Mitophagy as Potential Target in Sickle Cell Disease

镰状细胞病（SCD）是一种遗传性血液疾病，影响着全世界数百万人。在美国

Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide. In the United States, approximately 100,000 people have it, with heath care costs estimated to be $1.1 billion in the US alone. It is caused by a mutation in the γ-globin gene, causing glutamic acid to be substituted by valine. Because of this, when deoxygenated, the hemoglobin is able to polymerize, causing shape change of the red blood cell (RBC), RBC lysis, and innumerable other complications including acute and chronic pain, chronic anemia, multisystem organ damage, and a much shortened life expectancy. The symptoms appear shortly after birth, when fetal hemoglobin (HbF) levels decline, and are replaced by adult sickle hemoglobin. Because of this observation, much effort has been placed to induce fetal hemoglobin levels in those with SCD. Hydroxyurea, the only FDA approved drug for the treatment of SCD, is unfortunately effective in only about 50% of those who take it, and its mechanism is not clear. Therefore, our lab investigates alternate treatments for SCD in the SCD mouse model. It is believed that the red blood cell (RBC) is the most common cell in the body. In order to maintain a normal amount of hemoglobin to carry oxygen and remove carbon dioxide, adult humans, make more than 2 million red blood cells a second! This is the result of a highly orchestrated plan. Erythropoiesis in adult humans originates in the bone marrow and follows a path from progenitor to precursor to mature red blood cells. They follow the developmental scheme of the proerythroblast, followed by the basophilic erythroblast, the polychromatophilic erythroblast, and then the orthochromatic erythroblast. These are followed by reticulocytes, which are enucleated, and lose their organelles, and migrate from the marrow to the peripheral circulation. They normally account for 0.5 to 1.5% of all red blood cells, in those who are anemic, the percent increases. Reticulocytes have been found to have large vacuolar inclusions, which label for markers of the endoplasmic reticulum, Golgi, and mitochondria. It is thought that these vacuoles are eliminated by exocytosis and autophagy. PGCα1 is known to induce regulators of mitophagy and mitochondrial respiration. Recent studies on a knockout (Nix -/-) mouse also demonstrated the lack of mitophagy led to the short life span of RBCs Our preliminary data from untreated sickle cell mice show mature red blood cells retain mitochondria at a higher level than controls. The higher number of mitochondria rich reticulocytes in circulating blood could potentially promote the elevated levels of reactive oxygen species, changes in oxygen metabolism and the cell lysis seen in the disease. The molecular mechanism of increased mitochondria in red blood cells associated with SCD is not clear. Mitophagy regulated through the mammalian Target of Rapamycin (m-TOR) dependent and independent mitophagy pathway. This proposal seeks to provide pilot data that will link aberrant mitophagy with sickle cell pathology and develop new strategies for the treatment of SCD using mitophagy restoration drugs. Our goal is to obtain preliminary data that the reductions of mitochondrial retention in RBC will provide safe and effective therapy in SCD mouse.