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

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.,Mitochondria, the energy producers of cells, are vital for cell function and energy balance. But, when stressed, they can malfunction and contribute to brain diseases like Parkinson's and Alzheimer's. This study found that two proteins, Mst1/2, are important for triggering mitophagy-a process that removes damaged mitochondria, in response to different mitochondrial stresses. The researchers found that Mst1/2 control this process through their kinase activity-a type of protein modification, and the stabilization of another protein, BNIP3. They also discovered that Mst1/2 are key in maintaining mitochondrial health and cell survival under conditions harmful to neurons. This research, led by Dr. Jeanho Yun and team, suggests that targeting the Mst1/2 pathway could improve mitochondrial health and protect against brain diseases.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.,