Mitochondria are critical for production of ATP, the energy currency of a cell, but glucose utilization varies greatly among cell types. Inherited mitochondrial disorders affect neural tissues most prominently revealing the vulnerability of these tissues. In mice, prolonged exposure to mitochondrial toxins can lead to symptoms that mimic Parkinson's disease. The mammary gland is a tissue that, in its resting state, has relatively modest energy requirements. However, upon the onset of lactation, the energy required for synthesis of vast quantities of milk proteins and lactose can be limiting. The mitochondria also regulate activity of the p53 tumor suppressor protein. Specifically, impairment of mitochondrial function with a common pesticide (rotenone) abolished p53 function. We have shown that loss of p53 function renders the mammary epithelium highly susceptible to tumors. Thus, environmental exposure to mitochondrial toxins has caused growing concern limiting productivity of livestock and human health.
The goal of the project will be to develop methods to screen for mitochondrial impairment in tissues. In Aim 1 a novel mouse model bearing a 50% reduction in mitochondrial function will be used to define a signature of gene expressing that reflects impairment of mitochondrial function. Aim 2 uses human breast cell lines to examine the effects of common agricultural chemicals on cellular metabolism and respiration. The biomarkers will be used in Aim 3 to screen tissues of livestock for evidence of mitochondrial dysfunction. These experiments will provide a fundamental understanding of the molecular pathways affected by mitochondrial dysfunction and provide tests to assess mitochondrial sufficiency in livestock. These tools can be used to ensure optimal health and productivity of livestock.
