PARP Inhibition Modulates Mitochondrial Morphology and Metabolism Under Hypoxic Stress in Cancer Cells

Abstract Hypoxia, low oxygen availability, is one of the main factors that determine tumor growth and metastasis survival. The hypoxic response is orchestrated by HIF factors which guide an array of genetic and metabolic adaptations that promote angiogenesis, metabolic reprogramming or migration, and finally a clinically malignant phenotype. Mitochondria play a crucial role during hypoxia, as these organelles are not only the main consumers of oxygen in the cell, but their morphological and biochemical adaptations determine how the cell must respond to a more hostile microenvironment. In the current study we investigated the mechanism by which mitochondria in tumor cells adapt to hypoxia in response to PARP inhibitors (PARPi) treatment. PARP inhibition alters mitochondrial dynamics, promoting a small globular mitochondrial phenotype, where mitochondria undergo membrane depolarization (ΔΨm) showing an increased fission. The metabolic shift toward anaerobic glycolysis is inhibited during PARPi treatment, and consequently, tumor cells activate the AMPk/mitophagy pathway in an attempt to survive. Moreover, the high proliferation rates and malignancy properties of tumor cells during hypoxia when mitophagy is compromised are reduced, sensitizing to PARPi treatment. Our results uncover a novel pathway for mitochondria adaptation to hypoxia and reveal a promising crosstalk between mitochondria and ADP-ribosylation for designing of future innovative strategies, independent of PARPs effect on cellular genome stability.