A comprehensive new analysis from the Max Planck Institute for Biology of Ageing, Germany, and Karolinska Institutet, Sweden, provides insight on how the dysfunction of an important biological process causes disease.
The study in mice, published today in eLife, could open new avenues for research into the deficiency of a system called oxidative phosphorylation (OXPHOS) and provide a valuable reference for future diagnosis and treatment.
OXPHOS is a metabolic process whereby cells release energy from the food we eat by using enzymes to harvest it and convert it into a molecule called adenosine triphosphate – the cell’s ‘energy currency’. This currency is produced by structures called mitochondria. Given this central role, mitochondrial dysfunction is a major contributor to human disease and is also involved heavily in the ageing process.
“The molecular consequences of OXPHOS dysfunction are hard to predict,” says lead author Inge Kühl, formerly a postdoctoral researcher at the Max Planck Institute for Biology of Ageing and now at the National Center for Scientific Research (CNRS) in France. “Recent advances in high-throughput technologies in proteomics, metabolomics and sequencing have increased our knowledge of mitochondrial function. However, the events that accompany OXPHOS dysfunction and contribute to mitochondrial diseases are still poorly understood and the treatment options are limited.”
To help fill this knowledge gap, Larsson and his team analysed five strains of mice that were deficient in essential factors needed for mitochondrial DNA gene expression in the heart, subsequently leading to OXPHOS dysfunction.
Using an integrated sequencing and mass spectrometry approach, the scientists compared both the animals’ mitochondrial proteomes – the entire sets of proteins present in their mitochondria – and cellular transcriptomes – all messenger ribonucleic acid (RNA) molecules expressed from nuclear and mitochondrial genes.
The team then listed the various gene expression changes at the RNA and protein levels in the mice, caused by OXPHOS dysfunction. Surprisingly, they identified a novel response to OXPHOS dysfunction across all the animals, whereby enzymes in the mitochondria that are necessary for the production of ubiquinone (Q) were severely reduced.
“Q is an essential electron shuttle in the mitochondrial respiratory chain,” explains senior author Nils-Göran Larsson, Director of both the Max Planck Institute for Biology of Ageing and the Institute’s Mitochondrial Biology department. “Its deficiency, caused by impaired mitochondrial DNA gene expression in the mouse heart, could potentially be a target for future therapeutics.”
“Altogether, our comparative analyses provide a high-quality resource of altered gene expression patterns under OXPHOS deficiency,” adds co-author Maria Miranda, PhD student at the Max Planck Institute for Biology of Ageing. “Our datasets can be mined for future studies in this area and will hopefully contribute towards improved patient diagnosis and research on future treatment strategies.”
Media contacts
Emily Packer
eLife
e.packer@elifesciences.org
+441223855373
About
About the Max Planck Institute for Biology of Ageing
The Max Planck Institute for Biology of Ageing investigates the natural ageing process with the long-term goal to pave the way towards increasing health during ageing in humans. It is an institute within the Max Planck Society, which is one of Germany’s most successful research organisations. Since its foundation in 2008, the institute has become an integral part of a life science cluster in Cologne that pursues ageing research.
About eLife
eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open-source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust. Learn more at https://elifesciences.org.
