Mitophagy is required for cell survival upon ultrasound and microbubble therapeutic exposure

Ultrasound-stimulated microbubble (USMB) sonoporation treatment is an emerging strategy for cancer therapy that enhances drug delivery by perforating the plasma membrane. This membrane permeabilization also causes cellular metabolic stress as cells leak metabolites such as ATP and amino acids. Collectively, cells may die in response to excess membrane damage and stress. However, many cells survive the USMB insult by engaging membrane repair and adaptation pathways such as stimulation of AMPK. In this study, we investigated the impact of USMB treatment on mitochondria and their role in post-exposure cellular survival. We found that USMB causes mitochondrial fragmentation and decreases mitochondrial membrane potential. Subsequently, autophagy and Parkin-dependent mitophagy are triggered post-USMB treatment in an AMPK-dependent mechanism. Importantly, Parkin silencing and PINK1 inhibition augment cell death when combined with USMB exposure, suggesting that mitophagy is an important cell survival process in response to USMB. We propose that combining USMB with inhibitors of mitophagy and metabolic stress adaptation is a strong candidate for therapeutic development to treat solid tumours.