AUTHOR=Pandita Himanshi , Mezey Esteban , Ganapathy-Kanniappan Shanmugasundaram 

TITLE=Augmented Liver Uptake of the Membrane Voltage Sensor Tetraphenylphosphonium Distinguishes Early Fibrosis in a Mouse Model

JOURNAL=Frontiers in Physiology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.676722

DOI=10.3389/fphys.2021.676722

ISSN=1664-042X

ABSTRACT=Mitochondrial (mito-) oxidative phosphorylation (OxPhos) is a critical determinant of cellular membrane potential/voltage. Dysregulation of OxPhos is a biochemical signature of advanced liver fibrosis. However, little is known about the net voltage of the liver in fibrosis. Here, using the radiolabeled [3H] voltage sensor, tetraphenylphosphonium (TPP) that depends on membrane potential for cellular uptake/accumulation, we determined the net voltage of the liver in a mouse model of carbon tetrachloride (CCl4)-induced hepatic fibrosis. We demonstrate that the liver uptake of 3H-TPP significantly increased at 4-weeks of CCl4-administration (6.07±0.69 %ID/g, p<0.05) compared to 6-weeks (4.85±1.47 %ID/g) and the control (3.50±0.22 %ID/g). Analysis of the fibrosis, collagen synthesis and deposition showed that the increased 3H-TPP uptake at 4-weeks corresponds to early fibrosis (F1), according to METAVIR scoring system. Biodistribution data revealed that the 3H-TPP accumulation is significant in fibrogenic-liver but not in other tissues. Mechanistically, the augmentation of liver uptake of 3H-TPP in early fibrosis concurred with the upregulation of mito-electron transport chain enzymes, a concomitant increase in mito-oxygen consumption, and the activation of AMPK-signaling pathway. Collectively, our results indicate that mito-metabolic response to hepatic insult may underlie the net increase in the voltage of the liver in early fibrosis.