Back to Top
Charles H. Hood Foundation | Luke Chao, Ph.D. – July 2018
By identifying innovative pediatric advancements and providing funding in the critical phases of development, we are able to expedite high-impact breakthroughs that improve the health and lives of millions.
portfolio_page-template-default,single,single-portfolio_page,postid-17173,ajax_fade,page_not_loaded,,qode-title-hidden,qode-child-theme-ver-1.0.0,qode-theme-ver-10.0,wpb-js-composer js-comp-ver-4.12,vc_responsive
Luke Chao --

Luke Chao, Ph.D.

Assistant Professor

Massachusetts General Hospital

Characterization of OPA1 Membrane Phenotypes in Childhood Blindness


Key Words: Dominant Optic Atrophy, Membrane Dynamics, Membrane Morphology

Mutation in OPA1 results in dominant optic atrophy, the most frequent form of hereditary optic neuropathy resulting from devastating degeneration of retinal ganglion cells. A dynamin family GTPase, OPA1 catalyzes mitochondrial inner membrane fusion, maintains the mitochondrial network and mediates cristae structure. OPA1’s multiple roles make it an essential regulator of mitochondrial bioenergetics and an initiator of cytochrome-c mediated cell death. The importance of OPA1 in membrane homeostasis is underscored by the prevalence of mutations across the entire protein. Rescuing OPA1 activity is an attractive strategy to prevent the onset of childhood blindness. Yet, targeted design of treatments is limited by lack of molecular understanding of how specific mutations alter OPA1’s different activities.


Dynamin family GTPases mediate membrane rearrangement through a GTP-coupled series of conformational rearrangements. A central outstanding question is how OPA1 protein conformation relates to its membrane functions. We hypothesize that OPA1 conformational states sampled during membrane fusion are essential mediators of membrane morphology.


To test idea, we will reconstitute biochemically OPA1 activity and resultant membrane outcomes in vitro to decouple the functional effects of specific mutations. I have previously reconstituted and captured snapshots of flavivirus membrane fusion with single particle fluorescence imaging. This format allows controlled dissection of the interplay between membrane composition and protein state inaccessible in cellular environments. I have now reconstituted OPA1 to build an experimental system that allows us to functionally decouple the different stages of membrane fusion and membrane remodeling. We will investigate the effect of patient-derived mutations on membrane fusion using this system to determine specific functional signatures (Aim1). We will determine the effects of patient mutation on protein and membrane conformation to identify states important for therapeutic intervention (Aim 2). This work makes the essential first steps towards targeted treatment to relieve a devastating form of child blindness.