Oxygen, the invisible orchestrator of metabolism and disease : a focus on mitochondrial And peroxisomal dysfunction
Name
1022847989-MIT.pdf
Description
Full printable version
Size
16.14 MB
Format
Adobe PDF
Checksum (MD5)
a06abc66b48c9a442cc6ca02605d132b
Author(s)
Jain, Isha Himani
Advisor(s)
Vamsi K. Mootha.
Alternative Title
Focus on mitochondrial And peroxisomal dysfunction
Date Issued
2017
Publisher
Massachusetts Institute of Technology
Abstract
Variations in atmospheric oxygen levels can be traced over evolutionary time and track closely with the development of multicellular life, speciation events, appearance of placental mammals and the creation of a cardio-respiratory system. As the final electron acceptor for aerobic ATP production, oxygen allows energy-intensive metabolic pathways to exist. Furthermore, oxygen is the most utilized substrate for known biochemical reactions, surpassing even ATP and NAD+. As a result, variations in oxygen levels have far-reaching consequences on human physiology and health. Mitochondrial disorders are the most common inborn errors of metabolism, affecting approximately 1 in 5000 live births. Patients can present in infancy or adulthood with symptoms affecting multiple organ systems including blindness, deafness, muscle weakness, developmental delay and severe neurological impairment. Unfortunately, there are currently no proven therapies for mitochondrial disorders. My thesis work has focused on combining systems biology, animal physiology and cellular metabolism approaches to develop new therapies for these disorders. More specifically, I have identified hypoxic breathing, equivalent to living at 4500m altitude, as protective in the setting of severe mitochondrial disease. First, I performed a genetic screen and found paradoxically, that hypoxic breathing and hypoxia responses are protective in mitochondrial disease. I then characterized the physiology and preclinical regimens of hypoxia therapy, laying the groundwork for translation to human patients. Fascinated by such a vital role for oxygen in human disease, I went on to define adaptive pathways in varying oxygen tensions. This work highlights the differential reliance on entire organelles at extreme oxygen levels. And finally, I studied the metabolic and proteomic consequences of defects in peroxisome metabolism and disease.
Description
Thesis: Ph. D. in Health Sciences and Technology: Computer Science, Harvard-MIT Program in Health Sciences and Technology, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Subjects
Harvard--MIT Program in Health Sciences and Technology.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Terms of Use
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