Editors' ChoiceNeurodegeneration

ALS and Parkinson’s Disease Meet at Mitophagy

Sci. Signal.  04 Nov 2014:
Vol. 7, Issue 350, pp. ec309
DOI: 10.1126/scisignal.aaa2036

Autophagy is a quality control pathway that degrades unnecessary or dysfunctional intracellular components through the activity of specialized lysosomes called autophagosomes. The clearance of damaged mitochondria (called mitophagy) is mediated by the E3 ubiquitin ligase parkin, which deposits ubiquitin on outer mitochondrial membrane proteins, thereby targeting the organelle for degradation. Impaired clearance of dysfunctional mitochondria is implicated in Parkinson’s disease. Mitochondrial dysfunction is also implicated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that is linked to mutations in optineurin (OPTN), a protein that binds ubiquitin as well as the microtubule-associated protein LC3 on autophagosomes. Using live-cell imaging in HeLa cells, Wong and Holzbaur found that OPTN was critical for parkin-mediated mitophagy. In cells expressing yellow fluorescent protein (YFP)–labeled parkin and treated with carbonyl-cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial-depolarizing (damaging) agent, endogenous OPTN surrounded mitochondrial fragments. Live-cell imaging of cells coexpressing YFP-parkin and green fluorescent protein (GFP)–labeled OPTN showed that CCCP induced first YFP-parkin then GFP-OPTN recruitment to mitochondria. Expression of a catalytically inactive parkin mutant (T240R) abolished the recruitment OPTN to mitochondria. The ALS-associated OPTN mutant has a point mutation (E478G) in its ubiquitin-binding domain. In HeLa cells expressing YFP-parkin and treated with CCCP, GFP-OPTNE478G was not recruited to the surface of damaged mitochondria, despite the recruitment of parkin. Knocking down OPTN inhibited the engulfment of damaged mitochondria by autophagosomes. Mitochondrial engulfment by autophagosomes was rescued by expression of wild-type OPTN but not by the ALS-associated UBAN mutant or by a mutant unable to bind LC3. Thus, two distinct neurodegenerative diseases may be caused by defects in mitophagy.

Y. C. Wong, E. L. F. Holzbaur, Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl. Acad. Sci. U.S.A. 111, E4439–E4448 (2014). [Abstract] [Full Text]