What is it about?

GRACILE syndrome is a severe metabolic disease of newborns and found mainly in Finland. The respiratory chain, located in the inner membrane of mitochondria, is the hub of cellular energy metabolism, and complex III, an essential part of the respiratory chain, is dysfunctional in GRACILE syndrome. About 10 years ago, prof. Fellman’s group, then at Lund University, developed a mouse model in which the patient mutations in BCS1L was introduced into the mouse genome. The mutant mice develop a very similar multiorgan disease as the patients and lived only about six weeks. A few years thereafter, we imported these mice from Lund to Helsinki. To our great surprise, the mutant mice liver much longer, even up to six months. We pondered that a preexisting or novel genetic change in the Lund strain might explain the short survival of the mice and decided the sequence its whole genome. The sequencing revealed a previously unknown single nucleotide variant in the mitochondrial genome (mtDNA). Amazingly, the variant was located in the gene encoding the cytochrome b subunit of complex III, exactly the same part of respiratory chain affected in the patient and mutant mice. It seemed that in an astronomically unlikely coincidence a spontaneous mtDNA variant potentially directly affecting CIII function emerged in the colony that was used to maintain our mutant mice. Because mitochondria are inherited maternally, we re-crossed the females and males from the two colonies both ways. The result was clear: those mutant mice that carried variant mitochondrial from Lund mothers lived only 5-6 weeks, whereas mutant mice with normal mitochondria from Helsinki mothers lived about 5 months. Using delicate biochemical measurements we then showed that the mtDNA variant worsens CIII deficiency in several tissues in the mutant mice. We next wanted to learn more about how the new variant, changing aspartate 254 to asparagine, affects CIII function at molecular level. Our collaborator, professor emeritus Mårten Wikström, suggested that Dr. Vivek Sharma at the Department of Physics in Kumpula would do molecular structural modelling and simulations for us. The simulations suggested that the variant slows down the movement of a part of RISP protein during electron transfer. The last piece to the puzzle came from professor Artur Osyczka’s research group at Jagiellonian University, Poland. The group works on photosynthetic purple bacteria (Rhodobacter), in which the cytochrome b gene can be easily mutagenized. They showed by elegant spectroscopic measurements that, in line with the computational simulations, the mouse variant indeed slightly slows down RISP movement and thus likely inhibits electron transfer.

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Why is it important?

This is theoretically important because, to our knowledge, this is the first time that a genetic interaction between the nuclear and mitochondrial genomes has been functionally described down to near-atomic level. From a pragmatic point of view, genetic modification of the nuclear genome has been commonplace in experimental model organisms like mice for a long time, but there is still no technology to introduce specific mutations into the thousands of copies of mtDNA in each cell. Therefore, our mouse strain carrying the spontaneous mtDNA variant is a unique novel research tool. Thirdly, our serendipitous discovery highlights the effect of genetic background in the manifestations of mitochondrial disease, and as for mouse models, encourages replication of phenotyping in a different background to strengthen the biological significance of the findings.


Interestingly, according to DNA sequence databases the mtDNA variant we identified in mice is naturally present in the three-toed sloth species of South America. These animals feed on an energy-poor diet of tree leaves and have very slow metabolism. One is tempted to speculate that a genetic variant slightly impeding CIII function could even be beneficial under such circumstances. This is one of our main interests in further studies of the variant-carrying mice.

Dr Jukka Kallijärvi
Folkhälsan Research Center

Read the Original

This page is a summary of: A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice, Nature Communications, January 2020, Springer Science + Business Media,
DOI: 10.1038/s41467-019-14201-2.
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