Live imaging defines the dynamics and molecular basis of in vivo mitophagy

Mitophagy defects are linked to aging, sarcopenia, and neurodegenerative diseases. To target this process for clinical intervention, the in vivo mitophagy dynamics and molecular mechanisms under physiologically relevant stresses must be better understood. Here, we characterized newly generated mitophagy reporter zebrafish and discovered high basal mitophagy rates in many organs during embryonic development and organogenesis. Rapid time-lapse imaging revealed in vivo dynamics of fasting-induced mitophagy, which occur via a piecemeal process. Baseline and stress-induced mitophagy were precisely assessed through ratiometric and volumetric image quantification algorithms. Activation of Hypoxia-inducible factor through physiological stress or chemical or genetic modulation provoked bnip3-dependent mitophagy in muscle independent of pink1. Surprisingly, disruption of bnip3la (nix) or fundc1, putative hypoxia-associated mitophagy receptors, had no effect on mitophagy. Our results discover fundamental mitophagy dynamics and molecular mechanisms with important implications for mitochondrial quality control and highlight the importance of live imaging in vivo studies.