Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular, Molecular and Biomedical Sciences

First Advisor

Mercedes Rincon

Abstract

Methylation controlled J protein (MCJ) is a negative regulator of mitochondrial metabolism that has a substantial impact on overall cell metabolism and function. MCJ is highly expressed by naïve CD8+ T cells, however its role in their immune effector functions was unknown. In this dissertation, it will be demonstrated that MCJ restricts the mitochondrial metabolism of CD8+ T cells, in part by reducing respiratory supercomplex formation. MCJ deficiency enhances the immune effector functions and memory responses of CD8+ T cells in a mitochondrial ATP dependent manner. As a consequence, protection to influenza virus infection is substantially improved. Reduced expression of MCJ therefore promotes viral immunity, however the loss of MCJ is not always beneficial. In cancer, decreased MCJ expression is correlated with ATP binding cassette (ABC) transporter mediated chemotherapy resistance and poor patient responses. This dissertation will also address the role of MCJ in chemoresistance. Increased mitochondrial ATP production due to MCJ deficiency is sufficient to fuel ABC transporter activity, thereby directly promoting chemoresistance. This can be reversed by restoration of MCJ function in chemoresistant cells. Overall, the results presented in this dissertation identify MCJ as a potential therapeutic target, as modulating MCJ expression can significantly affect the severity of viral infections and the responses to chemotherapy.

Language

en

Number of Pages

272 p.

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