Mitochondrial dysfunction is a hallmark of many neurological diseases, from mitochondrial encephalopathies to neurodegenerative diseases like Parkinson?s disease. Although these diseases are devastating and common, most lack disease-modifying treatments. A critical step toward therapeutically restoring mitochondrial function in disease is to understand how cells adapt to mitochondrial stress and damage. To this end, we used a genetic screen to systematically identify genes that regulate the response to mitochondrial stress. Excitingly, we discovered that a gene of unknown function, TMA7, is essential for cell proliferation during mitochondrial dysfunction. TMA7 localizes to the nucleus and cytoplasm, positioning it to act in a signaling pathway between mitochondria and the rest of the cell. Given this localization, I investigated whether TMA7 acts a transcription factor regulating the best-characterized pathway that is activated by acute mitochondrial dysfunction, the integrated stress response (ISR). However, I found that TMA7 does not regulate the ISR-dependent transcriptional response, suggesting that it responds to mitochondrial stress by a novel mechanism. Although the function of TMA7 is unknown, previous studies provide clues to its molecular mechanism: TMA7 binds to polyadenylated RNA and ribosomes. Based on these previous and preliminary studies, this project will investigate the role of TMA7 in mitochondrial dysfunction, under the hypothesis that TMA7 translationally regulates protective mRNAs. This project will also determine the role of TMA7 in responding to neurological disease-causing mitochondrial mutations, as TMA7 is highly expressed in the brain. To establish the functional role of TMA7, my first aim will directly test the effect of TMA7 knockdown on translational regulation. I will perform ribosome and polysome profiling in TMA7 knockdown and wild-type cells under mitochondrial stress to identify specific mRNAs that are regulated by TMA7. To understand how TMA7 influences translation, I will identify the RNA and protein interaction partners of TMA7 using CLIP-seq and IP-MS, respectively. In my second aim, I will determine whether and how TMA7 responds to disease-causing mitochondrial loss-of-function mutations in neurons. Taken together, these experiments will uncover the mechanisms and contexts of TMA7 function in mitochondrial stress. As the fundamental mechanisms of cellular adaptation to mitochondrial stress are poorly understood, this work holds promise to identify a novel pathway with important implications for human neurological diseases.
Mitochondrial dysfunction is a hallmark of many neurological diseases, which affect millions of Americans in need of disease-modifying therapies. The cellular pathways that protect against mitochondrial dysfunction are incompletely understood, hindering therapeutic development. We discovered an uncharacterized gene that is essential for cell survival in mitochondrial stress, and the proposed work will determine the molecular function of this gene in mitochondrial dysfunction and disease.