Mitochondrial Biogenesis in Response to Chromium (VI) Toxicity in Human Liver Cells

Abstract

Hexavalent chromium (Cr(VI)) is a ubiquitous environmental pollutant, which poses a threat to human public health. Recent studies have shown that mitochondrial biogenesis can be activated by inflammatory and oxidative stress. However, whether mitochondrial biogenesis is involved in Cr(VI)-induced hepatotoxicity is unclear. Here, we demonstrated the induction of inflammatory response and oxidative stress, as indicated by upregulation of inflammatory factors and reactive oxygen species (ROS). Subsequently, we demonstrated that mitochondrial biogenesis, comprising the mitochondrial DNA copy number and mitochondrial mass, was significantly increased in HepG2 cells exposed to low concentrations of Cr(VI). Expression of genes related to mitochondrial function complex I and complex V was upregulated at low concentrations of Cr(VI). mRNA levels of antioxidant enzymes, including superoxide dismutase 1 and 2 (SOD1 and SOD2, respectively), kech like ECH associate protein 1 (KEAP1) and nuclear respiratory factor 2 (NRF-2), were also upregulated. Consistent with the above results, mRNA and protein levels of key transcriptional regulators of mitochondrial biogenesis such as the peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α), NRF-1 and mitochondrial transcription factor A (TFAM) were increased by low concentrations of Cr(VI) in HepG2 cells. Moreover, we found that PGC-1α and NRF-1 tended to translocate into the nucleus. The expression of genes potentially involved in mitochondrial biogenesis pathways, including mRNA level of silent information regulator-1 (SIRT1), forkhead box class-O (FOXO1), threonine kinase 1 (AKT1), and cAMP response element-binding protein (CREB1), was also upregulated. In contrast, mitochondrial biogenesis was inhibited and the expression of its regulatory factors and antioxidants was downregulated at high and cytotoxic concentrations of Cr(VI) in HepG2 cells. It is believed that pretreatment with α-tocopherol could be acting against the mitochondrial biogenesis imbalance induced by Cr(VI). In conclusion, our study suggests that the homeostasis of mitochondrial biogenesis may be an important cellular compensatory mechanism against Cr(VI)-induced toxicity and a promising detoxification target.

Pesticides Effect on the Level of Mtdna Damage in Bumblebees Heads (Bombus Terrestris L.)

“…An increase in the number of mtDNA copies is probably a compensatory effect in response to inhibition of mitochondrial respiration. It has been shown previously that many cytotoxic agents, such as Hexavalent Chromium (VI) (Zhong et al, 2017), Methamphetamine (Valian et al, 2016), Tert-Butyl Hydroperoxide (Rasbach & Schnellmann, 2007), Buthionine Sulfoximine (Lee et al, 2000), Doxorubicin, Mitoxantrone (Kluza et al, 2004) and ROS (Gutsaeva et al, 2006) are able to activate mitochondrial biogenesis as a compensatory reaction in mammalian cells. It is likely that some pesticides have a similar effect on insects, but this issue needs further study.…”

Protein acetylation effects on enzyme activity and metabolic pathway fluxes

“…The neurotoxic effects of lead also seem related to SIRT1 downregulation as well as decreased p‐AMPK/AMPK ratios and increased FOXO1 acetylation, ensuing antioxidant enzyme machinery (SOD, CAT, and GPx) depression. Chromium toxic effects are also related to upregulation or downregulation of SIRT1, FOXO1, AKT1, CREB1, and HIF1α 96 . In contrast, arsenic toxic effects seem more related to interference with the SIRT3/FOXO1 signaling pathway, leading to MnSOD, PGC‐1a and mitochondrial dysregulation 92 …”

“…Chromium toxic effects are also related to upregulation or downregulation of SIRT1, FOXO1, AKT1, CREB1, and HIF1α. 96 In contrast, arsenic toxic effects seem more related to interference with the SIRT3/ FOXO1 signaling pathway, leading to MnSOD, PGC-1a and mitochondrial dysregulation. 92…”

Analysis of Hazardous Elements in Children Toys: Multi-Elemental Determination by Chromatography and Spectrometry Methods

“…This is important especially for children because they are considered more susceptible to hazardous metal substances compared to adults; they have higher basal metabolic rates, higher comparative uptakes of food, and lower toxins elimination rates. Moreover, children’s organs or tissues are developing, and thus, more sensitive to perturbed cellular processes [ 7 , 8 , 9 ]. Children typically spend a large amount of time playing with toys; toxic chemicals can be transferred from contaminated surfaces or soil to the hand and then ingested via hand-to-mouth activity.…”

“…Human oral exposure to Cr(VI) produces hepatotoxicity and there is evidence that Cr(VI) accumulation occurs by oral exposure route mostly in the liver, which is the largest detoxification organ. Moreover, Cr(VI) may cause primary liver cancer and increase the risk of deterioration of cancer patients [ 7 ]. In Europe, toys must meet the criteria and requirements set by the European Commission Toys Safety Directive to carry the CE (Conformité Européenne) mark.…”