Commitment in the PINK1/Parkin mitophagy decision circuit

Mechanisms that prevent accidental degradation of healthy mitochondria by the PINK1/Parkin mitophagy pathway are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we quantitatively mapped the relationship between PINK1 input levels and Parkin recruitment dynamics using live-cell microscopy and mathematical modeling. We found that Parkin is recruited to the mitochondria only if PINK1 levels exceed a threshold and only after a delay that is inversely proportional to PINK1 levels. The threshold and delay provide a “two-factor authentication” step for PINK1/Parkin activation. These properties arise from the PINK1/Parkin circuit topology and provide a mechanism for cells to assess damage signals before committing to mitophagy. ### Competing Interest Statement Steven J. Altschuler and Lani F. Wu are founders and scientific advisory board members of Nine Square Therapeutics.