Image of several pink mitochondria on a black background to illustrate how fumarate, a chemical byproduct of mitochondrial metabolism, is known to trigger inflammation in the absence of the enzyme fumarate hydratase
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One of the first population-scale studies on how common genetic traits are influenced by variations in mitochondrial DNA (mtDNA), the powerhouses of human cells, has been published by scientists at the Wellcome Sanger Institute, the University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI), and their collaborators. The team identified associations between mtDNA variants and an amino acid, N-formylmethionine (fMet), and effects of fMet on the risk of developing a range of common, late-onset illnesses.

“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,” said Aurora Gomez-Duran, a first author of the study, and who is from the University of Cambridge.

Their report,  published in Nature Medicine found that higher fMet levels are associated with increased risk of a wide range of late-onset diseases and all-cause mortality, demonstrating fMet’s potential as a biomarker of ageing and disease risk, as well as the importance of research into mitochondrial DNA variants.

Mitochondria are found in the cells of all complex organisms. They perform a number of vital biological functions, including the production of around 90 per cent of the energy that cells need to function. They are unique in that they have their own genetic code, known as mitochondrial DNA (mtDNA), which is distinct from the DNA contained in the nucleus. mtDNA is passed on from mother to child.

Many common diseases are influenced by mitochondrial damage or disruption, including genetic diseases such as diabetes, heart disease and depression.

Over time, the accumulation of mutations in mtDNA leads to distinct lineages in the population, known as haplogroups, which confer particular traits. Previous research has shown that haplogroup Uk, found in 10% of the European population, is protective against diseases such as Parkinson’s Disease and ischemic stroke.

In this study, two large-scale datasets were analyzed to look for associations between genetic variants in mtDNA and thousands of common molecular traits such as blood cell counts and plasma proteins, in order to understand the molecular mechanisms behind mtDNA associations with diseases.

In the INTERVAL dataset of up to 16,000 participants, the researchers identified significant associations between levels of fMet and mtDNA variants in haplogroups Uk and H32. The team then verified these associations using cellular models. When fMet levels were measured in a cohort of ischemic stroke patients, they found lower fMet levels compared to those in a healthy control group.

The researchers then analyzed data from EPIC-Norfolk, a study that tracked the health of participants over a 20-year period, to ask whether differences in fMet between individuals were associated with a wider-range of late onset diseases. Higher fMet levels were associated with increased risk of illnesses such as kidney disease and heart failure.

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 ischemic 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.”

The next step will be to scale up this research in order to identify other traits associated with mtDNA variants.

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