One of the first population-wide studies of how common genetic traits are influenced by DNA variations in mitochondria, the powerhouses of human cells, was carried out by scientists at the Wellcome Sanger Institute, Cambridge University, EMBL European Bioinformatics Institute (EMBL-EBI) and their collaborators. The team 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 diseases.
The study, published today in Natural medicine found that higher levels of fMet are associated with an increased risk of a wide range of late-onset diseases and all-cause mortality, demonstrating the potential of fMet as a biomarker of aging and disease risk, as well that the importance of research on mitochondrial DNA variants.
Mitochondria are organelles found in the cells of all complex organisms. They perform a number of vital biological functions, including producing about 90% of the energy cells need to function. Mitochondria are unique in that they have their own genetic code, called mitochondrial DNA (mtDNA), which is distinct from the DNA contained in the nucleus of every cell in an organism’s body1. MtDNA is passed from mother to child.
Many common diseases are influenced by mitochondrial damage or disruption, including genetic diseases such as diabetes, heart disease, and depression that are influenced by mutations in mtDNA.
Over time, the accumulation of mutations in mtDNA leads to distinct lineages in the population, called haplogroups, which confer particular traits. Previous research has shown that Haplogroup Uk, found in 10 percent of the European population, protects against diseases such as Parkinson’s disease and ischemic stroke (IS).
In this study, two large-scale datasets were analyzed to look for associations between genetic variants of mtDNA and thousands of common molecular traits such as blood cell counts and plasma proteins, in order to understand the mechanisms molecules behind mtDNA associations with disease.
In the INTERVAL dataset of up to 16,000 participants, researchers identified significant associations between the levels of fMet and mtDNA variants in the Uk and H32 haplogroups. The team then verified these associations using cell models. When fMet levels were measured in a cohort of ischemic stroke patients, they found lower fMet levels than in a healthy control group.
The researchers then analyzed data from EPIC-Norfolk, a study that followed the health of participants over a 20-year period, to ask whether differences in fMet between individuals were associated with a wider range of illnesses in the body. late onset. Unlike ischemic stroke, higher levels of fMet were associated with an increased risk of diseases such as kidney disease and heart failure.
“We knew that the British haplogroup offered some protection against ischemic stroke and Parkinson’s disease, and our results suggest that mitochondrial DNA variants that upregulate N-formylmethionine (fMet) may play a role. What was surprising was that these same variants are also associated with a higher risk of other diseases. Although further study of the molecular mechanisms at work is needed, fMet appears to be a promising biomarker that we could use to better predict an individual’s risk of developing a wide range of common diseases, ”says Dr Na Cai, lead author of the Wellcome Sanger Institute and European Institute study of bioinformatics at EMBL (EMBL-EBI).
“When we examined molecular processes using human cell models, we found that variants of the Uk haplogroup modulate protein synthesis and degradation in both mitochondria and cytoplasm, which affects the cells. cellular processes beyond mitochondrial bioenergetics. In the case of ischemic stroke (IS), our results suggest that part of the protective effect of the Uk haplogroup of mtDNA may be attributed to reduced clearance protein mediated by fMet, ”says Professor Patrick Chinnery, lead author of the Cambridge University study.
“Our results reveal the important role that mtDNA variants play in several pathologies, and that they play a deeper role in cell homeostasis than we previously thought. For this reason, mtDNA must be carefully processed. taken into account when investigating a diagnosis and providing treatment for age. associated diseases, ”says Dr Aurora Gomez-Duran, lead author of the Cambridge University study.
With only about 6,000 individuals on which to assess about 1,000 molecular traits in this study, other important associations between mtDNA variants and genetic traits remain hidden at this time. The next step will be to intensify this research to identify other traits associated with mtDNA variants.
“Our study highlights the vast potential of large-scale, hypothesis-free research on mitochondrial DNA as a means to better understand health and disease. N-formylmethionine (fMet) is a promising biomarker that may one day help us understand health and disease. help monitor individual disease risk and plan preventive interventions.This study was a truly collaborative effort with data from genome-wide association studies, cell lines, and combined computational analyzes to offer rich information on human biology, ”said Professor Nicole Soranzo, lead author of the Wellcome Sanger Institute study.
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Na Cai et al, Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and the risk of late-onset human disease, Natural medicine (2021). DOI: 10.1038 / s41591-021-01441-3
Quote: Amino Acid Link to a Range of Common Diseases Could Help Predict Personal Risk (2021, Aug 24) Retrieved Oct 1, 2021 from https://medicalxpress.com/news/2021-08-link- amino-acid-range-common .html
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