Mitochondrial diseases: here’s the metabolism-helper gene

A case of malfunctioning mitochondria? Considerable help may be provided by OPA1 – a gene which, when altered, is known to be responsible for a hereditary disease of the eye, dominant optic atrophy.

Luca Scorrano

This development is described in the major journal, Cell* by the research group at the Dulbecco Telethon Institute, headed by Luca Scorrano, Professor of Biochemistry at the University of Padua, in collaboration with the group headed by Professor Enriquez (CNIC, Madrid, Spain).

In clarifying the function of this gene, the researchers in Padua have highlighted its capacity as a potential "helper" in cellular metabolism, which may be exploited for the purposes of therapy within the ambit of many mitochondrial diseases.

"Within cells, the role of mitochondria is fundamental, because they are responsible for producing the energy required for cellular activities. They are vital also because they can be decisive in ensuring the cell’s survival under conditions of stress", explains Scorrano, one of the world's top researchers engaged in the study of these important organelles.

"Thanks to Telethon, for more than a decade we have been studying these hereditary diseases like dominant optic atrophy, characterised by a malfunction of mitochondria. Understanding the mechanisms causing these diseases is essential in order to develop a targeted therapy, but also to clarify how our cells work, thus impacting even more on biomedical research".

The OPA1 gene, which is mutated in dominant optic atrophy patients , normally contains information for a protein which Scorrano's group has gradually characterised over the years and which actually regulates the shape of these organelles. Its dysfunction in patients results in the progressive death of a type of neuron, the ganglion cells of the retina, responsible for transmission of the visual signals from the eye to the area of the brain responsible for image elaboration. This loss of these neurons, and therefore of sight, is slow, but also progressive: the disease generally becomes manifest at a pre-school age, with various degrees of seriousness, also within a single family.

"With this work," Scorrano tells us, "we demonstrated that OPA1 has the task to regulate the respiration efficiency , influencing how the components of the so-called respiratory chain (i.e., the complex of proteins which transforms nutrients into an energy token that is exploited for energy consuming cellular activities) join together at the level of the inner membrane of mitochondria. This membrane is like a soap bubble, whose shape and curvature is not random, but regulated by OPA1. By increasing OPA1 activity, it is possible to enhance the respiratory chain efficiency and to increasecellular growth.""Our work advances very much our knowledge on the relationship between function and shape in cellular structures. In particular, mitochondria cristae structure is very peculiar and surprisingly shows a huge variability among different tissues and when physicalactivity, diet change, or in disease. However, the link between shape and mitochondrial activity remained unclear for a long time. This work demonstrate that changing cristae structure directly changes mitochondrial respiratory capacity through the modulation of how proteins congregate in the membrane," says José Antonio Enriquez, Program coordinator from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) of Spain and coauthor of the study.

Scorrano concludes: "We may consider the prospect of exploiting this possibility to intervene in certain mitochondrial diseases, improving metabolism irrespectively of the genetic defect responsible for them. For rare and heterogeneous diseases like those ones, we a broad therapeutic approaches applicable to multiple diseases might be a viable option. We are working on this, but it’s still too early to speak of a possible treatment".

*S. Cogliati, C. Frezza, M.E. Soriano, T. Varanita, R. Quintana Cabrera, M. Corrado, S. Cipolat, V. Costa, A. Casarin, L.C. Gomes, E. Perales-Clemente, L. Salviati, P. Fernandez-Silva, J.A. Enriquez, L. Scorrano, "Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency". Cell, 2013.

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