Department of Anesthesiology

The research in Dr. Szczesny's Laboratory combines biochemical, cellular, in vivo, and ex vivo models to address roles of the mitochondria in physiological and pathological conditions. Our main areas of research include:

Mitochondrial DNA induce inflammatory response. We are exploring mitochondrial DNA (mtDNA) as a target and active mediator that links oxidative stress to innate inflammatory response. We have detected that prolonged, low-level oxidative stress damages the mtDNA, without affecting integrity of the nuclear DNA. Damaged mtDNA is subsequently released to the cytoplasm, where it binds to Z-DNA binding protein 1 (ZBP1) and triggers inflammation via the TANK-binding kinase 1(TBK1)/interferon regulatory factor 3 (IRF3) signaling pathway. Fragments of the mtDNA are also released into the extracellular space via extracellular vesicles (EV). MtDNA-containing EVs are capable of inducing an inflammatory response in naïve (i.e., non-oxidatively stressed) cells. Cellular depletion of the mtDNA causes remodeling of cellular bioenergetics and morphology without any detectable impairment in cell viability. We are currently examining importance of this mtDNA/ZBP1 signaling pathway in induction of innate inflammation in pathologies that include acute lung injury, burn injury, and traumatic brain injury using in vitro and in vivo models.

Mechanisms of the mitochondrial DNA repair. We are investigating mechanisms of mitochondrial DNA (mtDNA) repair, particularly DNA base excision repair (BER) pathway. We have identified 5’ exonuclease, EXOG, as a critical mitochondria-specific BER enzyme. EXOG-depletion causes accumulation of the unrepaired intermediates (single strand breaks) in the mtDNA that induce mitochondrial dysfunction and consequently cell death. We are also exploring the unusual role of poly (ADP-ribose) polymerase 1 (PARP1) in regulation of the mtDNA repair. As opposed to nuclear PARP1, mitochondrial PARP1 negatively affect the repair of oxidatively damaged mtDNA. We are investigating organization and regulation of the mitochondrial “BERosome” in physiological and stress conditions.

Role of mitochondria in cancer. The importance of mitochondrial homeostasis, including preservation of the mtDNA integrity, in cancer cells has only recently come to be appreciated. We detected higher expression of H₂S producing enzymes, namely, cystathionine-β-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase, in lung adenocarcinomas that regulate mitochondrial bioenergetics and the mtDNA repair. Using pharmacological and cellular approaches, we seek to determine the essentiality of mitochondrial-H₂S in cancer cells and test whether reduction of intramitochondrial level of H₂S improve the efficacy of chemotherapeutic drugs. We are also developing strategies that target directly mtDNA transactions to enhance toxicity of the chemotherapeutic drugs.