Mitochondria are multifaceted organelles integral to many cellular processes including energy generation and programmed cell death. More recently, mitochondria have emerged as central hubs in the mammalian immune system, orchestrating signal transduction cascades and metabolic switches necessary for the activation and survival of immune cells. Mitochondria are also important sources of damage-associated molecular patterns (DAMPs), which can trigger inflammatory responses when released from the organelle. Given their pleiotropic roles, mitochondrial dysfunction is increasingly implicated as a cause or accelerant of numerous human diseases.
Mitochondrial DNA Sensing by the cGAS-STING Pathway in Immunity and Disease
Mitochondrial DNA (mtDNA) is a small, maternally inherited, circular genome housed in the matrix of mitochondria. We are characterizing the mechanisms by which mitochondrial dysfunction leads to mtDNA release and activation of innate immune signaling. Our lab has made significant contributions to understanding how the mtDNA-cGAS-STING axis governs disease-promoting metabolic and immune rewiring in mitochondrial disorders, heart failure, and cancer. (Supported by grants from the DoD
Image: Mitochondrial dynamics in real time. Fibroblast expressing mitochondria-targeted GFP was imaged live on a Zeiss LSM 800 confocal.
Inborn Errors of Innate Immunity in Inherited Mitochondrial Disorders
Mitochondrial diseases (MtD) are rare, clinically heterogeneous disorders caused by mutations in genes that govern mitochondrial metabolism. In addition to exhibiting metabolic and energetic deficits, patients with MtD are more susceptible to opportunistic pathogens and suffer elevated complications arising from these infections. We are employing faithful models of MtD to unravel how innate immune alterations and myeloid cell dysfunction predispose to opportunistic pathogens, inflammation, and metabolic decompensation. (Supported by the DoD and HHV-6 Foundation)
Image: GFP-tagged Pseudomonas aeruginosa bacteria in POLG D257A mutant macrophages. Mitochondria, orange; CellMask, red, DAPI, blue.
Mitochondrial Dysfunction in Cancer, Fatigue, and Gulf War Illness
Our lab is investigating how mitochondrial dysfunction promotes tumorigenesis and metastasis. We are utilizing a physiologically relevant mouse model of melanoma and patient-derived melanoma cell lines to explore how mitochondrial stress and mtDNA instability influence myeloid innate immune responses in the tumor microenvironment. In collaboration with Dr. Robert Dantzer at MD Anderson Cancer Center, we are studying how mitochondrial dysfunction contributes to cancer-associated fatigue. Finally, we are utilizing a neurotoxicant model of Gulf War Illness (GWI) to understand how mitochondrial dysfunction and aberrant innate immunity contribute to neuroinflammation and cognitive deficits in veterans with GWI. (Supported by grants from the NIH and DoD)
Image: Mitochondrial fission in a melanoma cancer cell captured by transmission electron microscopy.