When my daughters were young, they were unfortunately caught up in the Where's Waldo? craze of the early 1990s. For those of you who do not remember — or who have happily forgotten — this was a series of children's books in which readers had to find Waldo (or Wally in the United Kingdom and Walter in Germany) amidst hundreds of people on a crowded page. I was reminded of this craze when I came across two recent articles, by Sandoval et al. and Schweers et al., that show that the BCL-2-family member NIX (also known as BNIP3L) has a crucial role in the degradation of mitochondria through mitophagy, which is a form of autophagy.
“...how do autophagosomes recognize one or two bad mitochondria amidst a sea of healthy lookalikes?”
Strict mitochondrial quality control is necessary to keep cells and organisms healthy and so has an important role in ageing. Mitophagy enables this quality control by targeting old, unhealthy or unnecessary mitochondria to the autophagosome for degradation. But herein lies the Waldo-like conundrum: how do autophagosomes recognize one or two bad mitochondria amidst a sea of healthy lookalikes? Using a specific model of mitophagy that occurs during the maturation of red blood cells, these papers showed that knockout of NIX inhibits mitophagy. Notably, NIX-dependent mitophagy occurs independently of other BCL-2-family members and can be mimicked by chemically altering the mitochondrial membrane potential.
Although further work is needed to determine whether NIX also functions in other mitophagic settings, these findings suggest that NIX might make specific mitochondria stand out for destruction by mediating subtle changes, perhaps in mitochondrial membrane potential or in reactive oxygen species release. NIX is probably only one part of the mechanism that underlies the specificity of mitophagy. The full mechanism — although unlikely to start a new wave of children's books — will enable us to better understand mitochondrial quality control and will provide valuable insight into ageing and age-related diseases.
ORIGINAL RESEARCH PAPERS
Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232–235 (2008)
Schweers, R. L. et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl Acad. Sci. USA 104, 19500–19505 (2007)
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Finkel, T. Where's Waldo for autophagosomes. Nat Rev Mol Cell Biol 10, 89 (2009). https://doi.org/10.1038/nrm2603
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DOI: https://doi.org/10.1038/nrm2603
