Mitochondrial DNA Variants as Regulators of Immune Function and Disease Susceptibility

Gray Faculty of Medical and Health Sciences The Department of Pathology Seminar

Mitochondrial haplogroups have been associated with variable risks for cancer, neurodegenerative, metabolic, and cardiovascular diseases, yet the mechanisms underlying these associations remain poorly understood. Our lab investigates this question using conplastic mouse models that are genetically identical except for their mitochondrial DNA (mtDNA), allowing us to isolate the specific effects of mtDNA variation. Using these models, we have uncovered striking differences in immune function and tumor susceptibility driven by mtDNA variants. Our findings suggest that mitochondrial genetics regulate immune cell states and effector functions. Specifically, regulatory T cells (Tregs) display impaired suppressive capacity, while conventional CD4⁺ T cells show enhanced activation. Integrated metabolic, methylation, and transcriptomic analyses reveal that mtDNA variation induces distinct metabolic and epigenetic reprogramming, leading to modified immune functionality. In addition, preliminary data indicate that the innate immune arm is also affected, showing signs of enhanced inflammatory activation in the same direction as the T cell response. Together, these findings highlight a central role for mitochondrial genetics in shaping both adaptive and innate immune responses and provide a mechanistic framework linking mtDNA variation, metabolism, and epigenetic regulation to disease susceptibility. Understanding these connections may open new therapeutic avenues for targeting immune metabolism and mitochondrial signaling in cancer and other immune-related diseases.

Tal Yardeni, PhD Sheba Medical Center

Mitochondrial DNA Variants as Regulators of Immune Function and Disease Susceptibility

The Seminar will take place on Sunday, December 28, 2025 at 14:00, Room 119, School of Medicine Building.