UCSF

Mitochondria accumulate damage over time. Cells maintain a healthy pool of mitochondria by targeting damaged mitochondria for mitophagy (mitochondrial degradation) via the PINK1/Parkin biological circuit. Specifically, the kinase PINK1 accumulates on the surface of damaged mitochondria, where it triggers activation of a positive feedback loop involving Parkin. Activation of this positive feedback loop targets damaged mitochondria for lysosomal degradation (mitophagy). However, PINK1 is also present, at low levels, on healthy mitochondria where it could errantly activate the positive feedback loop and target healthy mitochondria for degradation. How, then, does the PINK1/Parkin circuit interpret mitochondrial PINK1 concentrations to differentiate between healthy and damaged mitochondria?

Here, I applied principles of systems and cell biology to identify emergent behaviors that could allow the PINK1/Parkin circuit to distinguish between damaged and healthy mitochondria. Using a synthetic circuit approach, I mapped the circuit’s activation response (Parkin recruitment to mitochondria) across a range of circuit input levels (PINK1 concentration on mitochondria). I found that Parkin is only recruited to mitochondria when the mitochondrial PINK1 concentration exceeds a threshold, and then only after a delay that is inversely proportional to PINK1 concentration. Next, I used a combination of PINK1 and Parkin mutants, to explore the dependencies of the identified regulatory behaviors. I found that both the PINK1 input threshold and the input-reciprocal activation delay behaviors are linked to the circuit’s positive feedback architecture, termed here as input-coupled positive feedback. Finally, I collaborated with a mathematician to show that input-coupled positive feedback in the PINK1/Parkin circuit is sufficient to generate these two regulatory behaviors. In sum, these results describe a pair of emergent regulatory properties that can allow the PINK1/Parkin positive feedback circuit to avoid activation on healthy mitochondria by interpreting the strength and duration of a PINK1 input signal.