Experimental gene therapy tripled the lifespan of mice suffering from a severe mitochondrial disease.

GRACILE syndrome is a currently untreatable mitochondrial disease belonging to the Finnish disease heritage. The mouse model employed in the study was based on the cross-breeding of two mouse strains: one carrying the human GRACILE syndrome patient mutation, developed by the Fellman, Kallijärvi group, and one expressing alternative oxidase (AOX), provided by Professor Howard Jacobs. Mammals do not normally have the AOX gene, but since mitochondria are so similar in all organisms, it maintains its function even after being transferred from a sea squirt (Ciona intestinalis) to mice. AOX is a mitochondrial enzyme that has the ability to improve electron flow in the respiratory chain when a part of the chain, complex III in this case, becomes dysfunctional due to a disease-causing mutation.

In the recently published study, the research group found out that a fatal cardiac disease did not develop at all in mice carrying the AOX transgene. Subsequently, the mice lived three times longer than the control group. Furthermore, AOX improved their kidney disease and brain cell changes. AOX transgene extended the lifespan of the mice dramatically by enhancing respiration in the tissues that require the most energy, such as the heart. These remarkable findings encourage further investigations of respiratory chain bypass in this and other mouse models of mitochondrial disease.


Original Article

Rajendran J, Purhonen J, Tegelberg S, Smolander OP, Mörgelin M, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Auvinen P, Mervaala E, Jacobs HT, Szibor M, Fellman V, Kallijärvi J.  Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy. EMBO Mol Med 11(1) pii: e9456, 2019 (doi: 10.15252/emmm.201809456)