Skip to main content

Neutrophil dysfunction and dysregulation in Barth syndrome

Barth syndrome (BTHS) is a rare X-linked genetic disease, caused by mutations in the gene tafazzin, which encodes for a mitochondrial protein involved in remodelling the mitochondrial phospholipid cardiolipin. This lack of cardiolipin processing causes defective mitochondrial formation and leads to neutropenia, an enlarged and weakened heart and skeletal muscle weakness. This reduction in neutrophil numbers coincides with increases in bacterial infections. Neutrophils are often thought to be metabolically very simplistic, wholly dependent on glucose and containing very little mitochondria. However, BTHS, a defect in mitochondrial lipid formation, demonstrates that defects in mitochondria have drastic effects on neutrophil formation. We therefore aimed to uncover the link between defective mitochondria, reduced neutrophil development and reduced host defence in BTHS.

We analysed protein content, metabolic output and various effector functions of neutrophils from healthy individuals and Barth syndrome sufferers. Tandem mass tag (TMT) mass spectrometry uncovered significant differences in expression of various proteins, suggesting alterations to protein expression during neutrophil development. Functional comparisons between these cohorts demonstrated that Barth syndrome neutrophils display excessive degranulation and a reduced ability to produce neutrophil extra cellular traps (NETs), large structures of DNA and proteins which can ensnare and kill pathogens. Additionally, metabolic output of neutrophils from BTHS suffers and tafazzin deficient (taz-/-) mice was also assessed. Surprisingly, mitochondrial protein content and metabolic function was not defective in BTHS patients and appeared to be enhanced due to GCSF treatment.

This data infers that mitochondrial contribution to neutrophil development, as opposed to active neutrophil metabolic function, alters neutrophil protein content and their subsequent behaviour when released to the circulation. We hypothesise that these alterations in BTHS neutrophils may compromise their antimicrobial function and leaves them hardwired to inappropriately release their granular proteins. 

Christopher M. Rice1, Drinalda Cela1, Fernando Ponce-Garcia1, Sarah Groves1, Ted Roberts2, Phil Lewis3, Kate Heesom3, Doug Strathdee4, Colin Stewart1 and Borko Amulic1.

  1. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  2. School of Biochemistry, University of Bristol, Bristol, UK.
  3. Bristol Proteomics Facility, University of Bristol, Bristol, UK.
  4. Transgenic Technology Lab, Cancer Research UK Beatson Institute, Glasgow, UK.


Powered by Firespring