Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung

Abstract

Cadmium (Cd) causes acute and chronic lung toxicities at occupational exposure levels, yet the impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Health concerns arise because humans do not have an effective Cd elimination mechanism, resulting in a long (10-to 35-y) biological half-life. Previous studies showed increased mitochondrial oxidative stress and cell death by Cd yet the details of mitochondrial alterations by low levels of Cd remain unexplored. In the current study, we examined the impacts of Cd burden at a low environmental level on lung metabolome, redox proteome, and inflammation in mice given Cd at low levels by drinking water (0, 0.2, 0.6 and 2.0 mg Cd/L) for 16 weeks. The results showed that mice accumulated lung Cd comparable to non-smoking humans and showed inflammation in lung by histopathology at 2 mg Cd/L. The results of high resolution metabolomics combined with bioinformatics showed that mice treated with 2 mg Cd/L increased levels of lipids in the lung, accompanied by disruption in mitochondrial energy metabolism. In addition, targeted metabolomic analysis showed that these mice had increased accumulation of mitochondrial carnitine and citric acid cycle intermediates. The results of redox proteomics showed that Cd at 2 mg/L stimulated oxidation of isocitrate dehydrogenase, malate dehydrogenase and ATP synthase. Taken together, the results showed impaired mitochondrial function and accumulation of lipids in the lung with a Cd dose response relevant to non-smokers without occupational exposures. These findings suggest that dietary Cd intake could be an important variable contributing to human pulmonary disorders.

Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets

“…Interestingly, approximately 41% of the metabolites can be characterized as xenobiotics being derived from the environment or pollutants. These findings are important since they support the concept that exposure to environmental pollutants impact bioenergetic function [ 56 ].…”

“…Untargeted metabolomics was performed using previously established HRM methods [ [33] , [34] , [35] , [36] ]. Washed platelets were diluted to a concentration of 100 × 10 6 /well in 0.75 ml DMEM assay buffer (DMEM with 1 mM pyruvate, 5.5 mM glucose, 4 mM glutamine, pH 7.4) and treated with oligomycin (1 μg/ml) for 30 min at 37 °C in a non-CO 2 humidified incubator in 6-well plates (9 cm 2 /well).…”

Cell organelles as targets of mammalian cadmium toxicity

“…A recent report analyzed lung tissue from cadmium-exposed rats (up to 2 mg/L cadmium in drinking water, 16 weeks) using high resolution metabolomics and redox proteomics as well as performing metabolic pathway analyses. Cadmium was found to induce oxidation of multiple citric acid cycle proteins, leading to impaired enzyme activities and accumulation of citric acid cycles intermediates (Hu et al 2019). The loss of ATP generation through the citric acid cycle and ETC could be an important step in the transformation progression of normal cells, ultimately making the switch to glycolysis, also known as the Warburg effect, which is a hallmark of cancer cells (Potter et al 2016).…”

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

“…In this process, mitochondrial reactive oxygen species (ROS) increase and affect redox-sensitive transcription factors. Even low levels of cadmium in drinking water affect energy metabolism in the lung [ 135 ]. Because the ZIP8 and ZIP14 zinc transporters also transport cadmium, exposure to cadmium exacerbates the effects of zinc deficiency on the innate immune system and the pro-oxidant effects of zinc deficiency in inflammation [ 136 ].…”