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Updated: Aug 17, 2025
Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
Published on: February 25, 2016
Regulation of mitochondrial complex III activity and assembly by TRAP1 in cancer cells
Danilo Swann Matassa1, Daniela Criscuolo1, Rosario Avolio1
1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131, Naples, Italy.
Background:
Metabolic reprogramming is an important issue in tumor biology. A recently-identified actor in this regard is the molecular chaperone TRAP1, that is considered an oncogene in several cancers for its high expression but an oncosuppressor in others with predominant oxidative metabolism. TRAP1 is mainly localized in mitochondria, where it interacts with respiratory complexes, although alternative localizations have been described, particularly on the endoplasmic reticulum, where it interacts with the translational machinery with relevant roles in protein synthesis regulation.
Results:
Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival. Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A.
Conclusions:
These results shed new light on the molecular mechanisms involved in TRAP1-dependent regulation of cancer cell metabolism and point out a potential novel target for metabolic therapy in ovarian cancer.
Insights
The molecular chaperone TRAP1 regulates mitochondrial complex III activity, impacting cancer cell metabolism. This finding suggests TRAP1 as a potential therapeutic target for ovarian cancer metabolic therapy.
Area of Science:
- Mitochondrial biology
- Cancer metabolism
- Molecular chaperones
Background:
- Metabolic reprogramming is crucial in tumor biology.
- TRAP1 acts as an oncogene or oncosuppressor depending on cancer type and metabolism.
- TRAP1 localizes to mitochondria and endoplasmic reticulum, influencing protein synthesis and respiration.
Purpose of the Study:
- To elucidate the role of TRAP1 in regulating mitochondrial complex III activity.
- To investigate TRAP1's impact on cancer cell metabolism under varying glucose conditions.
- To explore the therapeutic potential of targeting TRAP1 in ovarian cancer.
Main Methods:
- Mitochondrial TRAP1 binding to UQCRC2 was analyzed.
- Complex III activity and respiration rates were measured under basal and glucose-limiting conditions.
- Correlation of complex III components and TRAP1 with patient survival and therapy response was assessed in ovarian cancer.
Main Results:
- TRAP1 directly binds to UQCRC2, a core component of mitochondrial complex III.
- TRAP1 binding regulates complex III activity, decreasing basal respiration but sustaining oxidative phosphorylation when glucose is scarce.
- In high-grade serous ovarian cancers, complex III components correlate inversely with survival and platinum-based therapy response, while TRAP1 shows inverse correlation with stage/grade and direct correlation with survival.
Conclusions:
- TRAP1 plays a key role in regulating cancer cell metabolism through its interaction with mitochondrial complex III.
- TRAP1's influence on oxidative phosphorylation offers a novel therapeutic strategy for metabolic interventions in ovarian cancer.
- Targeting TRAP1 may represent a promising approach for treating drug-resistant ovarian cancers.
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