The role of Optineurin in neuronal mitophagy

Identification: Evans, Chantell


The role of Optineurin in neuronal mitophagy
Chantell S. Evans1 and Erika L. F. Holzbaur1
1Department of Physiology, University of Pennsylvania
The mitochondrial network is a system of dynamic, interconnected organelles that continuously undergo rearrangement and renewal to maintain cellular demands. Due to their high metabolic needs, neurons rely heavily on the targeted delivery and regulated removal of mitochondria at fusion sites located far from the soma. Defects in the selective removal of acutely damaged or aged mitochondria, a process termed mitophagy, have been linked to multiple neurodegenerative diseases. In addition, mutations in proteins involved in this pathway were found to cause Parkinson's disease, amyotrophic lateral sclerosis (ALS), and glaucoma, suggesting that mitochondrial turnover may be a key mechanism contributing to disease. Due to these findings, it is now essential to characterize the functional significance of these proteins in neurons. Here, we use multicolor live-cell imaging to observe the recruitment of optineurin, and other mitophagy-associated proteins, to damaged mitochondrial fragments in primary hippocampal neurons. We find that mild oxidative stress induces low levels of mitochondrial damage without compromising the entire neuronal network, as determined by the mitochondrial content. Under stressed conditions, we visualized the dynamic recruitment of optineurin to damaged mitochondria, visualized as optineurin rings around spherical mitochondrial fragments. Subsequently, we observed that optineurin recruits LC3 which allows for autophagosome engulfment and degradation of damaged mitochondria via lysosomal fusion. Imaging neuronal compartments, we find an enhanced accumulation of optineurin positive mitochondria in the somal compartment of treated neurons; however, optineurin recruitment was rarely visualized in dendrites and axons. Together, these results indicate that neuronal optineurin-mediated mitophagy is compartmentally restricted. It is predicted that expression of disease-associated mutations of optineurin in neurons will impede this process, resulting in inefficient turnover and an increase in damaged mitochondria. Thus, an understanding of mitochondrial quality control in neurons could provide key insights into the pathobiology of neurodegenerative diseases.


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