Journal Article

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer

Piyarathna, Danthasinghe Waduge Badrajee, Siddiqui, M. Minhaj, Kittles, Rick A., Park, Jun Hyoung, Johnson, Jabril R., Jung, Sung Yun, Putluri, Vasanta, Kamal, Abu Hena Mostafa, Kami Reddy, Karthik Reddy, Parsawar, Krishna, Terris, Martha K., Lerner, Seth P., Sreekumar, Arun, Gao, Jianjun, Kaipparettu, Benny Abraham, Langer Gramer, Adriana, Lotan, Yair, Eberlin, Livia S., Huang, Shixia, Putluri, Nagireddy, Ballester, Leomar Y., Kraushaar, Daniel, Amara, Chandra Sekhar, Xu, Jun, Creighton, Chad J., Bollag, Roni J.

2024

Overview

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: African Americans / Animals / Black or African American - genetics / Bladder cancer / Cell Line, Tumor / Cell Proliferation / Electron transport chain / Electron Transport Complex I - genetics / Electron Transport Complex I - metabolism / Female / Glutaminase - genetics / Glutaminase - metabolism / Glutamine / Glutamine - metabolism / Health care access / Humans / Male / Metabolism / Metabolites / Metabolomics / Metabolomics - methods / Mice / Middle Aged / Mitochondria / Mitochondria - metabolism / Molecular modelling / Mortality / Oncology / Oxidative Phosphorylation / Phenotypes / Phosphorylation / Proteins / Proteomics / Respiration / Self report / Tumors / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - metabolism / Urinary Bladder Neoplasms - pathology