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Mitochondrial hyperfusion


We have more recently become interested in roles of mitochondrial dynamics and how this controls rates of mitophagy.  Mitochondria constantly undergo cycles of fission to generate smaller organelles, counterbalanced by fusion, which forms larger interconnected networks.  Fusion has been shown to be an adaptive response nutrient starvation, thereby generating larger mitochondrial structures that are able to avoid capture by autophagosomes.   Fusion has been shown to be an adaptive response nutrient starvation, thereby generating larger mitochondrial structures that are able to avoid capture by autophagosomes.  While we have indeed observed this adaptive mechanism, surprisingly we discovered that addition of signaling amino acids stimulated more extensive mitochondrial hyperfusion (Abdullah et al 2022).   


Through investigation of the underlying mechanism, we found that supplementation of amino acids glutamine, leucine and arginine leads to metabolic reprogramming via the TCA cycle and the formation of the nucleotide GTP. In our model, we hypothesize that amino acid derived GTP is being sensed by the mitochondrial fusion factors mitofusin 1 and mitofusin 2.  

Our current research aims to address:
How does nutrient-dependent hyperfusion regulate mitochondrial pathways?  (i.e. how does structure affect function?)

What are the normal physiological roles for nutrient-dependent mitochondrial hyperfusion?

Targeting mitochondrial dynamics in cancer

Both sides of mitochondrial dynamics – fission and fusion – are critical to maintain an overall healthy functional pool of mitochondria.  It is interesting that altered levels of mitochondrial fission and fusion have both been implicated to help maintain metabolic output or regulate apoptosis in cancer cells, although details remain unclear.  As our work has pointed to a critical inter-relationship between cell metabolic flux and mitochondrial fusion, we are interested to explore if these mechanisms can be exploited to better inhibit the growth of cancer cells.  Indeed, we can see that growth of breast cancer cells is strongly suppressed when we inhibit OPA1, the protein that drives fusion of the mitochondrial inner membrane.  We are now interested in developing strategies to target mitochondrial fusion to inhibit the growth of cancer cells or make them more sensitive to chemotherapeutics. 


protein interaction mapping


pathways of similar co-dependencies from cancer cell CRISPR screens

Cancer cells are extraordinarily heterogeneous: some cell types are highly dependent on mitochondrial fusion for survival while others are insensitive to loss of this mitochondrial maintenance pathway, likely due to other underlying compensatory mechanisms.   What are these key pathways?  To address this, we are aiming to identify cell stress mechanisms that are coordinately regulated by mitochondrial fusion, guided by the networks of key interaction partners.  We also use data derived from CRISPR gene inactivation screens from large panels of human cancer cell lines that are particularly dependent on mitochondrial fusion. Information can be extracted from these data to suggest closely inter-related functional pathways.

Our current research aims to address:
How does targeting of mitochondrial fusion inhibit cell metabolism to inhibit tumourigenesis? 
What are the cell stress mechanisms that are inter-dependent upon mitochondrial fusion and can these liabilities be exploited to more effectively kill a cancer cell?

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