Mitochondria and Hematologic Disorders.

Abstract SCI-3

Mitochondria have a special relationship with the erythroid lineage. Although RBC are devoid of mitochondria, during RBC development the mitochondria is the site of multiple steps in heme biosynthesis, and is essential for proper utilization of iron. As evidence of this special relationship, multiple mutations in both mitochondrial DNA (hereditary and acquired) and in nuclear genes encoding mitochondrial localized proteins (hereditary) result in sideroblastic anemia—where the hallmark pathologic lesion is intramitochondrial iron accumulation in erythroid progenitors. The erythroid-lineage specific readout of these mitochondrial genetic lesions raises the possibility that mitochondrial dysfunction is a contributor to anemia in other contexts as well. In this view, red cell development can be considered an early warning system for mitochondrial dysfunction in hematopoiesis. A focus of our laboratory is to investigate how increased mitochondrial-derived reactive oxygen species affect hematopoietic development. Gene expression and proteomic analyses of erythroblasts demonstrate that mitochondrial biogenesis during erythroid development is inhibited by oxidant stress. Transcriptional control of mitochondrial biogenesis in erythroid cells involves induction of the distinct transcriptional coactivator PRC1—perhaps helping to explain the erythroid specificity of phenotypes noted above. As has been elegantly demonstrated by Wallace and others, mitochondrial dysfunction is an important determinant of age-related decline in functional capacity of many tissues. This decline in function is accompanied by an increase in mitochondrial DNA mutations—both point mutations and deletions found primarily in post-mitotic cells. Modeling of this process through creation of mice with an error prone mtDNA polymerase accelerates the appearance of age-related tissue changes—including the development of anemia. Transplantation of murine hematopoietic stem cells harboring a large deletion of mtDNA also leads to anemia in reconstituted animals. Are these findings relevant for age-related hematologic abnormalities in people—and if so, for what disorders? There is considerable epidemiologic evidence indicating an increase in the frequency of anemia in the elderly, peaking at a prevalence of greater than 20% for individuals in their 80's. Approximately 1/3 of these elderly anemic cases are idiopathic—that is, no underlying disease process is identified. In studying this group with idiopathic anemia, we have investigated a number of hypotheses including the possibility of mitochondrial dysfunction. To date we have found altered mitochondrial DNA content and a higher mutation frequency in mtDNA isolated from peripheral blood cells when comparing anemic versus age/sex matched controls. However, these studies are correlative, and do not prove causality. Proving a direct role for specific acquired mitochondrial DNA lesions in development of anemia, myelodysplasia or hematologic malignancy remains a technical challenge because of the difficulty in introducing specific mutant mtDNA's into relevant cells or tissues. The development of more facile methods for evaluation of mitochondria in few or even single cells promises to expand our understanding of how mitochondrial functional changes impact diverse hematopoietic cells, in addition to the erythroid lineage effects highlighted above.