Mechanisms of Berberine (Natural Yellow 18)–Induced Mitochondrial Dysfunction: Interaction with the Adenine Nucleotide Translocator

Abstract

Berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo (5,6-a) quinolizinium] is an alkaloid present in plants of the Berberidaceae family and used in traditional Chinese and North American medicine. We have previously demonstrated that berberine causes mitochondrial depolarization and fragmentation, with simultaneous increase in oxidative stress. We also demonstrated that berberine causes an inhibition of mitochondrial respiration and a decrease on calcium loading capacity through induction of the mitochondrial permeability transition (MPT). The objective of the present work is to investigate a common target for both induction of the MPT and inhibition of respiration. The hypothesis is that berberine induces the MPT through interacting with the adenine nucleotide translocator (ANT). By measuring induction of the MPT through increased mitochondrial swelling, membrane depolarization and loss of calcium retention, we observed that the effects of berberine were not inhibited by bongkrekic acid although adenosine diphosphate (ADP)/oligomycin completely prevented the MPT. Also, we observed that berberine increased the depolarization effect of oleic acid on liver mitochondria. The initial depolarization observed when berberine is added to mitochondria was not affected by ANT inhibitors. Taken together, we propose that berberine acts on the ANT, altering the binding of the protein to bongkrekic acid but not to cyclosporin A or ADP. It is also clear that the membrane potential is required for berberine effects, most likely for allowing for its mitochondrial accumulation. Mitochondrial effects of berberine can be relevant not only for its proposed antitumor activity but also for the assessment of its organ toxicity, depending on factors such as tissue accumulation or delivery.

Mitochondria and NMDA Receptor-Dependent Toxicity of Berberine Sensitizes Neurons to Glutamate and Rotenone Injury

“…In contrast to control cells, BBR increased the proportion of spherical mitochondria (Figure 2E). These morphological changes indicate that BBR induces mitochondrial swelling, known to associate with the opening of the mitochondrial permeability transition pore (PTP), a drop in the mitochondrial membrane potential and loss of mitochondrial Ca 2+ retention [22], [35].…”

“…BBR, and its derivative dihydroberberine, have been shown to specifically target the mitochondrial complex I [11]. Recently, Pereira et al characterized the effects of BBR on melanoma cell mitochondria as well as isolated mitochondrial fractions [22], [35]. They demonstrated that BBR can accumulate in mitochondria causing mitochondrial depolarization and fragmentation, mitochondrial PTP induction, increased oxidative stress, decreased cellular ATP content, and cell cycle arrest [35].…”

“…Pharmacological data suggest that berberine has poor bioavailability and that only nanomolar plasma concentrations are reached in both humans and animals [20]. According to several reports, however, BBR accumulates in organs such as lungs, liver and the brain, resulting in effective concentrations in the low micromolar range [13], [20]–[22]. Additionally, pro-drug development efforts aim at increasing BBR bioavailability [11], [23].…”

Renoprotective effect of berberine via intonation on apoptosis and mitochondrial-dependent pathway in renal ischemia reperfusion-induced mutilation

“…12 It has been acknowledged that berberine has a strapping antitumor and antioxidant potential. 13 It has been ascribed that berberine has potential to assuage gastrointestinal infections, inflammatory responses, carcinoma, and diabetes.…”

Electrochemical Oxidation of Berberine and of Its Oxidation Products at a Glassy Carbon Electrode

“…On the other hand, several studies have demonstrated that berberine can inhibit several enzymes including Na þ , K þ -ATPase and even inhibits protein and nucleic acid biosynthesis [16 -17]. We have previously demonstrated that berberine is selectively accumulated by mitochondria in mouse melanoma cells [18,19], which results in several effects including inhibition of the adenine nucleotide translocator [20], oxidative stress [19], arrest of cell cycle progression [18] and overall mitochondrial damage [19].…”