All living organisms that are able to perform cellular aerobic respiration undergo oxidation reactions, producing highly reactive oxygen-containing molecules. These “reactive oxygen species” (ROS) are a part of normal metabolism: the bulk of cellular ROS is produced by mitochondria and is usually metabolized to protect the cell from damage due to uncontrolled ROS. However, the environment in which we live exposes us to numerous compounds that increase oxidative reactions and ROS beyond normal metabolism - creating “oxidative stress.” Oxidative stress plays a pathologic role in nearly all diseases including cardiac, oncologic, liver, and neurological conditions, as well as the aging process. Recently the tumor suppressor and cell-cycle regulator protein, TP53, has been linked to oxidative stress metabolism in its native state. Furthermore, it is recently appreciated that mutant TP53 can accelerate the production of oxidative species by an unknown mechanism. Many diseases including certain malignancies present with anemia or have associated chronic anemia which is inadequately explained. How a mutant form of TP53 increases ROS is unknown. These researchers have investigated the effects of mutant TP53 in primitive erythrocytes to determine if there are intrinsic metabolic defects. They have shown that primitive erythrocytes have a shortened lifespan, are more sensitive to a pro-oxidant challenge, and generate significantly higher amounts of ROS when harboring mutant TP53. Furthermore, the data suggest that mutant TP53 exerts these effects via a reduction in mitophagy (thereby increasing mitochondrial numbers) and increasing necroptosis driven by high ROS.
This group's long-term goal is to develop a better understanding of how oxidative stress affects erythroid progenitors and mitochondrial function. The objectives of this work are to better understand how TP53 (wild-type and mutated) regulates mitophagy, ROS, and necroptosis in two animal models: zebrafish and mouse. Secondly, the researchers will verify the effect of TP53 mutation in patients with myelodysplastic syndromes (MDS). MDS are blood cancers characterized by a heterogeneous disruption of the hematopoietic stem cell system. MDS accounts for significant morbidity and mortality with over 20,000 people diagnosed each year in the U.S. Notably, anemia through inadequate red blood cell formation is the most common clinical presentation for MDS. However, it is unclear why erythropoiesis is disrupted. It is known that patients with MDS and TP53 mutation have lower hemoglobin levels, are more transfusion dependent, and have worse prognosis. This group's overall hypothesis is that mutations in TP53 contribute to mitochondrial deregulation increasing ROS leading to erythrocyte progenitor cell death by necroptosis. The rationale for this research is that TP53, a commonly mutated gene in disease, has new links in regulating ROS and mitochondria. The development and demonstration of this dysregulation in vivo will allow researchers to pursue more in-depth studies of the complicated pathologic consequences of oxidative stress. To achieve this goal and to test their hypotheses, the researchers are undertaking the following aims:
- Understand the role of tp53 in ROS metabolism in primitive erythrocytes
- Determine the mechanism of Tp53 driven mitochondrial deregulation
- Determine if mitochondrial deregulation and ROS lead to necroptosis in primitive erythrocytes
- Determine the relationship of mutated Tp53 and oxidative stress in patients with MDS
By understanding the role of TP53 and mitochondria, new targeted therapies designed to inhibit mutant TP53, increase mitophagy, or reduce oxidative stress could be pursued.