Mitochondrial DNA and traumatic brain injury

Abstract

ObjectiveTraumatic brain injury (TBI) is a multifactorial pathology with great interindividual variability in response to injury and outcome. Mitochondria contain their own DNA (mtDNA) with genomic variants that have different physiological and pathological characteristics, including susceptibility to neurodegeneration. Given the central role of mitochondria in the pathophysiology of neurological injury, we hypothesized that its genomic variants may account for the variability in outcome following TBI.MethodsWe undertook an analysis of mitochondrial haplogroups in a large, well‐characterized cohort of 1,094 TBI patients. A proportional odds model including age, brain computed tomography characteristics, injury severity, pupillary reactivity, mitochondrial haplogroups, and APOE was applied to Glasgow Outcome Score (GOS) data.ResultsmtDNA had a significant association with 6‐month GOS (p = 0.008). Haplogroup K was significantly associated with favorable outcome (odds ratio = 1.64, 95% confidence interval = 1.08–2.51, p = 0.02). There was also a significant interaction between mitochondrial genome and age (p = 0.002), with a strong protective effect of both haplogroups T (p = 0.015) and K (p = 0.017) with advancing age. We also found a strong interaction between APOE and mitochondrial haplogroups (p = 0.001), indicating a protective effect of haplogroup K in carriers of the APOE ε4 allele.InterpretationThese findings reveal an interplay between mitochondrial DNA, pathophysiology of TBI, and aging. Haplogroups K and T, which share a common maternal ancestor, are shown as protective in TBI. The data also suggest that the APOE pathways interact with genetically regulated mitochondrial functions in the response to acute injury, as previously reported in Alzheimer disease. Ann Neurol 2014;75:186–195

Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study

“…Additionally, it is likely that multiple genes influence recovery and susceptibility to brain injury and one cannot study a single genetic polymorphism in isolation. For example, in a study of over 1000 European patients with TBI, Bulstrode and colleagues69 completed an analysis of mitochondrial (mt) DNA haplogroups, APOE genotype, advancing age and Glasgow Outcome Score data. The mtDNA K haplogroup was positively associated with the 6 month Glasgow Outcome Score (p=0.0008).…”

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

“…According to the cited study, the effects of carriership of haplogroup K were independent from the effects of carriership of APOE4. Generally, carriership of APOE4 is associated with poorer outcomes after brain injury, but carriership DNA repair capacity-a factor in late-onset dementia of mitochondrial DNA of haplogroup K apparently neutralised the effects of APOE4 [113]. Haplogroups K and the closely related haplogroup U were demonstrated to have a protective effect against AD in European populations [114].…”

“…Carriership of haplogroup K (common in Western Europe and the British Islands) may protect against transient ischaemic attack and ischemic stroke [112]. In individuals with traumatic brain injury carriership of mitochondrial DNA of haplogroup K was associated with significantly better outcomes 6 months after the injury [113]. According to the cited study, the effects of carriership of haplogroup K were independent from the effects of carriership of APOE4.…”

Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy

“…In this vein, different mtDNA haplgroups have been implicated in playing a role in TBI outcome in a number of studies. A population study conducted in England showed that mtDNA has a significant association with TBI outcomes, as certain haplogroups (K and T) have strong protective effect in TBI [15]. Another study reported that there is a strong correlation between mtDNA deletions in patients of acute brain injury [64].…”