E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia
Summary: 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 th...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714001648 |
| _version_ | 1818256570039926784 |
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| author | Bill B. Chen Tiffany A. Coon Jennifer R. Glasser Chunbin Zou Bryon Ellis Tuhin Das Alison C. McKelvey Shristi Rajbhandari Travis Lear Christelle Kamga Sruti Shiva Chenjian Li Joseph M. Pilewski Jason Callio Charleen T. Chu Anuradha Ray Prabir Ray Yulia Y. Tyurina Valerian E. Kagan Rama K. Mallampalli |
| author_facet | Bill B. Chen Tiffany A. Coon Jennifer R. Glasser Chunbin Zou Bryon Ellis Tuhin Das Alison C. McKelvey Shristi Rajbhandari Travis Lear Christelle Kamga Sruti Shiva Chenjian Li Joseph M. Pilewski Jason Callio Charleen T. Chu Anuradha Ray Prabir Ray Yulia Y. Tyurina Valerian E. Kagan Rama K. Mallampalli |
| author_sort | Bill B. Chen |
| collection | DOAJ |
| description | Summary: 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. : It is unknown why people with severe bacterial infections develop mitochondrial dysfunction with impaired cellular oxygenation. Here, Mallampalli and colleagues show that S. aureus lung infection in cells and mice induces an ubiquitin E3 ligase subunit to mediate degradation of a mitochondrial biosynthetic enzyme, CLS1, after its phosphorylation by PINK1. The data provide mechanistic insights into mitochondrial bioenergetics during pneumonia. |
| first_indexed | 2024-12-12T17:29:51Z |
| format | Article |
| id | doaj.art-f58f4fba805b4b1fa45cbc1c553cb1b9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T17:29:51Z |
| publishDate | 2014-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f58f4fba805b4b1fa45cbc1c553cb1b92022-12-22T00:17:26ZengElsevierCell Reports2211-12472014-04-0172476487E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in PneumoniaBill B. Chen0Tiffany A. Coon1Jennifer R. Glasser2Chunbin Zou3Bryon Ellis4Tuhin Das5Alison C. McKelvey6Shristi Rajbhandari7Travis Lear8Christelle Kamga9Sruti Shiva10Chenjian Li11Joseph M. Pilewski12Jason Callio13Charleen T. Chu14Anuradha Ray15Prabir Ray16Yulia Y. Tyurina17Valerian E. Kagan18Rama K. Mallampalli19Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USAVascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USAVascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Neurology, Mt. Sinai School of Medicine, New York, NY 10029, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment 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; Corresponding authorSummary: 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. : It is unknown why people with severe bacterial infections develop mitochondrial dysfunction with impaired cellular oxygenation. Here, Mallampalli and colleagues show that S. aureus lung infection in cells and mice induces an ubiquitin E3 ligase subunit to mediate degradation of a mitochondrial biosynthetic enzyme, CLS1, after its phosphorylation by PINK1. The data provide mechanistic insights into mitochondrial bioenergetics during pneumonia.http://www.sciencedirect.com/science/article/pii/S2211124714001648 |
| spellingShingle | Bill B. Chen Tiffany A. Coon Jennifer R. Glasser Chunbin Zou Bryon Ellis Tuhin Das Alison C. McKelvey Shristi Rajbhandari Travis Lear Christelle Kamga Sruti Shiva Chenjian Li Joseph M. Pilewski Jason Callio Charleen T. Chu Anuradha Ray Prabir Ray Yulia Y. Tyurina Valerian E. Kagan Rama K. Mallampalli E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia Cell Reports |
| title | E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia |
| title_full | E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia |
| title_fullStr | E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia |
| title_full_unstemmed | E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia |
| title_short | E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia |
| title_sort | e3 ligase subunit fbxo15 and pink1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714001648 |
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