Quinones and aromatic chemical compounds in particulate matter induce mitochondrial dysfunction: implications for ultrafine particle toxicity.
Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O2 .- generation, decrease of membrane potential (Delta-Psi m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on Delta-Psi m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in Delta-Psi m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and Delta-Psi m are mediated by adsorbed chemicals rather than the particles themselves.
Division of Clinical Immunology and Allergy, Department of Medicine, UCLA School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1680, USA.
Tian
T
Xia
Paavo
P
Korge
James N
JN
Weiss
Ning
N
Li
M Indira
MI
Venkatesen
Constantinos
C
Sioutas
Andre
A
Nel
D000818:Animals; D008099:Liver / Q000166:cytology; D008264:Macrophages; D051379:Mice; D008928:Mitochondria / Q000473:pathology*; D018384:Oxidative Stress; D010316:Particle Size; D010539:Permeability; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D001335:Vehicle Emissions / Q000633:toxicity*
D011084:Polycyclic Aromatic Hydrocarbons; D001335:Vehicle Emissions