Having three genetic parents makes mice age better

Different variants of mitochondrial DNA alter tumor incidence, DNA damage.

Diana Gitig – Jul 11, 2016 12:45 pm | 43

The cell's powerhouse, which looks a bit like a heavily compartmentalized kidney bean. Credit: NIH

Mitochondria are “the powerhouse of the cell” (or so every fifth grade biology book will tell you) because they use aerobic respiration to generate ATP, the molecular form of energy that enables cellular processes to occur.

Structurally, mitochondria are unusual in that they have their own DNA. This is because they were initially bacterial cells that long ago got subsumed by other cells, relinquishing their independence for a safe harbor and giving their hosts an energy boost in exchange.

Mitochondrial DNA (mtDNA) encodes many of the proteins required for aerobic respiration—but not all of them. Respiration still requires many proteins that are encoded by the cell’s regular chromosomes. A new study suggests that the right match between mtDNA genes and chromosomal genes could be key to an organism’s health and that some mtDNA may actually be beneficial.

This could become an issue because mutations in mtDNA have been associated with a number of diseases, and mitochondrial replacement has been posited as a means to avoid mitochondrial disease. Such a procedure would create people containing DNA from three sources: a mother (nuclear DNA), a father (nuclear DNA), and a third person (mitochondrial DNA).

Being somewhat unprecedented, this idea has caused some debate, primarily on ethical grounds. The new study suggests that it might be worth evaluating the idea on additional medical grounds.

The authors of the paper studied the effects of the mitochondrial-nuclear match by comparing mice with identical nuclear DNA but differing mtDNA. This was possible because scientists have bred several strains of genetically identical mice, letting them match the chromosomal DNA of one strain with the mitochondria of another. These mitochondrial genomes differed by thirty-four bases, a level of variability that the authors say is similar to that between African and Eurasian humans.

The research team subjected the mice to a whole battery of tests, examining their RNA and proteins they made, plus the chemicals associated with their metabolism, and then assaying their physiological and biochemical functionality. Here’s where you might be expecting to see some strange problems emerge, but weirdly, most of the mtDNA effects seem positive.

The mice with the foreign mtDNA had a longer median lifespan (but not a longer maximum lifespan) and fewer tumors than the mice whose mtDNA matched their mothers’ mtDNA. These mice were better able to tolerate the DNA-damaging reactive oxygen species that are a normal byproduct of metabolism, and they were better able to regulate their insulin and cholesterol levels. The authors conclude that the new mtDNA “promotes healthier aging” against this chromosomal DNA background.

Of course, that’s just one chromosomal DNA background among those in dozens of different mouse strains. And the paper doesn’t get into the complex genetic background present in the human population. The main takeaway here is that mtDNA matters. Different variants can affect cellular function and metabolism, which can in turn impact an organism’s health over the course of its life.

Now that we know, it’s probably worth taking a look into whether this might happen with human mitochondrial transplants, too.

Nature, 2016. DOI: 10.1038/nature18618 (About DOIs).