Benzo[a]pyrene induces an adaptive mitochondrial-dynamics response in endothelial cells, at human relevant...

Although polycyclic aromatic hydrocarbons (PAHs) are a public health concern in many countries, the cellular response at concentrations representative of human exposure remains poorly defined. At the cellular level, because of their function and composition, mitochondria are privileged targets of these contaminants. PAHs such as benzo[a]pyrene (B[a]P) can compromise mitochondrial functions. Using an integrated approach, we examined how low-dose B[a]P disrupts the three determinants of mitochondrial homeostasis (biogenesis, mitophagy, and dynamics) and triggers apoptosis. We assessed the cellular response to a low-dose of B[a]P (100 nM) in the human microvascular endothelial cell line HMEC-1. Endothelial cells are sensitive to PAHs and display marked reactivity to effectors of B[a]P toxicity, such as oxidative stress. We show that B[a]P doesn't modify mRNA expression of mitochondrial biogenesis markers but causes a blockage of autophagic flux. In parallel, we observe early and transient mitochondrial elongation accompanied by decreased expression of the fission factors DRP1 and MFF, and increased intracellular concentration of ATP. These events constitute cellular signatures of stress-induced mitochondrial hyperfusion (SIMH), a mechanism of resistance to apoptosis. B[a]P eventually causes apoptosis of HMEC-1 cells, which is mitochondria-dependent, caspase-independent, requires B[a]P bioactivation by CYP1 family enzymes, and is only detectable after 24 h of exposure when SIMH markers decline. Our results show that endothelial cells can mobilize SIMH to delay and limit B[a]P-induced apoptosis. We confirm that mitochondria, at human-relevant doses, are early sensitive targets of B[a]P and show that changes in mitochondrial dynamics constitute an early readout of cellular responses to B[a]P.