Significance: The complex etiology of type 1 diabetes (T1D) is the outcome of failures in regulating immunity in combination with beta cell perturbations. Mitochondrial dysfunction in beta cells and immune cells may be involved in T1D pathogenesis. Mitochondrial energy production is essential for the major task of beta cells (the secretion of insulin in response to glucose). Mitochondria are a major site of reactive oxygen species (ROS) production. Under immune attack, mitochondrial ROS (mtROS) participate in beta cell damage. Similarly, T cell fate during immune responses is tightly regulated by mitochondrial physiology, morphology, and metabolism. Production of mtROS is essential for signaling in antigen-specific T cell activation. Mitochondrial dysfunction in T cells has been noted as a feature of some human autoimmune diseases.

Recent Advances: Preclinical and clinical studies indicate that mitochondrial dysfunction in beta cells sensitizes these cells to immune-mediated destruction via direct or indirect mechanisms. Sensitivity of beta cells to mtROS is associated with genetic T1D risk loci in human and the T1D-prone nonobese diabetic (NOD) mouse. Mitochondrial dysfunction and altered metabolism have also been observed in immune cells of NOD mice and patients with T1D. This immune cell mitochondrial dysfunction has been linked to deleterious functional changes.

Critical Issues: It remains unclear how mitochondria control T cell receptor signaling and downstream events, including calcium flux and activation of transcription factors during autoimmunity.

Future Directions: Mechanistic studies are needed to investigate the mitochondrial pathways involved in autoimmunity, including T1D. These studies should seek to identify the role of mitochondria in regulating innate and adaptive immune cell activity and beta cell failure.