Title:
Mitochondrial quality control and Parkinson’s disease

 

Koji Yamano
Ubiquitin project, Tokyo Metropolitan Institute of Medical Science

 

Abstract:
Excess mitochondrial stress and/or mitochondrial dysfunction are implicated in the development of neurodegenerative disease such as Parkinson’s disease. Damaged mitochondria, in which the inner membrane potential is reduced, are known to be degraded by autophagy machinery in a process called mitophagy. Two gene products mutated in the autosomal recessive forms of familial early-onset Parkinson’s disease, Parkin and PINK1, have been found to play a central role in triggering mitophagy. Genetic and cell biological studies indicate that a mitochondrial serine/threonine kinase PINK1 acts in the same pathway as the cytosolic E3 ligase Parkin by recruiting Parkin to damaged mitochondria to induce their elimination through mitophagy. Furthermore, recent progress has been made in understanding how PINK1 and Parkin work together through a novel stepwise cascade to identify and eliminate damaged mitochondria, a process that relies on the orchestrated crosstalk between ubiquitin signaling and autophagy. In this seminar, I will highlight our current understanding of the detailed molecular mechanisms governing Parkin/PINK1-mediated mitophagy.

 

References:
1) Yamano, K. et al. (2016) The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation. EMBO Rep. in press
2) Yamano, K. et al. (2015) Site-specific interaction mapping of phosphorylated ubiquitin to uncover Parkin activation. J. Biol. Chem. 290, 25199-25211.
3) Yamano, K., et al. (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. Elife, 3:e01612.
4) Hasson, SA., Kane, LA., Yamano, K., et al. (2013) High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504, 291-295.
5) Yamano, K., and Youle, RJ. (2013) PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758-1769.