Our research is focused on understanding the mechanism of mitochondrial fusion and how it’s integrated into cellular functions.
Mitochondria form dynamic networks that constantly move, fuse and divide. These dynamic properties are essential for normal mitochondrial function and are regulated by diverse processes including the cell cycle, cell stress or programmed cell death.
Mitochondrial dysfunction has been implicated in a variety of human diseases including Huntington’s, Alzheimer’s, Parkinson’s, diabetes, heart disease and cancer. The role of mitochondrial dysfunction in the etiology of these diseases has been hard to elucidate due to the relatively little knowledge of how mitochondrial functions are coupled to one another or to extra-mitochondrial processes.
We are using biochemical, structural and cellular approaches to dissect the mechanism of membrane fusion.
1. The mechanism of mitochondrial membrane fusion. There are two proteins required for vertebrate mitochondrial fusion. Mitofusin1 and Mitofusin2 (Mfn1 & Mfn2) are large GTPases that mediate membrane tethering and fusion. Mfn1 and Mfn2 are an interesting pair. Each is capable of supporting fusion, but are much more effective when located on opposing membranes of the fusion pair. 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?
2. The regulation of mitochondrial fusion. There are many ways to regulate the rate of mitochondrial fusion in cells. We are interested in identifying pathways that regulate Mfn1, Mfn2 or both and to interrogate the molecular mechanism that mediates the change.
3. Molecular basis for CMT-2a, the neurodegenerative disease caused by mutations in Mfn2. Although Mfn1 and Mfn2 both function non-redundantly in fusion, only mutations in Mfn2 have been associated with a human disease. Mfn2 has also been implicated in other cellular functions including a role in mitochondrial-ER contact sites, apoptotic cell death, and anti-viral signaling pathways. We are investigating the loss of function associated with CMT2a alleles of Mfn2.