Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Mitochondria-derived reactive oxygen species (mROS) are crucial for cancer cell survival, proliferation, and metastasis.
• The precise mechanisms linking mitochondrial metabolism to mROS regulation in cancer remain incompletely understood.

Purpose of the Study:

• To investigate the role of mitochondrial metabolism in regulating mROS levels to support cancer cell fitness.
• To identify metabolic vulnerabilities in cancer cells related to mROS production.

Main Methods:

• A metabolism-focused CRISPR-Cas9 genetic screen was employed to identify genes critical for cancer cell survival under specific conditions.
• Inhibition of mitochondrial complex I and III was performed using genetic or pharmacologic approaches.
• Mitochondria-targeted antioxidants, mito-vitamin E (MVE) and MitoTEMPO, were utilized.
• The integrated stress response (ISR) was assessed.
• In vitro cell survival and proliferation assays were conducted.
• A mouse model of T cell acute lymphoblastic leukemia was used to evaluate therapeutic efficacy.

Main Results:

• Loss of genes encoding mitochondrial complex I subunits was detrimental in the presence of mito-vitamin E (MVE).
• Inhibition of mitochondrial complex I, alongside MVE or MitoTEMPO, triggered a significant integrated stress response (ISR), reducing cancer cell survival and proliferation.
• Inhibition of mitochondrial complex III did not yield similar results.
• Combined administration of MitoTEMPO and phenformin (a mitochondrial complex I inhibitor) reduced leukemic burden in a mouse model.

Conclusions:

• Mitochondrial complex I is a critical metabolic regulator of mROS levels, influencing cancer cell fitness.
• Targeting mitochondrial complex I in combination with mitochondria-targeted antioxidants presents a potential therapeutic strategy for T cell acute lymphoblastic leukemia.