Experimental and Molecular Medicine (Mar 2024)

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress

  • Dae Jin Jeong,
  • Jee-Hyun Um,
  • Young Yeon Kim,
  • Dong Jin Shin,
  • Sangwoo Im,
  • Kang-Min Lee,
  • Yun-Hee Lee,
  • Dae-sik Lim,
  • Donghoon Kim,
  • Jeanho Yun

DOI
https://doi.org/10.1038/s12276-024-01198-y
Journal volume & issue
Vol. 56, no. 3
pp. 674 – 685

Abstract

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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.