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, Shanmugasundaram Ganapathy-Kanniappan

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)2210-2219
Number of pages10
JournalJournal of Cellular and Molecular Medicine
Volume22
Issue number4
DOIs
StatePublished - Apr 2018

Keywords

  • hepatic stellate cells
  • liver fibrosis
  • mitochondrial membrane potential
  • mitochondrial respiration
  • mitotropic doxorubicin

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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