Mitochondrial quality control beyond PINK1/Parkin

Neurons strictly rely on proper mitochondrial function and turnover. They possess a high energy requirement which is mostly fueled by mitochondrial oxidative phosphorylation. Moreover the unique morphology of neurons implies that mitochondria need to be transported along the axons to sites of high energy demand. Finally, due to the non-dividing state of neurons, cellular mitosis cannot dilute dysfunctional mitochondria, which can produce harmful by-products such as reactive oxygen species (ROS) and thus a functioning mechanism of quality control (QC) is essential. The critical impact of mitochondria on neuronal function and viability explains their involvement in several neurodegenerative diseases such as Parkinson’s disease (PD) [1]. Mitophagy, a selective form of autophagy, is employed by cells to degrade dysfunctional mitochondria in order to maintain a healthy mitochondrial network, a process also called mitochondrial QC. In order for mitophagy to take place it essentially requires molecules that on the one hand sense the dysfunctional mitochondria and on the other hand tag the latter for autophagic degradation. Most studies on mitophagy are focused on a canonical pathway including the PD-related proteins PINK1 and Parkin. PINK1 is a kinase that recruits the E3 ubiquitin ligase Parkin to depolarized mitochondria, where it ubiquitinates several target proteins on the outer mitochondrial membrane (OMM) leading to their proteasomal degradation and serving as a signal to recruit the autophagic machinery [1] (Figure 1, upper left corner). A large number of studies on PINK1/Parkin mitophagy are based on treatment of cell lines with the uncoupler CCCP collapsing the mitochondrial membrane potential (ΔΨm), as well as overexpression of Parkin, conditions that are far from physiological [1]. Furthermore, Parkin translocation to mitochondria in neuronal cells occurs only under certain stimuli and is much slower, possibly due to their metabolic state and low endogenous Parkin expression [2]. Thus, in recent years several studies have highlighted pathways of mitophagy induction that are independent of PINK1 and/or Parkin and could act in parallel or addition to the latter. We want to discuss what is known about these QC mechanisms and hypothesize on their role in neuronal physiology and neurodegeneration. Alternative mitophagy pathways can basically branch into or parallel the PINK1/Parkin pathway at any point ranging from Parkin translocation to autophagosome formation. However, most studies are focused on two steps: ubiquitination of OMM proteins by E3 ubiquitin ligases Editorial