Tuesday 26 September 2017

Live imaging reveals the dynamics and regulation of mitochondrial nucleoids during the cell cycle in Fucci2-HeLa cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595809/

Taeko Sasaki, Yoshikatsu Sato, Tetsuya Higashiyama, Narie Sasaki

  •  Authors investigate the dynamics of mitochondrial DNA replication through the cell cycle by labelling HeLa cells with Fucci markers (a fluorescent probe which changes color according to the cell cycle stage) and SYBR Green I (which stains mtDNA)
  • Observe that mitochondrial nucleoids often attach/detach from each other
  • Mitochondrial replication occurs throughout the cell cycle, but peaks during the S-phase

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

http://jcb.rupress.org/content/early/2017/09/11/jcb.201612106.long

  • 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

Tuesday 12 September 2017

Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster

Rana A, Oliveira MP, Khamoui AV, Aparicio R, Rera M, Rossiter HB, Walker DW

https://www.nature.com/articles/s41467-017-00525-4 


  • Transient induction of Drp1-mediated fission for 7 days during midlife of the fruit fly D. melanogaster is sufficient to extend lifespan. (Note that Drp-1 upregulation in early life had no significant impact on longevity)
  • Short-term midlife Drp1 induction gave increased day-time physical activity levels, suggesting an extension of healthy lifespan, rather than prolonging frailty. These flies also had improved starvation resistance, improved fertility, and delayed intestinal aging.
  • In flight muscle, elongated mitochondrial morphology was associated with lowered mitochondrial membrane potential, accumulation of dysfunctional mitochondria, lowered OXPHOS complex activity, increased ROS and lowered respiration with aging. These phenotypes are reversed upon short-term midlife Drp1 induction.
  • These effects were not mediated by the mitochondrial unfolded protein response. 
  • Short-term midlife Drp1 induction reduced levels of protein aggregates in aged muscle and aged brain tissue
  • Disruption of mitophagy, via Atg1 inhibition, inhibits the anti-aging effects of midlife Drp1 induction.