Cell & Molecular Biology

     The main interest of our laboratory is red blood cell development.  Inherited and acquired diseases of red blood cells affect a significant proportion of the world?s population and are a major cause of human morbidity and mortality.  Study of the mechanisms of red blood cell development has contributed to the development of novel therapies for the treatment of these diseases.  Further, red blood cells provide an excellent model with which to study basic cellular processes.  Along this line, our laboratory is studying red blood cells to gain insights into the general regulation of gene expression, signal transduction, and most recently the trafficking of subcellular organelles.

     Mitochondria are the primary site of oxidative phosphorylation and energy production in animal (and human) cells and are critical for life.  Mitochondria are also the major site of reactive oxygen species (ROS) production.  ROS are a natural byproduct of mitochondrial activity; but, when present in excess can damage cellular proteins and nucleic acids.  Dysfunctional mitochondria produce more ROS than healthy mitochondria, and are implicated in a broad range of human disease, including aging, degenerative disease, and cancer.  Recent studies from many laboratories, including our own, suggest that the principle mechanism for the elimination of dysfunctional mitochondria is mitophagy (literally, "mitochondrial eating").  In mitophagy, the cell compartmentalizes, destroys, and eliminates dysfunctional or unwanted mitochondria.  Related processes include the elimination of peroxisomes (pexophagy), ribosomes (ribophagy), endoplasmic reticulum (reticulophagy), and even intracellular pathogens (xenophagy).  Defective mitophagy has been strongly implicated in the pathogenesis of childhood Parkinson's disease.
 

     Consistent with a dedicated role in gas transport, mature red blood cells contain hemoglobin and other proteins, but little else.  Specifically, they lack membrane-bound, intracellular organelles, such as mitochondria.  In this regard, one of the final steps in red blood cell development is the programmed elimination of mitochondria.  About five years ago, our laboratory discovered that an integral, outer mitochondrial membrane protein, called NIX, is essential for mitochondrial elimination during red blood cell development.  Given the importance of mitophagy in human disease, and how little we know about this process, our laboratory is dedicated to solving the mechanism of NIX-mediated mitochondrial elimination.  In the past five years, we have published a series of papers, which have helped define this process.  Our goal is to identify the components of this pathway,  to understand its regulation, and to establish its relationship with core cellular activities.