엄지현 (동아대학교 의과대학) | 한빛사논문 > 한빛사

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엄지현Jee-Hyun Um

동아대학교 의과대학

Exp. Mol. Med., Mar 05 2024, | https://doi.org/10.1038/s12276-024-01198-y The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress

Dae Jin Jeong^1,2,6, Jee-Hyun Um^1,2,6, Young Yeon Kim^1,2,6, Dong Jin Shin^1,2, Sangwoo Im^1,2, Kang-Min Lee^1,2, Yun-Hee Lee³, Dae-sik Lim⁴, Donghoon Kim^2,5 and Jeanho Yun^1,2

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

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

³College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

⁴Department of Biological Sciences, National Creative Research Center for Cell Plasticity, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.

⁵Department of Pharmacology, College of Medicine, Dong-A University, Busan, Korea.

⁶These authors contributed equally: Dae Jin Jeong, Jee-Hyun Um, Young Yeon Kim.

Corresponding author : Correspondence to Jeanho Yun.

Abstract

Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-07)
연구진국내 연구진
분야 생명과학 > 세포생물학

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