The Brain Accumulates Mitochondrial DNA Inserts into the Nuclear Genome
A cell is a bag of molecules moving at incredible velocities, all running into one another countless times every second. Almost anything is possible in this high speed environment, albeit that some outcomes are highly unlikely in any given second. There are a lot of seconds and even more cells, however. Thus it is possible for fragments of mitochondrial DNA to somehow find their way into the cell nucleus and then somehow be incorporated into nuclear DNA. Evolution has made full use of this rare happenstance, as most of the original mitochondrial DNA, the genome of symbiotic bacteria that lived within the first eukaryotic cells, has shifted over evolutionary time: firstly forming viable genes in the nuclear genome, and then secondly the mitochondrial sequences deleted through forms of DNA damage.
Researchers here measure the occurrence of mitochondrial DNA inserts into the nuclear genome in human brain tissue. Interestingly, they find a correlation with mortality. This could be indicative that this sort of mutational damage is producing materially detrimental effects on tissue function; the arguments to be made here are similar to those for the role of somatic mosaicism in degenerative aging. Equally this may be a case in which greater age-related mitochondrial dysfunction produces a greater chance of mitochondrial DNA making its way into the nucleus. It is already known that aging is associated with inflammation driven by innate immune recognition of mislocalized mitochondrial DNA fragments in the cytosol. It seems sensible to hypothesize that more of this means more rare nuclear localization events.
The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer.
Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.
Combined, our data documents spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.