Mitochondria May Mechanically Regulate Nuclear Function

Newswise — In a paper being presented in two American Physiological Society sessions at Experimental Biology 2006, a joint Estonian-French team demonstrated "for the first time that mitochondria are able to induce nuclear deformation, suggesting that mitochondria may mechanically regulate nuclear function."

The team, which has been collaborating for over 10 years, reported that it recently "found a very interesting and unexpected phenomenon: various substances which increase mitochondrial size, also increased contractile force of cardiac fibers," or myofibrils. This effect isn't related to the mitochondrial energy production, they noted, and so a hypothesis was developed that "there might be in cardiac cells some form of mechanical signaling between organelles."

Vladimir Veksler, a former Soviet scientist who maintained his contacts with Estonian researchers after moving to Paris, said their latest research "shows that substances increasing the mitochondria can also compress the nuclear organelles, ensuring storage and treatment of genetic information."

Taken together, the results indicate that "the existence of such mechanical signaling between mitochondria and myofibrils opens a new possibility to search for drugs capable of increasing cardiac contractility," Veksler said.

*Presentations: The paper, "Direct mechanical communication between mitochondria and nucleus in cardiac cells," was chosen to be part of the "Physiological Genomics of Skeletal Muscle Adaptation in Health and Disease" Featured Topic session 199, sponsored by the APS Muscle Biology Group. Sunday April 2 at 10:30 a.m. in the Convention Center, Room 130, Moscone North. The paper will be presented at 11:15 a.m.

The research also will be presented 12:30-3 p.m. Monday April 3, APS Physiology Signaling in muscle session 486.6/board #C732. Research was performed by Allen Kaasik, Department of Pharmacology, University of Tartu, Estonia, who collaborates with Renée Ventura-Clapier and Vladimir Veksler of INSERM, University of Paris-Sud, France.

Health

Veksler said the team has been interested for many years in mechanisms of interaction between mitochondria and other organelles. They use "skinned cardiac fibers" whose outer membranes have been chemically removed which allows them to control the intracellular medium. They believed that in the tightly packed myocyte, that "mitochondria could push and compress nearby structures like myofibrils and modulate their functional properties."

This additional evidence of intracellular mechanical signaling "may have important physiological significance," Veksler said. He noted that a "number of studies indicate a sensitivity of nuclei to external mechanical forces and suggest that nuclear deformation could influence gene expression processes. Thus, we hypothesize that drugs or intracellular conditions inducing mitochrondrial swelling could by mechanical means influence gene expression.

"More studies are needed to explore this very intriguing and promising field of knowledge," he concluded.

In the experiment, the researchers found that in an artificial medium mimicking the cytosol, 10 micro-molar of valinomycin (a potassium ionophore that induces mitochondrial matrix swelling) decreased nuclear volume by a significant 12% ± 2%. And 150 micro-molar of diazoxide (a mitochondrial ATP-sensitive potassium channel opener) reduced nuclear volume a similar amount. "However, 150 micro-molar of 5-hydrooxydecanoate (thought to be a specific inhibitor of these channels), completely blocked the effect," according to the report, leading to the conclusion that: "mitochondria are able to induce nuclear deformation, suggesting that mitochondria may mechanically regulate nuclear function."

Next steps

Veksler said one idea that needs to be checked out is: If this mechanical communication changes nuclear geometry, does it also impact nuclear function, namely transcription?

Indeed, he said one reason for presenting their findings at Experimental Biology is to find collaborators interested in studying the relevant transcriptional processes.

Funding: Research was supported by Egide, a French government short-term travel program and by INSERM, the French government health institute.

A searchable online program for EB is at http://www.faseb.org/meetings/eb2006/call/default.htm

The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,500 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.

APS provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In May 2004, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).

Experimental Biology is an annual scientific meeting convened by the Federation of American Societies of Experimental Biology, including the American Physiological Society (APS) and other biomedical societies. The meeting features "nominated" lectures, symposia, research presentations, awards, a job placement center, and an exhibit of scientific equipment, supplies, and publications. This year's participating Societies are APS, American Association of Anatomists, American Society for Biochemistry and Molecular Biology, American Society for Investigative Pathology, American Society for Nutritional Sciences, and the American Society for Pharmacology and Experimental Therapeutics.