{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:09:39Z","timestamp":1767204579349,"version":"build-2238731810"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    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, less is known about the net voltage of the liver in fibrosis. In this study, using the radiolabeled [\n                    <jats:sup>3<\/jats:sup>\n                    H] voltage sensor, tetraphenylphosphonium (TPP), which depends on membrane potential for cellular uptake\/accumulation, we determined the net voltage of the liver in a mouse model of carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    )-induced hepatic fibrosis. We demonstrated that the liver uptake of\n                    <jats:sup>3<\/jats:sup>\n                    H-TPP significantly increased at 4 weeks of CCl\n                    <jats:sub>4<\/jats:sub>\n                    -administration (6.07 \u00b1 0.69% ID\/g,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05) compared with 6 weeks (4.85 \u00b1 1.47% ID\/g) and the control (3.50 \u00b1 0.22% ID\/g). Analysis of the fibrosis, collagen synthesis, and deposition showed that the increased\n                    <jats:sup>3<\/jats:sup>\n                    H-TPP uptake at 4 weeks corresponds to early fibrosis (F1), according to the METAVIR scoring system. Biodistribution data revealed that the\n                    <jats:sup>3<\/jats:sup>\n                    H-TPP accumulation is significant in the fibrogenic liver but not in other tissues. Mechanistically, the augmentation of the liver uptake of\n                    <jats:sup>3<\/jats:sup>\n                    H-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 the 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.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2021.676722","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T01:41:10Z","timestamp":1635126070000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Augmented Liver Uptake of the Membrane Voltage Sensor Tetraphenylphosphonium Distinguishes Early Fibrosis in a Mouse Model"],"prefix":"10.3389","volume":"12","author":[{"given":"Himanshi","family":"Pandita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esteban","family":"Mezey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanmugasundaram","family":"Ganapathy-Kanniappan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1111\/j.1349-7006.2009.01087.x","article-title":"Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma","volume":"100","author":"Amann","year":"2009","journal-title":"Cancer Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1093\/toxsci\/kfr116","article-title":"Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity","volume":"122","author":"Bajt","year":"2011","journal-title":"Toxicol. 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