Metabolic Rewiring in Response to Biguanides Is Mediated by mROS/HIF-1a in Malignant Lymphocytes

Area of Science:

• Cancer Metabolism
• Mitochondrial Biology
• Cellular Adaptation

Background:

• Metabolic flexibility enables cancer cells to adapt, limiting therapeutic efficacy of metabolic drugs.
• Targeting cancer metabolism requires understanding its dynamic network and identifying vulnerabilities.
• Pharmacological inhibition of mitochondrial complex I is a strategy to disrupt cancer cell metabolism.

Purpose of the Study:

• To characterize metabolic reprogramming in response to mitochondrial complex I inhibition.
• To identify cancer-specific metabolic vulnerabilities and resistance mechanisms.
• To investigate the role of mitochondrial reactive oxygen species (mROS) and HIF-1a in adaptation.

Main Methods:

• Pharmacological inhibition of mitochondrial complex I.
• Analysis of transcriptional reprogramming of glucose metabolism.
• Investigation of the mROS/HIF-1a signaling axis using antioxidants and HIF-1a suppression.

Main Results:

• Malignant lymphocytes adapt to complex I inhibition by reprogramming glucose metabolism, conferring resistance to biguanides (phenformin, metformin).
• Metabolic adaptation is mediated by mitochondrial reactive oxygen species (mROS) acting as a stress signal activating hypoxia-inducible factor-1a (HIF-1a).
• Inhibition of the mROS/HIF-1a axis selectively disrupts adaptation and survival during complex I dysfunction in malignant lymphocytes.

Conclusions:

• HIF-1a signaling is critical for resistance to biguanide-induced mitochondrial dysfunction in cancer.
• Targeting the mROS/HIF-1a axis offers a selective strategy for treating leukemia and lymphoma.
• Understanding metabolic adaptation is key to developing effective cancer therapies.