Pathological features of mitochondrial respiratory chain dysfunction
Author(s)Chen, Walter W
Massachusetts Institute of Technology. Department of Biology.
David M. Sabatini.
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Mitochondria are essential organelles that carry out a multitude of important metabolic processes in mammalian organisms. These processes include ATP generation by the respiratory chain, aspartate synthesis by matrix aminotransferases, and long-chain fatty acid catabolism by the beta oxidation pathway. Given the role of mitochondria in maintaining cellular physiology, mitochondrial dysfunction often leads to disease. One major class of mitochondrial pathologies is caused by defects in the mitochondrial respiratory chain (RC). Yet while the genetic etiologies of these RC disorders are well-studied, the molecular defects that actually link RC dysfunction with impaired cellular viability are still unclear. In the work described here, we demonstrate that loss of mitochondrial membrane potential and aspartate contributes significantly to cellular pathology during RC dysfunction. In addition, we develop a novel method for rapidly isolating mitochondria and profiling their metabolite contents to study the changes in mitochondrial metabolism across various states of RC function. From this work, we find numerous alterations in matrix metabolites that had been previously unappreciated using traditional profiling of whole-cells and identify new metabolic abnormalities downstream of RC dysfunction. Collectively, this work uncovers distinct molecular events connecting RC pathology with impaired cellular viability and expands our understanding of the metabolic processes affected by RC dysfunction, thus opening up new areas for exploration.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis. "June 2016."Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Biology.
Massachusetts Institute of Technology