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

• Published in: Cell reports (Cambridge) 2014-04, Vol.7 (2), p.476-487
• Main Authors: Chen, Bill B., Coon, Tiffany A., Glasser, Jennifer R., Zou, Chunbin, Ellis, Bryon, Das, Tuhin, McKelvey, Alison C., Rajbhandari, Shristi, Lear, Travis, Kamga, Christelle, Shiva, Sruti, Li, Chenjian, Pilewski, Joseph M., Callio, Jason, Chu, Charleen T., Ray, Anuradha, Ray, Prabir, Tyurina, Yulia Y., Kagan, Valerian E., Mallampalli, Rama K.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; B7-2 Antigen - genetics; B7-2 Antigen - metabolism; Case-Control Studies; Cell Line; Cells, Cultured; Child; Enzyme Stability; F-Box Proteins - genetics; F-Box Proteins - metabolism; Female; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondria - metabolism; Pneumonia - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Subunits - genetics; Protein Subunits - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.02.048

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. [Display omitted] •S. aureus activation of Fbxo15 mediates degradation of cardiolipin synthase1•S. aureus activates PINK1 that binds CLS1 to phosphorylate and control CLS1 disposal•S. aureus activates a Fbxo15-PINK1 pathway to impair mitochondrial integrity 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.