Succinate and Leukocyte Function
Research type
Research Study
Full title
Succinate and Leukocyte Function
IRAS ID
130543
Contact name
John Newell−Price
Contact email
Sponsor organisation
Sheffield Teaching Hospitals
Research summary
Summary of Research
Over their lifetime people with mutations in the gene encoding succinate dehydrogenase subunits (SDHB, SDHC, SDHD – often referred to as SDHx) are at increased risk (30-40%) of developing paraganglioma and phaeochromocytoma, and require life-long monitoring, which involves taking a blood sample at least every year, and an imaging test every few years.
We propose to look at whether succinate levels in the blood of people with SDHx mutations are different from people without this gene change and also to investigate if their white blood cell (leukocyte) function differs from their family members without this mutation, from people with the condition without the mutation, and from control individuals.
If differences are found, then it will allow us to gain a better understanding of how plasma succinate levels can be used to as an additional biomarker that may help in the follow-up of patients with SDHx mutations, and may also give us new information about white blood cell function.
This is a pilot case-control, observational study and no therapeutic interventions are planned. Samples collected for the study will include blood samples taken from patients and controls.Summary of Results
By comparing neutrophils isolated from patients with SDHx mutations, who have increased levels of succinate due to decreased activity of SDH, with those from healthy controls we were able to assess the role of succinate in neutrophil survival. We found that levels of succinate in the blood were increased in patients with SDH mutations, and that succinate levels were also increased within neutrophils. Furthermore, neutrophils from patients with SDH mutations showed increased survival in both normal (normaxia) and reduced oxygen conditions.
As succinate is known to regulate hypoxia signalling by increasing the activity of HIFs, and that a specific HIF called HIF-1α is important for the survival of neutrophils in hypoxic conditions, we examined whether the increased survival of SDH mutant neutrophils was due to increased HIF-1a activity. We found that although HIF-1a was elevated in under hypoxic conditions in these neutrophils, it was undetectable under normoxia, despite increased survival in these conditions. Therefore increased survival of SDH mutant neutrophils is not due to increased HIF-1a. Instead we found that the increased survival of SDH mutant neutrophils is linked to impaired mitochondrial function (the energy-producing part of the cell) and reduced oxidative stress.REC name
North West - Greater Manchester South Research Ethics Committee
REC reference
13/NW/0429
Date of REC Opinion
22 May 2013
REC opinion
Favourable Opinion