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Mitochondrial Respiration Quantification in Yeast Whole Cells
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β-Naphthoflavone-Induced Mitochondrial Respiratory Damage in Cyp1 Knockout Mouse and in Cell Culture Systems:
Suresh Kumar Anandasadagopan1, Naveen M Singh1, Haider Raza2
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6009, USA.
Abstract:
A number of xenobiotic-inducible cytochrome P450s (CYPs) are now known to be localized in the mitochondrial compartment, though their pharmacological or toxicological roles remain unclear. Here, we show that BNF treatment markedly inhibits liver mitochondrial O2 consumption rate (OCR), ADP-dependent OCR, and also reserve OCR, in wild-type mice but not in Cyp1a1/1a2(-/-) double knockout mice. BNF treatment markedly affected mitochondrial complex I and complex IV activities and also attenuated mitochondrial gene expression. Furthermore, under in vitro conditions, BNF treatment induced cellular ROS production, which was inhibited by mitochondria-targeted antioxidant Mito-CP and CYP inhibitor proadefin, suggesting that most of the ROS production was intramitochondrial and probably involved the catalytic activity of mitochondrial CYP1 enzymes. Interestingly, our results also show that the AHR antagonist resveratrol, markedly attenuated BNF-induced liver mitochondrial defects in wild-type mice, confirming the role of AHR and AHR-regulated CYP1 genes in eliciting mitochondrial dysfunction. These results are consistent with reduced BNF-induced mitochondrial toxicity in Cyp1a1/1a2(-/-) mice and elevated ROS production in COS cells stably expressing CYP1A1. We propose that increased mitochondrial ROS production and respiratory dysfunction are part of xenobiotic toxicity. Resveratrol, a chemopreventive agent, renders protection against BNF-induced toxicity.
Insights
Benzoflavone (BNF) treatment impairs liver mitochondrial respiration and increases reactive oxygen species (ROS) production, mediated by mitochondrial CYP1 enzymes. Resveratrol protects against this xenobiotic-induced mitochondrial toxicity.
Area of Science:
- Mitochondrial biochemistry
- Xenobiotic metabolism
- Toxicology
Background:
- Mitochondrial localization of xenobiotic-inducible cytochrome P450s (CYPs) is known, but their roles are unclear.
- Understanding the impact of xenobiotics on mitochondrial function is crucial for assessing toxicity.
Purpose of the Study:
- To investigate the role of mitochondrial CYP1 enzymes in xenobiotic-induced mitochondrial dysfunction.
- To explore the protective effects of resveratrol against benzoflavone (BNF)-induced mitochondrial toxicity.
Main Methods:
- Assessment of liver mitochondrial oxygen consumption rate (OCR) and respiratory parameters in wild-type and Cyp1a1/1a2(-/-) knockout mice following BNF treatment.
- Measurement of mitochondrial complex I and IV activities and gene expression.
- Evaluation of reactive oxygen species (ROS) production in vitro using cell cultures and in vivo in mice.
- Administration of AHR antagonist resveratrol to assess its protective effects.
Main Results:
- BNF treatment significantly inhibited liver mitochondrial OCR, ADP-dependent OCR, and reserve OCR in wild-type mice, but not in Cyp1a1/1a2(-/-) mice.
- BNF exposure affected mitochondrial complex I and IV activities, attenuated mitochondrial gene expression, and induced intramitochondrial ROS production.
- Resveratrol significantly attenuated BNF-induced mitochondrial defects in wild-type mice, confirming the involvement of the aryl hydrocarbon receptor (AHR) and CYP1 genes.
Conclusions:
- Mitochondrial CYP1 enzymes contribute to xenobiotic-induced mitochondrial dysfunction and ROS production.
- AHR-regulated CYP1 genes play a role in mediating BNF-induced mitochondrial toxicity.
- Resveratrol exhibits protective effects against xenobiotic-induced mitochondrial toxicity, highlighting its chemopreventive potential.
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