Mitochondria (mt) play key roles in cellular energy production and cell death. Beta cell function is tightly linked to mitochondria, as both insulin synthesis and glucose stimulated insulin secretion require mitochondrial ATP production. In this context, reports of mitochondrial DNA (mtDNA) mutations associated with Type 2 diabetes (T2D) pedigrees in humans account for up to 1% of human T2D. Mutations in mtDNA are not commonly associated with autoimmune Type 1 diabetes (T1D), although a C to A transversion resulting in a leucine to methonine substitution in the mt-ND2 gene has been associated with protection from T1D in both an at risk human population and in crosses of the T1D-prone NOD with T1D-resistant ALR mice. The goal of this application is to understand how this single amino acid change can protect against T1D. Genetic analysis of T1D susceptibility has focused attention on candidate genes controlling aberrant immune cell function with little focus on genes that may contribute susceptibility or resistance at the B cell level. Pancreatic islets from the ALR mouse strain maintain an unusual genetic resistance to functional impairment and killing by autoimmune effectors. Preliminary results have linked some of this heightened ft cell resistance to the mt-Nd2 allele of ALR. Our goal is to understand the role this gene plays in B cell resistance to autoimmune killing.
The first aim i s to determine the extent of protection from spontaneous T1D provided by ALR's mt-Nd2 allele, and then detail this resistance using adoptive transfer experiments with specific cell populations. In the second aim the impact of the mt-Nd2 allele on mt function will be examined by studying isolated mt. The mt will also be tested to determine if ALR's mt-Nd2a allele provides a gain of function to mt when stressed with free radicals or apoptotic stimuli. As the SNP and its accompanying amino acid change in the T1D resistant human population and ALR mouse are similar, it is likely that the information gleened from this application can directly impact future work to prevent or cure T1D.
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