{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/155353"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/155353","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Control of Cellular Redox State and Biomass Synthesis","abstract":"To proliferate, tumors must synthesize sufficient biomass, such as proteins, nucleotides, and lipids. Many nutrients that produce biomass undergo oxidation reactions that require the redox cofactor NAD+ as an electron acceptor. Thus, the cellular redox state, measured by the NAD+/NADH ratio, can constrain the synthesis of oxidized biomass. This dissertation aims to uncover the determinants of the cellular NAD+/NADH ratio and how the cellular redox state governs biosynthetic capabilities of cancer cells in response to elevated biomass demands. In serine depleted conditions, which increase the NAD+ demand to support serine synthesis, we find that modulating the NAD+/NADH ratio proportionally alters serine synthesis rates. We uncover that some cancer cells elevate mitochondrial respiration and increase the NAD+/NADH ratio following serine withdrawal while others do not. Increasing mitochondrial respiration is sufficient to elevate the NAD+/NADH ratio and improve serine synthesis and proliferation in serine depleted conditions. Exogenous lipid withdrawal can also elevate mitochondrial respiration and the NAD+/NADH ratio, leading to increased serine synthesis despite no change in serine demand. Together, we find that the cellular NAD+/NADH ratio is regulated by mitochondrial respiration in a cell and environment specific manner, impacting oxidative biosynthesis reactions to determine the proliferative capacity of cancer cells in different nutrient environments.","abstract_html":"To proliferate, tumors must synthesize sufficient biomass, such as proteins, nucleotides, and lipids. Many nutrients that produce biomass undergo oxidation reactions that require the redox cofactor NAD+ as an electron acceptor. Thus, the cellular redox state, measured by the NAD+/NADH ratio, can constrain the synthesis of oxidized biomass. This dissertation aims to uncover the determinants of the cellular NAD+/NADH ratio and how the cellular redox state governs biosynthetic capabilities of cancer cells in response to elevated biomass demands. In serine depleted conditions, which increase the NAD+ demand to support serine synthesis, we find that modulating the NAD+/NADH ratio proportionally alters serine synthesis rates. We uncover that some cancer cells elevate mitochondrial respiration and increase the NAD+/NADH ratio following serine withdrawal while others do not. Increasing mitochondrial respiration is sufficient to elevate the NAD+/NADH ratio and improve serine synthesis and proliferation in serine depleted conditions. Exogenous lipid withdrawal can also elevate mitochondrial respiration and the NAD+/NADH ratio, leading to increased serine synthesis despite no change in serine demand. Together, we find that the cellular NAD+/NADH ratio is regulated by mitochondrial respiration in a cell and environment specific manner, impacting oxidative biosynthesis reactions to determine the proliferative capacity of cancer cells in different nutrient environments.","abstract_has_math":false,"creators":["Chang, Sarah Mary"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Biology","school":null,"contributors":[],"advisors":["Vander Heiden, Matthew G."],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05","date_published":"2024-05","updated_at":"2026-07-22T22:22:19Z","subjects":[],"languages":[],"rights":["Attribution 4.0 International (CC BY 4.0)","Copyright retained by author(s)"],"rights_urls":["https://creativecommons.org/licenses/by/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1721.1/155353","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vander Heiden, Matthew G."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. 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Many nutrients that produce biomass undergo oxidation reactions that require the redox cofactor NAD+ as an electron acceptor. Thus, the cellular redox state, measured by the NAD+/NADH ratio, can constrain the synthesis of oxidized biomass. This dissertation aims to uncover the determinants of the cellular NAD+/NADH ratio and how the cellular redox state governs biosynthetic capabilities of cancer cells in response to elevated biomass demands. In serine depleted conditions, which increase the NAD+ demand to support serine synthesis, we find that modulating the NAD+/NADH ratio proportionally alters serine synthesis rates. We uncover that some cancer cells elevate mitochondrial respiration and increase the NAD+/NADH ratio following serine withdrawal while others do not. Increasing mitochondrial respiration is sufficient to elevate the NAD+/NADH ratio and improve serine synthesis and proliferation in serine depleted conditions. Exogenous lipid withdrawal can also elevate mitochondrial respiration and the NAD+/NADH ratio, leading to increased serine synthesis despite no change in serine demand. Together, we find that the cellular NAD+/NADH ratio is regulated by mitochondrial respiration in a cell and environment specific manner, impacting oxidative biosynthesis reactions to determine the proliferative capacity of cancer cells in different nutrient environments."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Control of Cellular Redox State and Biomass Synthesis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Vander Heiden, Matthew G."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Biology"],"dc:creator":["Chang, Sarah Mary"],"dc:date.accessioned":["2024-06-27T19:47:06Z"],"dc:date.available":["2024-06-27T19:47:06Z"],"dc:date.issued":["2024-05"],"dc:description.abstract":["To proliferate, tumors must synthesize sufficient biomass, such as proteins, nucleotides, and lipids. Many nutrients that produce biomass undergo oxidation reactions that require the redox cofactor NAD+ as an electron acceptor. Thus, the cellular redox state, measured by the NAD+/NADH ratio, can constrain the synthesis of oxidized biomass. This dissertation aims to uncover the determinants of the cellular NAD+/NADH ratio and how the cellular redox state governs biosynthetic capabilities of cancer cells in response to elevated biomass demands. In serine depleted conditions, which increase the NAD+ demand to support serine synthesis, we find that modulating the NAD+/NADH ratio proportionally alters serine synthesis rates. We uncover that some cancer cells elevate mitochondrial respiration and increase the NAD+/NADH ratio following serine withdrawal while others do not. Increasing mitochondrial respiration is sufficient to elevate the NAD+/NADH ratio and improve serine synthesis and proliferation in serine depleted conditions. Exogenous lipid withdrawal can also elevate mitochondrial respiration and the NAD+/NADH ratio, leading to increased serine synthesis despite no change in serine demand. Together, we find that the cellular NAD+/NADH ratio is regulated by mitochondrial respiration in a cell and environment specific manner, impacting oxidative biosynthesis reactions to determine the proliferative capacity of cancer cells in different nutrient environments."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["https://hdl.handle.net/1721.1/155353"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["Attribution 4.0 International (CC BY 4.0)","Copyright retained by author(s)"],"dc:rights.uri":["https://creativecommons.org/licenses/by/4.0/"],"dc:title":["Control of Cellular Redox State and Biomass Synthesis"],"dc:type":["Thesis"],"thesis:degree_name":["Doctoral","Doctor of Philosophy"]},"updated_at":"2026-07-22T22:22:19Z"}