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EXD2 is key to mitochondria

Research reveals EXD2 as the key protein giving mitochondria their ability to generate energy...


Researchers from the Genomic Instability and Cancer Laboratory, Institute for Research in Biomedicine (IRB), Barcelona, Spain, have identified the protein EXD2 as responsible for the majority of a cell's energy from mitochondria organelles.
"We have provided extensive evidence that EXD2 is a mitochondrial protein and that its main function is to facilitate the production of proteins in mitochondria."

Travis H. Stracker PhD, Principle Investigator, Genomic Instability and Cancer Laboratory, Institute for Research in Biomedicine (IRB), Barcelona, Spain.

The work, published in Nature Cell Biology, challenges the interpretation of previous studies which suggested that EXD2 performs a DNA repair function in the nucleus. "However, at this point we can't rule out other possible functions," declares Stracker.

The study is the result of a collaborative and multidisciplinary approach, using state of the art proteomics on the fruit fly, Drosophila melanogaster, to pinpoint the function of EXD2. Scientists identified the mitochondrial ribosome, the cellular machine required for protein production in mitochondria, as a major interactor of EXD2.
"EXD2 targets messenger RNA to keep the mitochondrial ribosome (or mitoribosome) "clean" until it is mature and ready to generate proteins. In the absence of EXD2, cells are severely defective for mitochondrial protein production."

Joana Silva PhD, first author, Institute for Research in Biomedicine (IRB); and The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

EXD2's role in the mitoribosome is critical for suppressing generation of Reactive Oxygen Species (ROS) which can arise from mitochondrial defects, therefore facilitates normal development in Drosophila. Flies lacking EXD2 showed increased ROS levels, delayed development and reduced fertility.

"Research results highlight the complexity of mitochondrial protein production and demonstrate that many levels of regulation remain to be explained," explains Stracker. These studies may have implications for understanding and treating metabolic disorders such as diabetes and cancer. With regards to cancer, in recent years the importance of mitochondrial energy generation in tumors has been revisited and inhibition of protein production is proposed as a therapeutic target by many groups.

As EXD2 acts as an enzyme requiring mitochondrial translation, it is possible that targeting EXD2 could have antitumor affects, a possibility that will be tested in future experiments.

Abstract
Mitochondria are subcellular organelles that are critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, and on their coordinated translation, import and respiratory complex assembly. Here, we characterize EXD2 (exonuclease 3?–5? domain-containing 2), a nuclear-encoded gene, and show that it is targeted to the mitochondria and prevents the aberrant association of messenger RNAs with the mitochondrial ribosome. Loss of EXD2 results in defective mitochondrial translation, impaired respiration, reduced ATP production, increased reactive oxygen species and widespread metabolic abnormalities. Depletion of the Drosophila melanogaster EXD2 orthologue (CG6744) causes developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that is reversed with an antioxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and ageing.

Authors: Joana Silva, Suvi Aivio, Philip A. Knobel, Laura J. Bailey, Andreu Casali, Maria Vinaixa, Isabel Garcia-Cao, Étienne Coyaud, Alexis A. Jourdain, Pablo Pérez-Ferreros, Ana M. Rojas, Albert Antolin-Fontes, Sara Samino-Gené, Brian Raught, Acaimo González-Reyes, Lluís Ribas de Pouplana, Aidan J. Doherty, Oscar Yanes & Travis H. Stracker.


This study was supported by the Ministry of Economy, Industry and Competiveness (MINECO), as well as the Finnish Cultural Society and the Fundação para a Ciência e a Tecnologia that funded the theses of the first two authors.

The work was performed in collaboration with several other labs that made important contributions, including Aidan Doherty in the University of Sussex, Brian Raught in the University of Toronto, Oscar Yanes in the Universitat Rovira i Virgili and Andreu Casali and Lluís Ribas de Pouplana in the IRB Barcelona.

Reference article:
Joana Silva, Suvi Aivio, Philip A. Knobel, Laura J. Bailey, Andreu Casali, Maria Vinaixa, Isabel Garcia-Cao, E?tienne Coyaud, Alexis A. Jourdain, Pablo Perez-Ferreros, Ana M. Rojas, Albert Antolin-Fontes, Sara Samino-Gené, Brian Raught, Acaimo Gonza?lez-Reyes, Lluis Ribas de Pouplana, Aidan J. Doherty, Oscar Yanes and Travis H. Stracker

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Jan 18, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Confocal microscopy shows the co-localization of EXD2 (purplish-red,) with the
mitochondrial ribosome (yellow). DNA is stained (greenish blue) to define the nucleus.
Image credit: Travis Stracker, IRB Barcelona


Phospholid by Wikipedia