Jin Jeong1,2,3, Dong Hyun Kim6, Kyung Hwa Kim7, Young Hye Kim8, Jihoon Nah9, Jeong-hee Jeong10, Eunhee Yoo10, Hwa Kyoung Shin11, Hwan Tae Park1,3,12, Jihoon Jo5✉, Jong Hyun Cho3,4✉, Jeanho Yun1,2,3✉

1. Peripheral Neuropathy Research Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
2. Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea.
3. Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea.
4. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea.
5. Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
6. Department of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, Republic of Korea.
7. Department of Health Sciences, The Graduate School of Dong-A University, 840 Hadan-dong, Saha-gu, Busan 49315, Republic of Korea.
8. Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Chungbuk, 28119, Republic of Korea.
9. Department of Biochemistry, Chungbuk National University, Cheongju, Republic of Korea.
10. Altmedical Co., Ltd. Seoul, 02792, Republic of Korea.
11. Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea.
12. Department of Molecular Neuroscience, College of Medicine, Dong-A University, Busan, Republic of Korea.
*J.H. Um, D.J. Shin, S.M. Choi and A. Nathan contributed equally to this paper.

✉ Corresponding authors: Jihoon.Joac.kr; Jong Hyun Cho: jhcho1ac.kr; Jeanho Yun: yunjac.kr.

Citation:
Um JH, Shin DJ, Choi SM, Nathan ABP, Kim YY, Lee DY, Jeong DJ, Kim DH, Kim KH, Kim YH, Nah J, Jeong Jh, Yoo E, Shin HK, Park HT, Jo J, Cho JH, Yun J. Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics 2024; 14(1):56-74. doi:10.7150/thno.88718. https://www.thno.org/v14p0056.htm
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Abstract

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Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD.

Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects.

Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy.

Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Keywords: mitophagy inducer, alternative mitophagy, Alzheimer's disease, mitochondrial dysfunction, Rab9

Citation styles

APA
Um, J.H., Shin, D.J., Choi, S.M., Nathan, A.B.P., Kim, Y.Y., Lee, D.Y., Jeong, D.J., Kim, D.H., Kim, K.H., Kim, Y.H., Nah, J., Jeong, J.h., Yoo, E., Shin, H.K., Park, H.T., Jo, J., Cho, J.H., Yun, J. (2024). Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics, 14(1), 56-74. https://doi.org/10.7150/thno.88718.

ACS
Um, J.H.; Shin, D.J.; Choi, S.M.; Nathan, A.B.P.; Kim, Y.Y.; Lee, D.Y.; Jeong, D.J.; Kim, D.H.; Kim, K.H.; Kim, Y.H.; Nah, J.; Jeong, J.h.; Yoo, E.; Shin, H.K.; Park, H.T.; Jo, J.; Cho, J.H.; Yun, J. Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics 2024, 14 (1), 56-74. DOI: 10.7150/thno.88718.

NLM
Um JH, Shin DJ, Choi SM, Nathan ABP, Kim YY, Lee DY, Jeong DJ, Kim DH, Kim KH, Kim YH, Nah J, Jeong Jh, Yoo E, Shin HK, Park HT, Jo J, Cho JH, Yun J. Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics 2024; 14(1):56-74. doi:10.7150/thno.88718. https://www.thno.org/v14p0056.htm

CSE
Um JH, Shin DJ, Choi SM, Nathan ABP, Kim YY, Lee DY, Jeong DJ, Kim DH, Kim KH, Kim YH, Nah J, Jeong Jh, Yoo E, Shin HK, Park HT, Jo J, Cho JH, Yun J. 2024. Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics. 14(1):56-74.

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