Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response

Abstract

Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis.

G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress

“…This is predicted to reduce corresponding protein synthesis, such as to support cytoprotective shifts in bioenergetics and to inhibit apoptosis, respectively, in stressed tumor cells. This was supported by our functional studies, which demonstrated that OCR and ECAR as well as ATP production were significantly reduced in arsenite treated cells, aligning with published data showing that arsenite reduces mitochondrial bioenergetics ( 49 , 50 ). A specific example of a pro-apoptotic factor in this category is BAX (which is also a mitochondrial associated protein).…”

“…Accordingly, as described above, OCR and ATP production were significantly reduced in arsenite treated cells compared to vehicle alone (Figure 2B and D ), supporting the ontology analysis. Moreover, arsenite treatment was previously reported to reduce mitochondrial bioenergetics ( 49 , 50 ). BAX functional studies are included in the next section.…”

Positive Association of Cardiovascular Disease (CVD) with Chronic Exposure to Drinking Water Arsenic (As) at Concentrations below the WHO Provisional Guideline Value: A Systematic Review and Meta-analysis

“…Such a conclusion has already been confirmed by several epidemiological and biological studies [36,53,61]. However, it has been illustrated that several mechanisms of As toxicity, ranging from the generation of oxidative stress, inhibition of DNA repair to modulation of signal transduction pathways and perturbation of DNA methylation patterns, are likely to give rise to nonlinear dose-response relationships, especially at low concentrations [98,99]. Besides, one recent study also revealed a steeper increase at lower As concentrations for fatal CVD [29].…”

Preliminary observations of mitochondrial dysfunction in Prader–Willi syndrome

“…However, whether and how mitochondrial functional capacity is altered in PWS is not known. Thus, we undertook a study using living cells (fibroblasts) from subjects with PWS and healthy controls in order to assess the impact of mitochondrial performance using Agilent Seahorse XF extra-cellular flux technology which allows real-time measurements of several metabolic parameters including cellular substrate utilization, ATP-linked respiration and mitochondrial capacity (Chavan et al, 2017; Tan et al, 2017).…”