Mitochondrial outer membrane fusion is mediated by the mitofusins. Vertebrates have two mitofusin paralogs, Mfn1 and Mfn2 which are large GTPases that mediate membrane tethering and drive membrane remodeling.
Mutations in MFN2 lead to the rare neurodegenerative disorder, Charcot-Marie-Tooth Syndrome Type 2A (CMT2A). There is no cure and no treatment for this disease, due in part to our limited understanding of the biochemical mechanism of mitochondrial fusion.
Our lab utilizes functionally unique mitofusin variants and in vitro tools to tease out specific properties of the mitofusins and uncover insights into the overall mechanism of mitochondrial fusion.
Questions we are interested in answering:
The mitofusins are an interesting pair. While both are able to mediate fusion alone, we have found mitochondrial fusion is more efficient when Mfn1 and Mfn2 are found on opposing membranes. Why are there two in vertebrates? How are they the same and different? How do these proteins couple membrane tethering to membrane fusion? What is the role of the catalytic cycle?
Techniques commonly utilized:
Tissue culture, widefield and confocal microscopy, Blue-Native PAGE, reconstituted in vitro fusion assay, pure protein enzymatic assays, transition metal förster resonance energy transfer (tmFRET).
Model of mitochondrial fusion:
