Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin |
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| Authors: | Priya Gajendiran Leonel Iglesias Vega Kie Itoh Hiromi Sesaki Mohammad Reza Vakili Afsaneh Lavasanifar Kelvin Hong Esteban Mezey Shanmugasundaram Ganapathy‐Kanniappan |
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| Affiliation: | 1. Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Department of Cell Biology, School of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada;4. Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA |
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| Abstract: | Activation of hepatic stellate cells (HSCs) is an integral component of the wound‐healing process in liver injury/inflammation. However, uncontrolled activation of HSCs leads to constant secretion of collagen‐rich extracellular matrix (ECM) proteins, resulting in liver fibrosis. The enhanced ECM synthesis/secretion demands an uninterrupted supply of intracellular energy; however, there is a paucity of data on the bioenergetics, particularly the mitochondrial (mito) metabolism of fibrogenic HSCs. Here, using human and rat HSCs in vitro, we show that the mito‐respiration, mito‐membrane potential (Δψm) and cellular ‘bioenergetic signature’ distinguish fibrogenic HSCs from normal, less‐active HSCs. Ex vivo, HSCs from mouse and rat models of liver fibrosis further confirmed the altered ‘bioenergetic signature’ of fibrogenic HSCs. Importantly, the distinctive elevation in mito‐Δψm sensitized fibrogenic HSCs for selective inhibition by mitotropic doxorubicin while normal, less‐active HSCs and healthy human primary hepatocytes remained minimally affected if not, unaffected. Thus, the increased mito‐Δψm may provide an opportunity to selectively target fibrogenic HSCs in liver fibrosis. |
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| Keywords: | liver fibrosis hepatic stellate cells mitochondrial membrane potential mitochondrial respiration mitotropic doxorubicin |
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