Ray NB, Durairaj L, Chen BB, McVerry BJ, Ryan AJ, Donahoe M et al.. Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nat Med 16: 1120-1127

Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
Nature medicine (Impact Factor: 27.36). 10/2010; 16(10):1120-7. DOI: 10.1038/nm.2213
Source: PubMed


Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia.

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    • "ATP8B1 CDC50A/B PtdCho, PtdSer PM Apical membrane barrier function Bile secretion; auditory and airway functions Paulusma et al., 2006 and 2008; Stapelbroek et al., 2009; Ray et al., 2010; Takatsu et al., 2014 ATP8B3 CDC50C? "
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    ABSTRACT: The plasma membrane, trans-Golgi network and endosomal system of eukaryotic cells are populated with flippases that hydrolyze ATP to help establish asymmetric phospholipid distributions across the bilayer. Upholding phospholipid asymmetry is vital to a host of cellular processes, including membrane homeostasis, vesicle biogenesis, cell signaling, morphogenesis and migration. Consequently, defining the identity of flippases and their biological impact has been the subject of intense investigations. Recent work has revealed a remarkable degree of kinship between flippases and cation pumps. In this Commentary, we review emerging insights into how flippases work, how their activity is controlled according to cellular demands, and how disrupting flippase activity causes system failure of membrane function, culminating in membrane trafficking defects, aberrant signaling and disease. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 04/2015; 128(11). DOI:10.1242/jcs.102715 · 5.43 Impact Factor
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    • "It has been shown that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin in lung fluid and that it impairs surfactant function, lung mechanics, modulation of cell survival and cytokine networks and lung consolidation [81]. "
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    ABSTRACT: Background Klebsiella pneumoniae strains are pathogenic to animals and humans, in which they are both a frequent cause of nosocomial infections and a re-emerging cause of severe community-acquired infections. K. pneumoniae isolates of the capsular serotype K2 are among the most virulent. In order to identify novel putative virulence factors that may account for the severity of K2 infections, the genome sequence of the K2 reference strain Kp52.145 was determined and compared to two K1 and K2 strains of low virulence and to the reference strains MGH 78578 and NTUH-K2044. Results In addition to diverse functions related to host colonization and virulence encoded in genomic regions common to the four strains, four genomic islands specific for Kp52.145 were identified. These regions encoded genes for the synthesis of colibactin toxin, a putative cytotoxin outer membrane protein, secretion systems, nucleases and eukaryotic-like proteins. In addition, an insertion within a type VI secretion system locus included sel1 domain containing proteins and a phospholipase D family protein (PLD1). The pld1 mutant was avirulent in a pneumonia model in mouse. The pld1 mRNA was expressed in vivo and the pld1 gene was associated with K. pneumoniae isolates from severe infections. Analysis of lipid composition of a defective E. coli strain complemented with pld1 suggests an involvement of PLD1 in cardiolipin metabolism. Conclusions Determination of the complete genome of the K2 reference strain identified several genomic islands comprising putative elements of pathogenicity. The role of PLD1 in pathogenesis was demonstrated for the first time and suggests that lipid metabolism is a novel virulence mechanism of K. pneumoniae.
    BMC Biology 05/2014; 12(1):41. DOI:10.1186/1741-7007-12-41 · 7.98 Impact Factor
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    • "As a whole, our data suggest that S. aureus severely disrupts cardiolipin biosynthesis perhaps through ubiquitination at the CLS1 step, which then leads to extracellular release of preformed cardiolipin (Figures 4D and 7). We have previously shown that extracellular cardiolipin potently disrupts lung homeostasis and recapitulates many features of pneumonia (Ray et al., 2010). Hence, our data suggest that, as one mechanism, severe bacterial infection triggers phosphorylation-dependent ubiquitination of a key substrate (CLS1) as a means to release a mitochondrial-derived DAMP to elicit pulmonary dyshomeostasis. "
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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.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.02.048 · 8.36 Impact Factor
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