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Atomic level information on a severe neonatal mitochondrial disease

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. 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.

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 spectroscopic measurements and Vivek Sharma's research group's computer simulations, 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. CSC's supercomputer was used in these simulations.

The article was published in highly esteemed Nature Communications

Janne Purhonen, Vladislav Grigorjev, Robert Ekiert, Noora Aho, Jayasimman Rajendran, Rafał Pietras, Katarina Truvé, Mårten Wikström, Vivek Sharma, Artur Osyczka, Vineta Fellman, Jukka Kallijärvi: A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nature Communications 2020 Jan 16;11(1):322. https://doi.org/10.1038/s41467-019-14201-2

Source: University of Helsinki Press Release