The role of mitochondrial superoxide in the development of the mammalian hematopoietic system [thesis]

Adam John Case
The SOD2 gene encodes the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD), which converts superoxide (O 2 •-) to hydrogen peroxide (H 2 O 2 ). Down-regulation of SOD2 has been reported in many cancer cells of diverse tissue origins, and forced over expression of this enzyme in carcinoma cells decreases their tumorigenicity. These findings suggest that SOD2 functions as an initiation or promotion tumor suppressor; however, it remains to be determined whether loss of SOD2
more » ... ether loss of SOD2 expression is sufficient for tumor formation since homozygous SOD2 knock-out mice die within weeks after birth. Additionally, due to the shortened lifespan of the constitutive SOD2 knock-out mouse limited studies have been performed in assessing the role of SOD2 in tissue-specific development in vivo. Using Cre-loxP genetics, we now have the capability to generate mice in which SOD2 may be knocked out in a cell type-specific manner and these mice can be used to query the effect of loss of SOD2 expression in tissue development, function, and oncogenesis. We primarily focused our studies on the hematopoietic system, but expanded our research to solid organs such as the liver and mammary gland as well. Our findings demonstrate that SOD2 does not act as an initiating tumor suppressing enzyme in any of these unchallenged systems, and in fact the loss of SOD2 may act to delay tumor formation. T-cell specific SOD2 knock-out demonstrated significant immunodeficiency as illustrated by a decreased immune response to influenza challenge secondary to decreased T-cell populations. Furthermore, hematopoietic stem cell specific SOD2 knock-out showed a severe anemia in the red blood cell population due to increased mitochondrial superoxide. Additional analysis revealed the anemia to be a result of a porphyria due to the inactivation of the heme synthesis enzyme ferrochelatase. The observed phenotypes in all conditional hematological SOD2 knockout models were rescued by the addition of mitochondrially targeted anti-oxidants. In conclusion, the tissue specific loss of SOD2 in various hematological organs appeared to 2 demonstrate significant developmental and functional aberrations, but the role in tumor initiation appears to be limited if any. The data presented here also suggest the potential for novel anti-oxidant therapy in a variety of hematological diseases. Abstract Approved: ____________________________________ Thesis Supervisor
doi:10.17077/etd.1tttyay1 fatcat:b2tbdglwjzf6fhwhgculncub7q