Mitophagy, the autophagic degradation of mitochondria, is an important housekeeping function in eukaryotic cells, and defects in mitophagy correlate with ageing phenomena and with several neurodegenerative disorders. A central mechanistic question regarding mitophagy is whether mitochondria are consumed en masse, or whether an active process segregates defective molecules from functional ones within the mitochondrial network, thus allowing a more efficient culling mechanism. Here we combine a proteomic study with a molecular genetics and cell biology approach to determine whether such a segregation process occurs in yeast mitochondria. We find that different mitochondrial matrix proteins undergo mitophagic degradation at distinctly different rates, supporting the active segregation hypothesis. These differential degradation rates depend on mitochondrial dynamics, suggesting a mechanism coupling weak physical segregation with mitochondrial dynamics to achieve a distillation-like effect. In agreement, the rates of mitophagic degradation strongly correlate with the degree of physical segregation of specific matrix proteins.
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We thank Orian Shirihai, Leslie Kane, Ian Holt and J.-C. Martinou for stimulating and fruitful discussions, members of the Youle lab for support and encouragement, and Dikla Journo-Eckstien for technical assistance. We also thank J.-C. Martinou and Zvulun Elazar for critical reading of the manuscript. This work was funded by Israel Science Foundation grants 1016/07 and 422/12 to H.A., by the intramural programme of NINDS, and by the Excellence Initiative of the German Federal and State Governments through Freiburg Institute for Advanced Studies (FRIAS), School of Life Sciences – LifeNet (JD) and the Center for Biological Signaling Studies (BIOSS, JD), by grants DE 1757/2-1 from the German Research Foundation, DFG, and through GerontoSys II – NephAge (031 5896A) from the German Ministry for Education and Research, BMBF (JD), and by a grant from the Danish Natural Sciences Research Council (KTGR).