Inside our cells are mitochondria, which act as their powerhouses – generating about 90 per cent of the energy required for the biochemical reactions required for them to function.
This is just one of the vital biological functions of these organelles, which are unique in having their own genetic code.
Known as mitochondrial DNA (mtDNA), it is distinct from the DNA contained in the nucleus of every cell in an organism’s body. This mtDNA is passed on from mother to child.
Now, one of the first population-scale studies on how common genetic traits are influenced by variations in mtDNA has been completed.
Scientists at the Wellcome Sanger Institute, the University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI), and their collaborators identified associations between mtDNA variants and an amino acid, N-formylmethionine (fMet), and the effects of fMet on the risk of developing a range of common, late-onset illnesses.
Higher fMet levels are associated with an increased risk of a wide range of late-onset diseases and of mortality from all causes, which demonstrates how this amino acid could be used as a biomarker of ageing and disease risk.
It also underscores the importance of research into mitochondrial DNA variants.
Dr Aurora Gomez-Duran, a first author of the study from the University of Cambridge, said: “Our findings reveal the important part that mtDNA variants play in several pathologies, and that they play a deeper role in cellular homeostasis than we previously thought.
“Due to this, mtDNA should be carefully considered when investigating a diagnosis and delivering a treatment for age-associated diseases.”
Mitochondrial damage or disruption influences many conditions, including genetic diseases such as diabetes, heart disease and depression.
The accumulation of mutations in mtDNA leads to distinct lineages in the population, known as haplogroups, which lead to particular traits.
Previous research has shown that haplogroup Uk – which is found in 10 per cent of the European population – is protective against diseases such as Parkinson’s and ischaemic stroke (IS).
For this study, the researchers analysed two large-scale datasets to look for associations between genetic variants in mtDNA and thousands of common molecular traits such as blood cell counts and plasma proteins.
The aim was to understand the molecular mechanisms behind mtDNA associations with diseases.
They found lower fMet levels in patients that had suffered ischaemic stroke compared to a healthy control group, but were surprised to see higher fMet levels were associated with an increased risk of illnesses such as kidney disease and heart failure.
Dr Na Cai, a first author of the study from the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute (EMBL-EBI), said: “We knew that the Uk haplogroup offered some protection against ischaemic stroke and Parkinson’s disease, and our findings suggest that variants in mitochondrial DNA that upregulate N-formylmethionine (fMet) may play a part in this protection. What was surprising is that these same variants are also associated with higher risk of other diseases.
“While further study of the molecular mechanisms at work is required, fMet does seem to be a promising biomarker that we could use to better predict an individual’s risk of developing a wide range of common diseases.”
Professor Patrick Chinnery, a senior author of the study from the University of Cambridge, said: “When we examined the molecular processes using human cellular models, we found that variants in Haplogroup Uk modulate protein synthesis and degradation in both the mitochondria and cytoplasm, and this affects cellular processes beyond mitochondrial bioenergetics. In the case of ischaemic stroke (IS), our findings suggest part of the protective effect of mtDNA haplogroup Uk may be attributed to reduced protein clearance mediated by fMet.”
The scientists say that as there were only around 6,000 individuals on which to assess around 1,000 molecular traits in this study, other significant associations between mtDNA variants and genetic traits remain hidden for now.
They intend to scale up the research to identify other traits associated with mtDNA variants.
Professor Nicole Soranzo, a senior author of the study from the Wellcome Sanger Institute, said: “Our study highlights the vast potential of large-scale, hypothesis-free research into mitochondrial DNA as a way of better understanding health and disease. N-formylmethionine (fMet) is a promising biomarker that could one day help us to monitor individual disease risk and plan pre-emptive interventions. This study has been a true collaborative effort with data from genome-wide association studies, cell lines and computational analysis combining to offer rich insights into human biology.”
The study was published on Monday in Nature Medicine.
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