What is it about?
GRACILE syndrome, described by neonatologist Vineta Fellman in Finland in 1998, is the most severe mitochondrial respiratory chain CIII deficiency disease. The causative mutation in BCS1L was found in 2002. To further investigate this devastating, incurable disease of newborn infants, prof. Fellman’s group generated mice carrying the GRACILE syndrome patient mutation about 10 years ago. These mice develop a very similar disease as the patients. Alternative oxidase (AOX) is a mitochondrial enzyme that can function as a shunt, allowing part of the mitochondrial respiratory chain to function even when, for example, CIII is blocked like in GRACILE syndrome. AOX is not normally present in mammalian mitochondria, but the enzyme from a sea squirt species (Ciona intestinalis) has been transferred into and works the same way in mice. In this study, we set out to test whether AOX expression is beneficial in the Bcs1l mutant mice by restoring electron flow upstream of cIII. We made the staggering finding that the sick Bcs1l mutant mice expressing AOX never developed lethal cardiomyopathy and lived three times longer than the plain mutant mice. AOX also improved their kidney disease and brain pathology. We show that just restoring electron flow, without affecting the mutated enzyme itself, can be sufficient to completely prevent severe symptoms, such as the cardiomyopathy, in a mouse model of cIII deficiency.
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Why is it important?
Mitochondrial disorders are genetic diseases of energy metabolism that can affect any one or several organs of the body. Early diagnosis is often possible using modern molecular genetics, but treatment options remain scarce.
Perspectives
Our study is the first proof-of-concept that cIII-cIV bypass can have a dramatic beneficial effect in a genetic mouse model of human mitochondrial disorder. As AOX can theoretically alleviate cIII or cIV blockade due to a wide variety of mutations, it is worth further preclinical investigations, such as using viral delivery to the affected tissues in mouse models.
Dr Jukka Kallijärvi
Folkhälsan Research Center
Our mouse model mimics many phenotypes of mitochondrial cIII disorders. Furthermore, the study proved that AOX bypassed electron transfer from cIII blockade and alleviated multiple-organ manifestations by ameliorating the mitochondrial oxide stress. Therefore, with proper AOX delivery and activation method, AOX-transgene can be a potential gene therapy for mitochondrial cIII disorders. Personally, It was a great pleasure to work with all the co-authors. Their immense knowledge and expertise helped to build the study more detailed. I hope that readers find this article interesting.
Jayasimman Rajendran
Helsingin Yliopisto
Read the Original
This page is a summary of: Alternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy, EMBO Molecular Medicine, December 2018, EMBO,
DOI: 10.15252/emmm.201809456.
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