Public Release:  Mitochondria restructuring protein provides new therapeutic target for heart disease

Reducing a protein called Siah2 in mice improves mitochondrial response to low oxygen, a condition cells experience when blood flow is restricted during a heart attack

Sanford-Burnham Medical Research Institute

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IMAGE: Hyungsoo Kim, Ph.D. is a postdoctoral researcher and first author of the study. view more

Credit: Sanford-Burnham Medical Research Institute

LA JOLLA, Calif., November 17, 2011 - Mitochondria are often called cellular "powerhouses" because they convert nutrients into energy. But these tiny structures also help determine cellular lifespan. Scientists at Sanford-Burnham Medical Research Institute (Sanford-Burnham) are now discovering how mitochondria alternate between duplicating and fragmenting and how these events help cells adapt to diverse physiological conditions. In a paper published November 18 in Molecular Cell, a team led by Ze'ev Ronai, Ph.D. discovered that the protein Siah2 regulates mitochondrial fragmentation under low oxygen conditions. The significance of these findings is demonstrated by the heart's response to oxygen shortage and ischemia, the tissue damage caused by lack of oxygen, when the researchers inhibited Siah2. In cells and mice lacking the protein, heart cell death was prevented. As a result, tissue damage was reduced in a mouse model that mimics a heart attack.

"Our work reveals key aspects to controlling mitochondrial dynamics in response to low oxygen tension," said Dr. Ronai, associate director of Sanford-Burnham's National Cancer Institute-designated Cancer Center and senior author of the study. "By manipulating mitochondrial dynamics, we can help cells adapt to ischemic conditions in a way that might translate into new treatment options for patients who've experienced a heart attack."

Siah2 is an ubiquitin ligase, meaning its job is to tag other proteins with a molecule called ubiquitin, marking them for destruction. This way, Siah2 controls which proteins are active and which are destroyed in response to environmental signals. In this study, Dr. Ronai and his team found that one such signal--low oxygen, a condition also known as hypoxia--engages Siah2 in the control mitochondrial fragmentation process by allowing two key regulators (the proteins Drp1 and Fis1) to get together. Their union, however, increases mitochondrial fragmentation, cell death, and cardiac tissue damage under ischemic conditions.

"In a hypoxic environment, increased Siah2 activity takes a protein called AKAP121 out of the picture, freeing up the Drp1-Fis1 complex to shift the balance in favor of mitochondrial fragmentation," explained Hyungsoo Kim, Ph.D., postdoctoral researcher in Dr. Ronai's lab and first author of the study. "This change in mitochondrial structure is accompanied by changes in function that lead to heart cell death under stress, giving us a new understanding of how cells respond to hypoxia and a new target to prevent the damage often seen in ischemic injury."

When the researchers mimicked heart attack in cells and mice lacking Siah2, AKAP121 levels increased (keeping a damper on the Drp1-Fis1 relationship), mitochondrial fission was reduced, and fewer heart cells died. Under hypoxic conditions, Siah2-deficient mice fared better than their normal counterparts.

Dr. Ronai credits a collaborative approach for the success in demonstrating both Siah2's role in mitochondrial fragmentation and its physiological importance. Teaming up with the laboratory of Sanford-Burnham's Mark Mercola, Ph.D. helped unravel Siah2's role in cardiovascular function. In addition, contributions by the laboratory of Andrew Dillin, Ph.D. at the Salk Institute for Biological Studies revealed the roles of Siah2 and mitochondrial fragmentation in the lifespan of C. elegans, a worm model.

Dr. Ronai and his team are now searching for chemical compounds that inhibit Siah2, which they hope can be further developed into new therapies for cardiac damage and cancer.

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This study was funded by the National Cancer Institute and the National Heart, Lung, and Blood Institute, at the National Institutes of Health, as well as the California Institute for Regenerative Medicine. Co-authors include Hyungsoo Kim, Sanford-Burnham; Maria C. Scimia, Sanford-Burnham; Deepti Wilkinson, Salk Institute for Biological Studies; Ramon D. Trelles, Sanford-Burnham; Malcolm R. Wood, The Scripps Research Institute; David Bowtell, Peter McCallum Cancer Centre and the University of Melbourne; Andrew Dillin, Salk Institute for Biological Studies; Mark Mercola, Sanford-Burnham; and Ze'ev A. Ronai, Sanford-Burnham.

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About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 - 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.

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