The results of a study by researchers at the University of Cambridge suggest that mitochondria—the “batteries” that power our cells—may play an unexpected role in common diseases such as type 2 diabetes (T2D) and multiple sclerosis. The study, involving data from more than 350,000 participants in the UK Biobank (UKBB), found that genetic variants in mitochondrial DNA passed to offspring could increase the risk of developing different conditions, as well as influence characteristics such as height and lifespan. There was also evidence that some changes in mitochondrial DNA were more common in people with Scottish, Welsh or Northumbrian genetic ancestry, implying that mitochondrial DNA and nuclear DNA (which accounts for 99.9% of our genetic make-up) interact with each other.
Research co-lead Joanna Howson, PhD, who carried out the work while at the Department of Public Health and Primary Care at the University of Cambridge, said, “Aside from mitochondrial diseases, we don’t generally associate mitochondrial DNA variants with common diseases. But what we’ve shown is that mitochondrial DNA— which we inherit from our mother—influences the risk of some diseases such as type 2 diabetes and MS as well as a number of common characteristics.” Research co-lead Patrick Chinnery, PhD, from the MRC Mitochondrial Biology Unit at Cambridge, added, “If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA. The ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets.”
The scientists say the findings could ultimately help to identify new drug targets, but they could also have implications for the success of a new technique known as mitochondrial transfer therapy that is being developed to prevent offspring developing mitochondrial diseases. Howson and colleagues report their findings in a paper titled in Nature Genetics, which is titled “An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank.”
Almost all the DNA that makes up the human genome is contained within the nuclei of our cells. Nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.
Our cells’ mitochondria provide the energy to power cellular processes. They do this by converting the food we consume into ATP, a molecule that can release energy very quickly. Mitochondria also contain a tiny amount of DNA—mitochondrial DNA, mtDNA —which makes up only 0.1% of the overall human genome, but is passed down exclusively from mother to offspring. The authors explained, “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 essential for oxidative phosphorylation (OXPHOS) and production of cellular energy in the form of ATP.”
While errors in mitochondrial DNA can lead to mitochondrial diseases, which can be severely disabling, until now there had been little evidence that variants in mitochondrial DNA can influence more common diseases. Several small-scale studies have hinted at this possibility, but scientists have been unable to replicate their findings. “Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored,” the University of Cambridge team noted. “Initial mtDNA association studies in complex traits were underpowered and yielded conflicting findings that were rarely replicated.”
For their newly reported research, the team developed a technique to study mitochondrial DNA and its relation to human diseases and characteristics in samples taken from 358,000 volunteers as part of U.K. Biobank, a large-scale biomedical database and research resource.
The results suggested that in fact mitochondrial DNA might influence diseases such as type 2 diabetes, multiple sclerosis, and factors such as liver and kidney function, blood count parameters, lifespan and height. “When applied to the UKBB, the workflow has provided a comprehensive reference dataset of mtDNA variant–trait associations to date, highlighting 260 new mtDNA–phenotype associations,” the authors wrote. Interestingly, they pointed out, “Mitochondrial dysfunction has been observed in several of the diseases that were associated with mtSNVs [mitochondrial single nucleotide variants] in our analyses, such as multiple sclerosis, T2D and abdominal aortic aneurysms.”
Some of the effects were seen more extremely in patients with rare inherited mitochondrial diseases—for example, patients with severe disease are often shorter than average—whereas the effects in healthy individuals tended to be much subtler, likely accounting for just a few millimeters’ height difference, for example.
There are several possible explanations for how mitochondrial DNA exerts its influence, the team suggested. One is that changes to mitochondrial DNA lead to subtle differences in our ability to produce energy. However, it is likely to be more complicated, affecting complex biological pathways inside our bodies—the signals that allow our cells to operate in a coordinated fashion.
Unlike nuclear DNA, which is passed down from both the mother and the father, mitochondrial DNA is inherited exclusively from the mother. This would indicate that the two systems are inherited independently, so that there should be no association between an individual’s nuclear DNA and mitochondrial DNA. However, this was not what the team’s results indicated. The study found that certain nuclear genetic backgrounds are associated preferentially with certain mitochondrial genetic backgrounds, particularly in Scotland, Wales and Northumbria. This suggested that our nuclear and mitochondrial genomes have evolved—and continue to evolve—side-by-side and interact with each other.
One reason that may explain this is the need for compatibility. ATP is produced by a group of proteins inside the mitochondria called the respiratory chain. There are over 100 components of the respiratory chain, 13 of which are coded for by mitochondrial DNA, the remainder being encoded by nuclear DNA. Even though proteins in the respiratory chain are being produced by two different genomes, the proteins need to physically interlock like pieces of a jigsaw.
If the mitochondrial DNA inherited by a child was not compatible with the nuclear DNA inherited from the father, the jigsaw would not fit together properly, thereby affecting the respiratory chain and, consequently, energy production. This might subtly influence an individual’s health or physiology, which over time could be disadvantageous from an evolutionary perspective. Conversely, matches would be encouraged by evolution and therefore become more common.
This could have implications for the success of mitochondrial transfer therapy, a new technique that enables scientists to replace a mother’s defective mitochondria with those from a donor, to prevent her child from having a potentially life-threatening mitochondrial disease.
“It looks like our mitochondrial DNA is matched to our nuclear DNA to some extent – in other words, you can’t just swap the mitochondria with any donor, just as you can’t take a blood transfusion from anyone,” Chinnery said. “Fortunately, this possibility has already been factored into the approach taken by the team at Newcastle who have pioneered this therapy.”
The authors concluded, “Our current findings establish the key role played by mtDNA variants in many quantitative human traits, and confirm their contribution to common disease risk … understanding mitochondrial genetic architecture and the interaction between the nuclear and mitochondrial genomes will be important for reducing the burden of cardiometabolic and neurodegenerative diseases, among others … The atlas of UKBB mtSNV–trait associations provided here lays a firm foundation for future studies at the whole-mitochondrial genome level.”