Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks

Area of Science:

• Biochemistry
• Oncology
• Mitochondrial Biology

Background:

• Metabolic pathway reprogramming is crucial in diseases like cancer.
• The specific regulators of metabolic reprogramming remain largely unknown.
• Mitochondrial function is increasingly recognized as a key player in cancer metabolism.

Purpose of the Study:

• To investigate the role of the mitochondrial chaperone TRAP-1 (tumor-resistance-associated protein 1) in metabolic regulation.
• To determine the in vivo effects of TRAP-1 deficiency on age-associated pathologies and tumor development.

Main Methods:

• Generation of a mouse knockout model for TRAP-1 (TRAP-1-/-).
• Assessment of age-associated pathologies, including obesity, inflammation, dysplasia, and spontaneous tumor formation in TRAP-1-/- mice.
• Analysis of transcriptomes, mitochondrial respiration, oxidative stress, and cell proliferation in TRAP-1-/- mice.

Main Results:

• TRAP-1-/- mice were viable and exhibited a reduced incidence of obesity, inflammatory tissue degeneration, dysplasia, and spontaneous tumors.
• Global upregulation of oxidative phosphorylation and glycolysis transcriptomes was observed in TRAP-1-/- mice.
• TRAP-1 deficiency led to deregulated mitochondrial respiration, increased oxidative stress, impaired cell proliferation, and a metabolic switch to glycolysis in vivo.

Conclusions:

• TRAP-1 is identified as a central regulator of mitochondrial bioenergetics.
• The TRAP-1 pathway plays a significant role in metabolic rewiring, particularly in the context of tumors.
• Targeting TRAP-1 may offer a novel therapeutic strategy for metabolic diseases and cancer.