Abstract
After being studied for approximately a century, berberine (BBR) has been found to act on various targets and pathways. A great challenge in the pharmacological analysis of BBR at present is to identify which target(s) plays a decisive role. In the study described herein, a rescue experiment was designed to show the important role of mitochondria in BBR activity. A toxic dose of BBR was applied to inhibit cell proliferation and mitochondrial activity, then α-ketobutyrate (AKB), an analogue of pyruvate that serves only as an electron receptor of NADH, was proven to partially restore cell proliferation. However, mitochondrial morphology damage and TCA cycle suppression were not recovered by AKB. As the AKB just help to regenerate NAD+, which is make up for part function of mitochondrial, the recovered cell proliferation stands for the contribution of mitochondria to the activity of BBR. Our results also indicate that BBR suppresses tumour growth and reduces energy charge and mitochondrial DNA (mtDNA) copy number in a HepG2 xenograft model. In summary, our study suggests that mitochondria play an important role in BBR activity regarding tumour cell proliferation and metabolism.
Highlights
Corresponding to the multiple functions, BBR has been found to impact on many molecules and cellular pathways
To investigate the role of mitochondria in BBR activity, we were inspired by a study led by Professor Vander Heiden[16] and designed an experiment to test whether pyruvate is able to rescue cell proliferation inhibited by BBR
As pyruvate partially restored the cell proliferation inhibited by BBR, pyruvate metabolism may play an important role in BBR activity
Summary
Corresponding to the multiple functions, BBR has been found to impact on many molecules and cellular pathways. One prevailing hypothesis is that BBR binds to nucleic acids and disturbs DNA and RNA metabolism[4,10]. Another representative hypothesis claims that, depending on the transmembrane potential, BBR accumulates on the inner membrane of mitochondria and inhibits mitochondrial respiratory complex I activity[11,12], BBR triggers oxidative stress, mitochondrial swelling and apoptosis[13,14]. Great progress on understanding the activity of BBR has been made in previous studies, the role of each target in BBR activity remains unclear. BBR should bind to and interact with different targets simultaneously; the activity of BBR represents a summational effect of all of its targets. We further investigated the effect of BBR on the regulation of cell metabolism and mitochondrial DNA copy number
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