Convergence of parkin, PINK1 and α-synuclein on stress-induced mitochondrial morphological remodelling

http://www.jbc.org/content/early/2015/04/10/jbc.M114.634063


Kristi L. Norris et al.

Parkin is a ubiquitin ligase proposed to promote the removal of damaged mitochondria. In this paper they observe that under moderate stress conditions in MEFs, parkin does not stimulate the degradation of mitochondria (mitophagy) but rather increases mitochondrial fusion.

In previous studies, treating cells with the mitochondrial uncoupler CCCP causes parkin to translocate to depolarized mitochondria which are then removed by mitophagy. However, as observed in this paper, when lowering concentrations of CCCP, no translocation of parkin to mitochondria or mitophagy is observed. Instead, mitochondria elongate.  Parkin negative MEFs underwent fission upon CCCP treatment. Various kinds of mitochondrial stress (rotenone and hypdrogen peroxide treatments) showed similar results.

Both the mitochondrial fusion proteins Mfn1,2 and PINK1 are required for Parkin-mediated mitochondrial fusion, as well as ubiquitin E3 ligase activity of Parkin. Under stress conditions, Parkin seems to form a complex with alpha-synuclein (alpha-synuclein has been shown to induce mitochondrial fission) and Parkin catalyzes ubiquitination of species. The interaction between Parkin and alpha-synuclein during stress negatively regulates the activity of alpha-synuclein which leads to the observed mitochondrial fusion.