Lack of β, β‐carotene‐9′, 10′‐oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice

Abstract

Scope β,β-carotene-9’,10’-dioxygenase 2 (BCO2) is a carotenoid cleavage enzyme localized to the inner mitochondrial membrane in mammals. This study was aimed to assess the impact of genetic ablation of BCO2 on hepatic oxidative stress through mitochondrial function in mice. Methods and Results Liver samples from 6 week old male BCO2−/− knockout (KO) and isogenic wild-type (WT) mice were subjected to proteomics and functional activity assays. Compared to the WT, KO mice consumed more food (by 18 %) yet displayed significantly lower body weight (by 12 %). Mitochondrial proteomic results demonstrated that loss of BCO2 was associated with quantitative changes of the mitochondrial proteome mainly shown by suppressed expression of enzymes and/or proteins involved in fatty acid β–oxidation, the tricarboxylic acid cycle, and the electron transport chain (ETC). The mitochondrial basal respiratory rate, proton leak, and ETC complex II capacity were significantly elevated in the livers of KO compared to WT mice. Moreover, elevated reactive oxygen species and increased mitochondrial protein carbonylation were also demonstrated in liver of KO mice. Conclusions Loss of BCO2 induces mitochondrial hyperactivation, mitochondrial stress and changes of the mitochondrial proteome, leading to mitochondrial energy insufficiency. BCO2 appears to be critical for proper hepatic mitochondrial function.

The DomesticBCO2Allele Buffers Low-Carotenoid Diets in Chickens: Possible Fitness Increase Through Species Hybridization

“…Lower expression levels of BCO2 in skin, muscle, and adipose tissue of chickens possessing the derived allele lead to accumulation of carotenoids in these tissues, but not in the liver and other internal organs, in which expression is not lowered. Indeed, BCO2 knockout in mice results in carotenoid accumulation in various tissues, giving rise to pathologic effects due to interference with mitochondrial function in hepatocytes (Lobo et al 2012;Wu et al 2017). Therefore, our findings suggest that the derived allele leads to carotenoid deposition in the tissues that are presumably less sensitive to the toxic effects of excess carotenoids such as skin and fat, but not in sensitive organs such as the liver.…”

“…By contrast, BCO2 cleaves nonprovitamin A carotenoids, including zeaxanthin, lutein, and lycopene, into colorless apocarotenoids such as b-apo-100-carotenal and b-ionone, which can be further catabolized by endogenous enzymes. Therefore, BCO2 functions as a carotenoid scavenger and prevents the adverse effects of excess carotenoids in sensitive tissues such as the liver (Lobo et al 2012;Wu et al 2017).…”

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

“…17 For detection of protein carbonyl groups, cellular proteins were treated with 2,4-dinitrophenylhydrazine (DNPH) in order to convert carbonyl groups to DNP-hydrazone using a commercial kit (Oxyblot, Millipore, Burlington, MA) according to manufacturer instructions and as described previously. 45 Proteins with DNP were detected by a rabbit anti-DNP antibody (Oxyblot) followed by goat anti-rabbit IgG (HRP-conjugated, Oxyblot). For all immunoblotting, signals were detected by chemiluminescence and captured digitally on a ProteinSimple FluorChem system (San Jose, CA).…”

Carotenoid pigmentation in salmon: variation in expression at BCO2-l locus controls a key fitness trait affecting red coloration

“…This carotenoid variation results in two flesh colour morphs (red and white) in Chinook salmon that vary in frequency among populations [15]. Phenotypic trade-offs associated with carotenoids exist between morphs, where, for example, carotenoids can improve immune function, mating success and embryo survival in salmon [2,[16][17][18], but also lead to greater predation risk [19] and potentially toxic effects at high levels [20,21]. Despite the large fitness effect of this genetic colour polymorphism [10], no studies have yet identified gene loci involved in the variation of this trait.…”