Tuesday, 19 September 2017

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

Jonathon L. Burman, Sarah Pickles, Chunxin Wang, Shiori Sekine, Jose Norberto S. Vargas, Zhe Zhang, Alice M. Youle, Catherine L. Nezich, Xufeng Wu, John A. Hammer, Richard J. Youle


  • This study focuses on the interplay between mitophagy and mitochondrial fission. Whilst many studies have suggested that fission is required for mitophagy, there is mixed evidence on the issue
  • Authors express a mutant form of ornithine transcarbamylase (ΔOTC) in HeLa cells, which creates insoluable protein aggregates which localise to the mitochondrial matrix, inducing the mitochondrial unfolded protein response
  • This induces PINK1-Parkin-mediated mitophagy, to clear the ΔOTC aggregates
  • Mitochondria associated with Parkin were observed to fragment and traffic away from their parental mitochondrion. These mitochondria remain coated in Parkin
  • The authors overexpressed a dominant-negative mutant of the fission protein Drp1, effectively inhibiting fission. They found that, for both wild-type and ΔOTC, inhibition of fission did not reduce protein aggregate clearance. In fact, inhibition of mitochondrial fission fosters excessive PINK1-Parkin-mediated mitophagy of entire fused mitochondrial networks, even in the wild-type case. [The authors showed that Drp1-independent mitophagy was not dependent upon mitochondrial-derived vesicles (MDVs) through knockout of syntaxin 17, a protein involved in MDVs]
  • The authors suggest that mitochondrial fission (via Drp1) restricts mitophagic activity (via PINK1-Parkin) to specific, dysfunctional, mitochondrial subdomains by localising the PINK1-Parkin positive feedback loop away from healthy mitochondria

No comments:

Post a Comment