Mitochondrial DNA insertions are common in human brain

Insertions of mitochondria DNA (mtDNA) are prevalent in our nuclear genome and could be linked to reduced lifespan.

US researchers found the occurrence of mtDNA insertions in our nuclear genome to be common, especially in regions of the frontal cortex, and more insertions are associated with increased mortality rates.

'We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence,' said co-author Dr Martin Picard, from the department of neurology at Columbia University in New York. 'It's stunning that it appears to be happening several times during a person's lifetime'.

Publishing their findings in PLOS Biology, the collaborators first compared the amount of mtDNA insertions in postmortem brain tissue and blood from a cohort of 1187 people. Brain tissue, specifically tissue in a region of the frontal cortex called the dorsolateral prefrontal cortex, contained between 15- and 16-fold higher frequency of mtDNA insertions compared to blood cells.

When comparing tissue in other regions of the brain, mtDNA insertions in the dorsolateral prefrontal cortex were between five- and six-fold higher than mtDNA insertions in the cerebellum, and between two- and three-fold higher than mtDNA insertions in the posterior cingulate cortex, other parts of the brain. An increased number of dorsolateral prefrontal cortex mtDNA insertions was linked with shorter lifespan in those without cognitive decline, with two additional mtDNA insertions observed per decade of life lost. The association was weaker for those with mild cognitive impairment and was not present in those with Alzheimer's disease.

Secondly, using cultured human fibroblast cells from three healthy donors, the team conducted a separate analysis with a fibroblast model that mimicked molecular ageing. The fibroblasts accumulated a novel mtDNA insertion every 12.6 days. In a sample of fibroblasts with a deficiency in the SURF1 gene that causes mtDNA instability and stress, mtDNA insertions accumulated between four and five times faster than the fibroblasts from healthy donors.

Nuclear mtDNA insertions are also referred to as nuclear-mitochondrial segments (NUMTs). Once integrated, NUMTs act like other types of genetic variant and are inherited by future generations.

'Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out' said co-author Dr Weichen Zhou, assistant professor in computational medicine and bioinformatics at the University of Michigan Medical School. 'But if a piece of mtDNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan.'

'Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place,' he added.