Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

Bharat Jaishy, Quanjiang Zhang, Heaseung S. Chung, Christian Riehle, Jamie Soto, Stephen Jenkins, Patrick Abel, L. Ashley Cowart, Jennifer E. Van Eyk, E. Dale Abel

Research output: Contribution to journalArticle

Abstract

Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.

Original languageEnglish (US)
Pages (from-to)546-561
Number of pages16
JournalJournal of Lipid Research
Volume56
Issue number3
DOIs
StatePublished - Mar 1 2015

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Keywords

  • Autophagy
  • Cardiomyocytes
  • Fatty acids
  • Lysosomes
  • NADPH oxidase 2
  • Protein kinase Cβ

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Jaishy, B., Zhang, Q., Chung, H. S., Riehle, C., Soto, J., Jenkins, S., Abel, P., Cowart, L. A., Van Eyk, J. E., & Abel, E. D. (2015). Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. Journal of Lipid Research, 56(3), 546-561. https://doi.org/10.1194/jlr.M055152