PROJECT SUMMARY This F32 proposal describes a comprehensive training and mentorship program for Dr. Rebecca Davidson, a postdoctoral research fellow in the Department of Internal Medicine at the University of Michigan. Dr. Davidson will participate in a rigorous training plan, guided by their mentor along with a multi-disciplinary advisory committee. Their training program will include hands-on molecular, bioinformatics, and physiological training, as well as mentored opportunities to engage in scientific writing, presentations, and grant applications. The ultimate goal of this proposal is to best position Dr. Davidson for an independent and productive scientific career. Diabetes is a global epidemic of increasing prevalence, where all forms of diabetes are linked by insufficient β-cell function or mass to meet peripheral insulin demands. Type 2 diabetes (T2D) is a metainflammatory disease additionally characterized by impairments in mitochondrial function and ultrastructure that contribute to overall disruption of β-cell function. Mitochondria rely on their own 16.6 kilobase-pair circular genome to generate the machinery required for oxidative phosphorylation. Recently, our group identified a reduction in mitochondrial DNA (mtDNA) copy number in islets from T2D donors compared to islets from non-diabetic donors, indicating a disruption in genome stability in diabetes. While mtDNA genome instability is implicated in several diseases, its impact on β- cell dysfunction in diabetes has yet to be explored. The long-term objective of my project is to better understand the molecular mechanisms underlying mitochondrial dysfunction in diabetic settings. My project focuses on the β-cell-specific role of mitochondrial genome integrity on maintaining healthy mitochondrial function to meet the energy demands of the β cell. My preliminary data indicate that the progressive accumulation of deletions in β-cell mtDNA impair glucose homeostasis and β-cell function. Thus, I hypothesize that loss of mtDNA genome integrity occurs in the presence of inflammatory stressors and contributes to mitochondrial and β-cell failure in diabetes, which I will test through 2 Specific Aims. Aim 1 will determine the importance of mtDNA genome integrity to β-cell function and survival in mouse models of β-cell-specific mtDNA disruptions. Aim 2 will evaluate how diabetogenic stressors impact mtDNA genome integrity utilizing primary human islets and mouse models of diabetes. Successful completion of these Aims will provide novel and critical insights into the mechanistic contribution of mtDNA genome integrity on overall mitochondrial health and β-cell function required to preclude diabetes development.