Regulation of mitochondrial fission in learning, memory and neurological disorders

Commonly regarded as the cell’s “powerhouse”, mitochondria are organelles responsible for energy production and maintain the health of every cell in the body. My thesis work focuses on how changes of mitochondria shape within the nervous systems impacts learning, memory and a disorder in diabetes called diabetic peripheral neuropathy (DPN). The structure of mitochondria is quite dynamic. Mitochondria within cells are constantly undergoing the processes of fission and fusion. In order to investigate the functional significance of these dynamic changes, I used different research tools and animal models that promote either mitochondrial fission or fusion. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial protein that mediates mitochondrial fusion. Hence, in a mouse where the AKAP1 gene has been deleted or knock-out (AKAP1 KO), we show the mitochondria are more fragmented upon genetically removal of this protein. We previously published that these AKAP1 KO mice, that have smaller mitochondria, are more prone to stroke damage in the brain. However, when it comes to learning and memory, my work demonstrates that AKAP1 KO mice have improved memory. In another knockout mouse, a Bβ2 regulatory subunit of a protein called protein phosphatase 2A (PP2A) was deleted and results in longer mitochondria in their neurons. Previous work from our lab showed these Bβ2 KO mice, which have longer mitochondria, are less prone to stroke damage in their brains. For my project, I further examine whether the protection seen in the brain can be applied as a potential therapeutic strategy in diabetic neuropathy (DPN). Patients with diabetes often develop peripheral neuropathy as their sensory nerve fibers in their hands and feet degenerate, but the neuron cell bodies remain and could potentially regenerate the nerves. We investigated these Bβ2 KO mice in type 1 and type 2 diabetes and tested their sensory responses. We found that the Bβ2 KO mice retained their sensitivity to heat stimulations when compared to normal diabetes mice. Since Bβ2 KO mice have longer mitochondria, promoting mitochondrial fusion could protect sensory nerve fiber degeneration in diabetes. Taken all these findings together, our data suggest that both mitochondria fission and fusion are important processes to carry out different functions based on the requirement of specific physiological circumstances.