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E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

Chen, BB and Coon, TA and Glasser, JR and Zou, C and Ellis, B and Das, T and McKelvey, AC and Rajbhandari, S and Lear, T and Kamga, C and Shiva, S and Li, C and Pilewski, JM and Callio, J and Chu, CT and Ray, A and Ray, P and Tyurina, YY and Kagan, VE and Mallampalli, RK (2014) E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia. Cell Reports, 7 (2). 476 - 487.

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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. © 2014 The Authors.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, BB
Coon, TA
Glasser, JR
Zou, Cchz4@pitt.eduCHZ40000-0003-1355-4726
Ellis, B
Das, T
McKelvey, AC
Rajbhandari, S
Lear, Ttravislear@pitt.eduTRL340000-0001-9156-0844
Kamga, C
Shiva, Ssss43@pitt.eduSSS43
Li, C
Pilewski, JMpilewski@pitt.eduPILEWSKI
Callio, J
Chu, CTctc4@pitt.eduCTC4
Ray, Araya@pitt.eduRAYA
Ray, Prayp@pitt.eduRAYP
Tyurina, YYyyt1@pitt.eduYYT1
Kagan, VEkagan@pitt.eduKAGAN
Mallampalli, RK
Centers: Other Centers, Institutes, Offices, or Units > Vascular Medicine Institute
Date: 24 April 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 7
Number: 2
Page Range: 476 - 487
DOI or Unique Handle: 10.1016/j.celrep.2014.02.048
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
School of Medicine > Cell Biology and Molecular Physiology
School of Medicine > Pathology
Refereed: Yes
Date Deposited: 22 May 2015 21:50
Last Modified: 31 Jul 2020 16:55
URI: http://d-scholarship.pitt.edu/id/eprint/24725

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