Disease-aggravating mutation found in a mouse model of neonatal mitochondrial disease

January 29, 2020

The new mitochondrial DNA (mtDNA) variant drastically speeds up the disease progression in a mouse model of GRACILE syndrome. This discovery provides a new tool for studies of mitochondrial diseases.

GRACILE syndrome, a member of the Finnish disease heritage, is a severe neonatal metabolic disease caused by a point mutation in the nuclear BCS1L gene.

About 10 years ago, Professor Vineta Fellman's group at Lund University generated GRACILE patient mutation-carrying mice to investigate disease mechanisms and develop therapies. Later on, the researchers exported the mice to Helsinki and maintained the mutants in a slightly different genetic background.

Astonishingly, the mutant mice lived five times longer in Helsinki than in the original strain in Lund. By whole genome sequencing, a novel point mutation was discovered in the mitochondrial DNA (mtDNA) of the short-lived Lund strain.

The work, carried out at the Folkhälsan Research Center and the University of Helsinki, revealed that, due to an extremely unlikely coincidence, a random mutation in the mt-Cyb gene had appeared, affecting exactly the same part of mitochondria as the GRACILE mutation and worsening the disease of the mice.

According to computer simulations and spectroscopic measurements performed by collaborators in Finland and Poland, the amino acid change identified in the mice slows down the movement of a part of Rieske protein needed in electron transfer during cellular respiration. The researchers say that this is the first time such an interaction between the nuclear and mitochondrial genomes has been delineated down to almost atomic level.

Docent Jukka Kallijärvi tells that the discovery is an extreme example of an unexpectedly large effect of the genetic background on the course of an inherited disease.

"Modifying the nuclear genome has been commonplace in experimental animal models for a long time, but we are yet to develop a technique with which to transfer mutations in a targeted manner to as many as thousands of copies of the mitochondrial genome in every cell. Our unique mouse model, which carries the spontaneous mtDNA variant, could prove a valuable tool in studies of both mitochondrial diseases and the function of mitochondria in general," Kallijärvi notes.

The otherwise wild-type mice carrying the newly discovered variant appear healthy, but their metabolism is not entirely normal. An equivalent mutation is found naturally in the three-toed sloth species of South America, an animal with an extremely slow metabolism and an energy-poor diet.

"It is interesting to speculate that the mtDNA variant may be beneficial in certain conditions, which is why it occurs in nature. In further studies, we are interested in the effect of this variant, which subtly affects mitochondrial functions, on metabolism and ageing in mice", Kallijärvi says.
-end-
The study, published in the journal Nature Communications, was carried out by the GRACILE research group, headed by Docent Jukka Kallijärvi and Professor Emerita Vineta Fellman at the Folkhälsan Research Center.

University of Helsinki

Related Nuclear Articles from Brightsurf:

Explosive nuclear astrophysics
An international team has made a key discovery related to 'presolar grains' found in some meteorites.

Nuclear medicine and COVID-19: New content from The Journal of Nuclear Medicine
In one of five new COVID-19-related articles and commentaries published in the June issue of The Journal of Nuclear Medicine, Johnese Spisso discusses how the UCLA Hospital System has dealt with the pandemic.

Going nuclear on the moon and Mars
It might sound like science fiction, but scientists are preparing to build colonies on the moon and, eventually, Mars.

Unused stockpiles of nuclear waste could be more useful than we might think
Chemists have found a new use for the waste product of nuclear power -- transforming an unused stockpile into a versatile compound which could be used to create valuable commodity chemicals as well as new energy sources.

Six degrees of nuclear separation
For the first time, Argonne scientists have printed 3D parts that pave the way to recycling up to 97 percent of the waste produced by nuclear reactors.

How to dismantle a nuclear bomb
MIT team successfully tests a new method for verification of weapons reduction.

Material for nuclear reactors to become harder
Scientists from NUST MISIS developed a unique composite material that can be used in harsh temperature conditions, such as those in nuclear reactors.

Nuclear physics -- probing a nuclear clock transition
Physicists have measured the energy associated with the decay of a metastable state of the thorium-229 nucleus.

Milestones on the way to the nuclear clock
For decades, people have been searching for suitable atomic nuclei for building an ultra-precise nuclear clock.

Nuclear winter would threaten nearly everyone on Earth
If the United States and Russia waged an all-out nuclear war, much of the land in the Northern Hemisphere would be below freezing in the summertime, with the growing season slashed by nearly 90 percent in some areas, according to a Rutgers-led study.

Read More: Nuclear News and Nuclear Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.