Research through the Program occurs in both the laboratory and clinic. Currently, Dr. Lawrence Grossman and Dr. John Kamholz are collecting mitochondrial DNA samples from patients with ischemic stroke to identify mitochondrial DNA mutations that might affect the clinical outcome of stroke or the response to treatment, such as tissue plasminogen activator (tPA), a protease used to open blocked arteries. In addition, Dr. Maik Hüttemann and his co-workers are involved in a project to identify therapies to modulate mitochondrial function to prevent ischemia/reperfusion injury in both the heart and brain. Results from both of these studies will have implications for understanding the role of mitochondria in stroke, and for the treatment of stroke patients.
Additionally, Drs. Grossman and Hüttemann have also identified a gene, COX4i2, encoding a subunit of cytochrome oxidase, a protein that acts in the final step in the oxygen-dependent mitochondrial pathway to produce cellular energy that is necessary for reducing blood flow in the lung in areas of low oxygen content. This is important for efficient lung function, and thus for the maintenance of normal levels of oxygen in the blood. These findings link directly the function of a mitochondrial protein with the physiological regulation of blood oxygenation. Although at a preliminary stage, this finding in basic molecular physiology could have very significant consequences for the treatment of patients with pulmonary diseases and for adaptation to environments with low levels of oxygen.
Drs. Grossman and Hüttemann are also studying another cytochrome oxidase subunit gene, COX7A2, that is expressed mainly in heart and muscle. This is important for producing the high amount of energy these tissues require. A mouse produced to lack this gene develops mild dilated cardiomyopathy, thus serving as a model for studying mitochondrial involvement in this condition.
Clinical manifestations of mitochondrial disorders, especially in adults, are often vague and can change over time. In the clinic, Dr. Kamholz and Ms. Yates are currently investigating new strategies to diagnose and treat mitochondrial disease in adults. For example, by collaborating with Dr. Samavati and her colleagues in the Department of Internal Medicine, Dr. Kamholz and Ms. Yates are investigating how cardiopulmonary exercise studies can be utilized to determine the underlying etiology of clinical symptoms that may be due to a mitochondrial disorder. Furthermore, Dr. Kamholz and Ms. Yates, along with Dr. Darren Fuerst, a Neuropsychologist and Associate Professor in the Department of Neurology, are investigating the psychological impact in suspected mitochondrial disease. The goal is to better identify which patients would benefit from psychological treatment to improve their overall quality of life.
We have also linked with a mitochondrial group at Michigan State University to enhance and broaden our attack on mitochondrial disease across Michigan.