**8. Conclusion**

been decreased, while cellular and plasma cholesterol levels increased in the heart of permethrin exposed rats. The pyrethroids may interact with TSPO protein with high affinity to affect its interaction with VDAC [93] to decrease cholesterol levels in mitochondria. Because mitochondrial function mostly depends on its membranous structures, a decrease in membranous and inner mitochondrial cholesterol levels could be effective on ROS production and abnormal autophagy as is exemplified above sections. Increased TSPO to VDAC ratio has been correlated with increased ROS production, decreased mitophagy, and accumulation of damaged mitochondria [155, 156]. Therefore, oxidative-stress inducing and apoptotic potential of pyrethroids could also be originated with this capability. TSPO attends to the ROS formation via mitochondrial membrane potential transition [148]. Produced ROS affect the bonding form of cytochrome c to cardiolipin through the tightly to loosely conformation and results in the release of it [157] to induce mitochondrial apoptotic pathway. Interestingly, in the events of VDAC closure and blockage of TSPO function cause a permeability increase of

There are very few studies on the mitochondrial DNA (mtDNA) alterations induced by pyrethroids in vertebrates. According to the results of Wang and Zhao [159] study, mtDNA somatic mutation frequency has been increased in the lung tissue of pesticide exposed (including pyrethroids) fruit growers. They have concluded that the increased frequency of mtDNA mutations may result from ROS formation, and the frequency has somewhat like cancer patients' tissues. Because of the adjacency of mtDNA to possible ROS formation centers in mitochondria [160], pyrethroid-induced mtDNA mutations could be linked to their ROS inducing potentials. In cypermethrin exposed zebrafish larvae, ROS induction has been augmented, while *ogg1* (8-oxoguanine DNA glycosylase) mRNA levels decreased [161]. This gene is responsible for the excision of 8-oxoguanine bases occurred via ROS action on DNA. This enzyme has many alternative splicing variants, all of them are targeted to the mitochondria for localization (PUBMED Gene ID:4968; https://www.ncbi.nlm.nih.gov/gene/4968, last access: January 7, 2018). According to the study of Sampath et al. [162], *Ogg*−/− mice exhibited a preference to carbohydrate metabolism over fatty acid oxidation via downregulated key fatty acid oxidation genes' and TCA genes' mRNAs. Then, they are susceptible to adiposity and hepatic steatosis. Therefore, pyrethroids might able to change the cellular substrate metabo-

Pyrethroids bifenthrin, cypermethrin, and deltamethrin have increased ρ-mutation frequency in *Saccharomyces cerevisiae* culture in a dose-dependent manner [163]. This type of mutation occurs mainly on mtDNA by large deletions [164], and mitochondrial protein synthesis and electron transport are blocked [163–165]. Interestingly, there are some studies related to the binding of pyrethroids to DNA macromolecule via different bonding mechanisms [166–169]. For example, permethrin can intercalate with DNA, and it is prone to bind G-C base pairs [167]. On the other hand, a complexation driven mechanism mainly by hydrogenbond and van der Waals forces has been observed between DNA and tau-fluvalinate and fluvalinate molecules [169]. AT-rich sequences are more susceptible sites for this complexation.

VDAC to Ca2+ and this can accelerate the mtPTP opening [158].

lism, and mtDNA mutations are probably involved in this process.

**7. Mitochondrial DNA and pyrethroids**

308 Mitochondrial Diseases

In conclusion, pyrethroids can perform their toxic action via their oxidative potentials including unbalanced Ca2+ flux in/out of the organelles and cells. Mitochondria might be the most vulnerable organelle for pyrethroid toxicity. Pyrethroids probably can change the interaction of mitochondrion and ER to create an imbalance between the fine equilibrium of ROS and Ca2+ signals. This affects the form of cellular metabolic energy production, accumulation of lipids and other metabolites, and cell death type. Pyrethroids can also change the mitochondrial membrane structures to affect their ability for metabolism and ROS production capacity. These effects may be related to the endocrine disruption, diabetic, dopaminergic, and obesity-induction potential of pyrethroids that are observed in exposed individuals as exemplified in the above sections such as altered lipid metabolism and cholesterol delivery into the mitochondria. However, there are many gaps that must be solved, such as, interaction with mitochondrial membrane proteins, specific mutagenesis caused by pyrethroid molecule and mtDNA interaction, etc.
