Breakthrough In Transferring Mitochondrial Genes To The Nucleus

Posted on 10 September 2016

In an exciting paper, researchers from the SENS Foundation have demonstrated that two mitochondrial genes can be successfully transferred into nucleus; an important first step in preventing age-related mitochondrial dysfunction

Mitochondria are especially vulnerable to damage and mutation. They not only produce the vast majority of free radicals within a cell at any one time, but their genome is also poorly protected and within close proximity to all of these reactive molecules. Over time the mitochondrial genome is inevitably subject to mutation, and while the cell usually catches this and disposes of any mutated varieties, with age very specific mutations can slip under the cell’s radar and cause all sorts of problems. 

The nucleus does build up mutations over the course of a lifetime, but in contrast to the miniscule mitochondrial genome which contains only 37 genes, your nuclear genome is a relatively safe harbour. It’s not clear how much nuclear mutations really matter when it comes to human aging, but we do know the mutation rate is massively reduced, and the chances of a mere 13 genes being mutated within the entire genome is more unlikely still. This theory led to an intriguing proposal by Aubrey de Grey and the SENS Foundation; that we should transfer all remaining mitochondrial genes into the nucleus and mitigate age-related dysfunction. 

The human mitochondrial genome

The human mitochondrial genome

Incomplete evolution

Evolution has already moved the bulk of mitochondrial genes into the nucleus and done much of the job for us, but a remnant remains and reminds us that mitochondria were likely once a separate organism, until they merged with a eukaryotic cell in a historic moment.  The nucleus therefore already codes for a large number of mitochondrial components, which are then shuttled to these cellular batteries. The proteins encoded by the remaining genes are apparently tricky to transfer through the fussy mitochondrial membrane – requiring a unique labelling component in order to gain entry. In evolutionary terms, this meant they were difficult to transfer and evolution either hasn’t had the time to implement this change or it wasn’t worth the effort to do so. 

A safe zone

Dysfunctional mitochondria have wide ranging and severe consequences connected to a plethora of age-related diseases and generalised aging processes. They’re a key hallmark of the aging process, and are therefore a juicy target in the pursuit of longevity. One of the most innovative ideas of how to deal with this issue is to simply transfer all of the remaining genes into the nucleus, where they would be far more secure. This is exactly what the iconic SENS Foundation is aiming to do with collaborating scientists. 

The electron transport chain within mitochondria

The electron transport chain within mitochondria

A milestone

In an exciting project, scientists were able to rescue a cell line with a mutation that led to zero complex V production and minimal protein levels. They successfully demonstrated that two genes (ATP8 and ATP6) could be expressed in the nucleus and their protein product was able to integrate into the mitochondrial machinery and rescue energy production. This is a landmark moment in both aging research and for mitochondrial diseases. Inherited mitochondrial defects are frequently devastating, fatal conditions with limited available treatment. Providing additional copies of corrected genes to be placed inside the nucleus has huge therapeutic prospects when it comes to these conditions. While we’re a long way off from transferring all 37 genes (or transferring any at all into the nucleus of every cell in the body), we have to start somewhere and this is a phenomenal achievement. 

Read more at Oxford Journals

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