Outstanding Questions in Mitophagy: What We Do and Do Not Know

The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. Mitophagy, therefore, has an important contribution to cell function and integrity, which extends to the whole organism for development and survival. Research in mitophagy has boomed in recent years, and it is becoming clear that mitophagy is a complex and multi-factorial cellular response that depends on tissue, energetic, stress and signaling contexts. However, we know very little of its physiological regulation and the direct contribution of mitophagy to pathologies like neurodegenerative diseases. In this review, we aim to discuss the outstanding questions (and questions outstanding) in the field and reflect on our current understanding of mitophagy, the current challenges and the future directions to take. [Display omitted] •Mitophagy is a key mitochondrial quality control mechanism but how it is integrated with other quality control mechanisms still needs to be determined.•Mitophagy can occur under diverse conditions but whether distinct mechanisms operate for each of these remains unclear.•Three main molecular events occur during mitophagy initiation: (1) Fission from mitochondrial network, (2) mitochondrial priming with “eat-me” signals, and (3) phagophore recruitment to mitochondria to be engulfed. We still do not know if these events have to occur sequentially or in concert.•Impaired mitophagy has been associated with pathologies such as neurodegenerative diseases, but we still have a limited understanding of how it contributes to the diseases state and whether there are therapeutic opportunities to manipulate this process.