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Cell Rep. 2014 Apr 24;7(2):476-87. doi: 10.1016/j.celrep.2014.02.048. Epub 2014 Apr 3.

E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia.

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  • 1Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 2Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 3Department of Neurology, Mt. Sinai School of Medicine, New York, NY 10029, USA.
  • 4Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 5Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 6Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA. Electronic address: mallampallirk@upmc.edu.

Abstract

Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S. aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S. aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S. aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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