Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR/Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I were deleterious in the presence of the mitochondria-targeted antioxidant Mito-Vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. Notably, this was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T-cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.

Creator

• Kong, Hyewon

DOI

• https://doi.org/10.21985/n2-yrdm-5a96

Subject

• Biology
• Health sciences
• Medicine

Language

• en

Alternate Identifier

• etdadmin_upload_775698
• http://dissertations.umi.com/northwestern:15362

Keyword

• Reactive oxygen species
• Cancer
• Mitochondria
• Metabolism

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright