Quinones and Aromatic Chemical Compounds in Particulate Matter Induce Mitochondrial Dysfunction: Implications for Ultrafine Particle Toxicity

Abstract

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 (ΔΨm), 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 ΔΨm 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 ΔΨm 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 ΔΨm are mediated by adsorbed chemicals rather than the particles themselves.

Mitochondrial Complex III-generated Oxidants Activate ASK1 and JNK to Induce Alveolar Epithelial Cell Death following Exposure to Particulate Matter Air Pollution

“…After combustion, this core rapidly cools and organic materials, and transition metals present in the combustion chamber are absorbed onto the particle. Xia et al (31,32) fractionated the organic component of the particles and demonstrated that the fraction enriched in quinones was sufficient to increase oxidant generation in an isolated liver mitochondria preparation. In A549 cells, Li et al (33) showed the accumulation of electron dense granules 1 h after particle administration.…”

The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles

“…Pro-inflammatory effects are mediated by the redox-sensitive MAP kinase and NF-κB cascades that are responsible for the expression of cytokines, chemokines, and adhesion molecules, many of which are involved in the inflammatory process of the lung [1,3,14,19]. Tier 3 cytotoxic effects (aka toxic oxidative stress) involve mitochondria, which are capable of releasing pro-apoptotic factors and inducing apoptosis of lung cells [20,21]. Taken together, the hierarchical cellular oxidative stress model provides a mechanistic platform against which to understand how PM generates adverse health effects.…”

“…For instance, electron microscopy has revealed that UFP are capable of localizing inside damaged mitochondria. Both aromatic organic compounds and quinones contribute to mitochondrial injury and ROS generation [21,22]. Thus, the extent of cellular toxicity is directly related to these organic chemical compounds.…”

“…In addition, once the NPs are taken up into the cell, for their interaction with subcellular organelles and biological systems can lead to further ROS production (Fig. 2) [3,21,121]. One example is disruption of one-electron transfers in the mitochondrial inner membrane.…”

Seasonal and spatial trends in particle number concentrations and size distributions at the children's health study sites in Southern California

“…To this date, however, there appears to be heterogeneity in particulate matter (PM) concentrations and PMassociated health effects between locations within an urban setting, which raises considerable uncertainties as to whether PM mass, number, size, bulk or surface chemistry are the appropriate metrics associated with PM toxicity. For example, recent studies have shown that atmospheric ultrafine particles (with physical diameter o100 nm) have the potential for eliciting adverse health effect (Oberdo¨rster and Utell, 2002;Li et al, 2003Li et al, , 2004Xia et al, 2004). Recent epidemiological studies by Peters et al (1997) have demonstrated a higher association between health effects and exposures to ultrafine particles compared to accumulation mode or coarse particles.…”