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Published on: August 6, 2021
Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types
Ilya N Boykov1,2, McLane M Montgomery1,2, James T Hagen1,2
1Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Abstract:
Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type.
Insights
Targeting cancer mitochondria is difficult due to side effects. This study found lower mitochondrial oxidative phosphorylation (OXPHOS) in cancers than in normal tissues, suggesting caution with OXPHOS inhibitors.
Area of Science:
- Mitochondrial biology
- Cancer bioenergetics
- Metabolic pathways in cancer
Background:
- Targeting cancer cell metabolism is a promising therapeutic strategy.
- Mitochondrial oxidative phosphorylation (OXPHOS) is crucial for cellular energy production.
- Challenges exist in selectively targeting cancer mitochondria due to similarities with normal cells.
Purpose of the Study:
- To comprehensively phenotype mitochondrial OXPHOS composition and function across diverse murine cancer types.
- To compare cancer mitochondrial OXPHOS with matched normal tissues and highly oxidative organs.
- To evaluate the potential of OXPHOS as a therapeutic target in cancer treatment.
Main Methods:
- Mitochondrial phenotyping across various murine cancer models.
- Comparative analysis of OXPHOS complex expression and function.
- Assessment of substrate-specific mitochondrial flux.
Main Results:
- Mitochondrial OXPHOS expression and flux are consistently lower in multiple cancer types compared to matched normal tissues and the heart.
- These findings suggest that non-selective OXPHOS inhibitors may impact healthy organs before affecting tumors.
- Significant heterogeneity in mitochondrial proteome composition and substrate-specific flux was observed among different cancer types.
Conclusions:
- Indiscriminate targeting of mitochondrial OXPHOS for cancer therapy may lead to severe side effects in healthy tissues.
- The observed heterogeneity in cancer mitochondrial metabolism suggests potential for developing targeted therapies.
- Further research into cancer-specific mitochondrial pathways is warranted for effective and safe cancer treatment.
