Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin

Priya Gajendiran, Leonel Iglesias Vega, Kie Itoh, Hiromi Sesaki, Mohammad Reza Vakili, Afsaneh Lavasanifar, Kelvin Hong, Esteban Mezey, Shanmugasundara Ganapathy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of Cellular and Molecular Medicine
DOIs
StateAccepted/In press - Jan 1 2018

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Hepatic Stellate Cells
Doxorubicin
Liver Cirrhosis
Energy Metabolism
Mitochondrial Membrane Potential
Extracellular Matrix Proteins
Wound Healing
Extracellular Matrix
Hepatocytes
Respiration
Collagen

Keywords

  • Hepatic stellate cells
  • Liver fibrosis
  • Mitochondrial membrane potential
  • Mitochondrial respiration
  • Mitotropic doxorubicin

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

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title = "Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin",
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.",
keywords = "Hepatic stellate cells, Liver fibrosis, Mitochondrial membrane potential, Mitochondrial respiration, Mitotropic doxorubicin",
author = "Priya Gajendiran and Vega, {Leonel Iglesias} and Kie Itoh and Hiromi Sesaki and Vakili, {Mohammad Reza} and Afsaneh Lavasanifar and Kelvin Hong and Esteban Mezey and Shanmugasundara Ganapathy",
year = "2018",
month = "1",
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TY - JOUR

T1 - Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin

AU - Gajendiran, Priya

AU - Vega, Leonel Iglesias

AU - Itoh, Kie

AU - Sesaki, Hiromi

AU - Vakili, Mohammad Reza

AU - Lavasanifar, Afsaneh

AU - Hong, Kelvin

AU - Mezey, Esteban

AU - Ganapathy, Shanmugasundara

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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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