The Neuronal Roles of Mitofilin, a Housekeeper for Mitochondrial Crista Architecture
Abstract
Mitochondria are the "powerhouses" of the cell, producing 90% of the energy needed by the body to maintain cellular activities and proliferation. Malfunction of mitochondria causes mitochondrial diseases, characterized by lack of adequate energy with variable clinical manifestations. Exposure to pesticides and organophosphates during the Gulf War and the Vietnam War poses potential risk to Veterans to develop mitochondrial diseases. Mitochondrial malfunction is well known to manifest as dysfunction of neurons, a special type of cell. Neurons conduct electrical signals enabling us to see, listen, feel, walk, eat, think, etc. In order to control every part of the body to accomplish these abilities, neurons have specialized and polarized projections, structures that include a long nerve fiber (axon) that can extend up to a meter away from their small cell bodies, which are only a few microns in diameter. A neuron s complex shape poses burdens for mitochondria to meet their high energetic demands. Mitochondrial diseases involve a wide range of neurodegenerative diseases, such as Charcot-Marie-Tooth, Amyotrophic Lateral Sclerosis, Alzheimer s, Parkinson s, and Huntington s disease. Unfortunately, there is no cure for mitochondrial diseases, since little is known about the pathogenic causes. Thus, it is crucial for us to understand how mitochondrial function is controlled and how these controls are needed for the health of a neuron. Mitochondria produce ATP to store the energy, via a series of chemical reactions on the crista membranes inside mitochondria. Efficient mitochondrial ATP synthesis relies heavily on the exquisite membrane organization of mitochondrial cristae. However, how mitochondria precisely control crista structure is largely unknown in multicellular organisms. In our preliminary study, we have revealed a novel molecular pathway that maintains crista structure, a pathway with critical links to Parkinson s disease (PD). PD is a major mitochondrial disease closely associated with exposure to pesticides and herbicides during military service. We hypothesize that mitochondrial crista structure regulated by this pathway constitutes a central component of PD pathogenesis and will test this in the proposal. We will combine genetic manipulations to alter this pathway, as well as chemical applications of pesticides to fruit flies to mimic exposure to war toxins by Veterans, to reveal the regulatory mechanisms by which mitochondrial crista structure is maintained in health and disease. Our proposal will have a significant impact in the healthcare needs and well-being of Veterans exposed to war toxins. Our immediate outcome will reveal the cellular and molecular causes of PD, which will yield the long-term and broader-range benefits for discovering novel therapeutic avenues to improve treatments by addressing the pathogenic causes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610282
Entities
People
- Xinnan Wang
Organizations
- Stanford University
- United States Army