Mitochondria inherited from the mother can affect the risk of common diseases in offspring

According to the findings of a study conducted by researchers at the University of Cambridge, mitochondria the "batteries" that power our cells might play an unexpected role in diseases like type 2 diabetes (T2D) and multiple sclerosis. The research, which used data from over 350,000 people in the UK Biobank (UKBB), discovered that genetic variants in mitochondrial DNA passed down to offspring can increase the risk of contracting various diseases and affect traits like height and lifespan. There was also evidence that certain mitochondrial DNA variations were more common in people with Scottish, Welsh, or Northumbrian genetic heritage, suggesting that mitochondrial DNA and nuclear DNA (which makes up 99.9% of our genetic makeup) interact.

“Aside from mitochondrial diseases, we don't usually connect mitochondrial DNA variants with common diseases,” said research co-lead Joanna Howson, PhD, who conducted the research while at the University of Cambridge's Department of Public Health and Primary Care. But what we've discovered is that mitochondrial DNA, which we get from our mother, has an effect on the risk of diseases like type 2 diabetes and MS, as well as a host of other traits.” “If you want a full picture of common diseases, then obviously you're going to have to factor in the influence of mitochondrial DNA,” said Patrick Chinnery, PhD, of the MRC Mitochondrial Biology Unit in Cambridge. The ultimate goal of DNA research is to discover new ways to cure diseases through understanding the mechanisms that cause them. Our research may lead to the discovery of new drug targets.”

The results, according to the researchers, could help establish potential drug targets in the future, but they could also affect the effectiveness of a new technique called mitochondrial transfer therapy, which is being developed to prevent offspring from developing mitochondrial diseases. Howson and colleagues publish their findings in Nature Genetics in a paper titled "An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank.”

The nuclei of our cells comprise almost all of the DNA that makes up the human genome. Nuclear DNA codes for both the features that distinguish us as individuals and the proteins that do the majority of the function in our bodies.

The mitochondria in our cells are responsible for supplying energy to our cells' processes. They do this by transforming the food we eat into ATP, a molecule that can rapidly release energy. Mitochondria also contain a small amount of DNA called mitochondrial DNA (mtDNA), which accounts for just 0.1 percent of the human genome but is only passed on from mother to offspring. “The 16,569-bp human mitochondrial genome has a compact genomic organization, with 95% of the sequence encoding 13 proteins, 22 transfer RNAs, and 2 ribosomal RNAs that are necessary for oxidative phosphorylation (OXPHOS) and the production of cellular energy in the form of ATP,” the researchers explained.

Though errors in mitochondrial DNA can cause life-threatening mitochondrial diseases, there has been little evidence that mitochondrial DNA variants can affect more common diseases until now. Several small-scale experiments have suggested this possibility, but scientists have yet to confirm their findings. The University of Cambridge team said, "Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored." “Early mtDNA association studies in complex traits were underpowered, yielding contradictory results that were rarely replicated.”

The team developed a methodology to analyze mitochondrial DNA and its relationship to human diseases and characteristics in samples collected from 358,000 volunteers as part of the U.K. Biobank, a large-scale biomedical database and testing resource, for their newly published research.

The findings indicated that mitochondrial DNA could play a role in diseases like type 2 diabetes and multiple sclerosis, as well as factors like liver and kidney function, blood count parameters, lifespan, and height. The workflow has provided a detailed reference dataset of mtDNA variant–trait associations to date, highlighting 260 new mtDNA–phenotype associations when applied to the UKBB, according to the authors. “Mitochondrial dysfunction has been found in many of the diseases associated with mtSNVs [mitochondrial single nucleotide variants] in our analyses, such as multiple sclerosis, T2D, and abdominal aortic aneurysms,” they pointed out.

Some of the effects were more pronounced in patients with rare inherited mitochondrial disorders, for example, patients with serious disease are often shorter than average, while the effects in healthy people were much subtler, likely accounting for just a few millimeters in height difference.

According to the researchers, there are many potential reasons for how mitochondrial DNA exerts its effect. Changes in mitochondrial DNA cause slight variations in our ability to generate energy, for example. However, it is likely to be more complex, influencing complex biological pathways within our bodies—the signals that enable our cells to work together.

Unlike nuclear DNA, which comes from both the mother and the father, mitochondrial DNA is only passed down through the mother. This would imply that the two systems are inherited separately, and that there should be no connection between a person's nuclear and mitochondrial DNA. The team's findings, however, did not support this conclusion. Certain nuclear genetic backgrounds are preferentially correlated with certain mitochondrial genetic backgrounds, according to the report, which was conducted in Scotland, Wales, and Northumbria. This suggests that our nuclear and mitochondrial genomes have formed alongside one another and interact with one another.

One explanation for this may be the need for compatibility. The respiratory chain, a collection of proteins within the mitochondria, produces ATP. The respiratory chain consists of over 100 elements, 13 of which are encoded by mitochondrial DNA and the rest by nuclear DNA. Despite the fact that proteins in the respiratory chain are formed by two separate genomes, they must physically interlock like jigsaw puzzle parts.

The jigsaw would not fit together properly if a child's mitochondrial DNA was incompatible with the nuclear DNA inherited from the parent, affecting the respiratory chain and, as a result, energy output. This may have a subtle impact on an individual's wellbeing or physiology, which could be detrimental to evolution over time. Matches, on the other hand, will be favored by evolution and therefore become more popular.

This could affect the effectiveness of mitochondrial transfer therapy, a new procedure in which scientists substitute a mother's damaged mitochondria with those from a donor in order to prevent her child from developing a potentially fatal mitochondrial disease.

“It seems that our mitochondrial DNA is to some degree matched to our nuclear DNA – in other words, you can't just exchange mitochondria with some donor, just as you can't take a blood transfusion from anyone,” Chinnery explained. “Fortunately, the Newcastle team, who pioneered this therapy, has already factored this possibility into their approach.”

“Our current findings identify the critical function of mtDNA variants in several quantitative human traits, and confirm their contribution to common disease risk,” the authors concluded. Understanding mitochondrial genetic architecture and the relationship between the nuclear and mitochondrial genomes, among other things, would be critical in reducing the burden of cardiometabolic and neurodegenerative diseases... The atlas of UKBB mtSNV–trait associations presented here provides a solid basis for future research at the whole-mitochondrial genome level.”