Mitochondrial Breakdown Promotes Death of Hypoxic Cells

Combining and breaking down of mitochondria are linked to how cells respond to changes in their environment. A recent study has identified a molecular pathway critical to this process.

Investigators at the Sanford-Burnham Medical Research Institute (La Jolla, CA; USA) exposed cardiomyocyte cultures to low oxygen concentrations (hypoxia) that were similar to conditions found in the heart muscle following a heart attack.

They reported in the November 18, 2011, issue of the journal Molecular Cell that hypoxia-induced fission of mitochondrial membranes, dependent on availability of the mitochondrial scaffolding protein AKAP121.

Mitochondrial fission, which caused the heart cells to die, was stimulated when the ubiquitin ligase Siah2 reduced availability of AKAP121. Siah2 gene is a member of the seven in absentia homolog (Siah) family of proteins. The enzyme is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia.

Suppressing the activity of Siah2 in hypoxic cells or in mice increased AKAP121 levels, which reduced mitochondrial fission and resulted in death of fewer heart cells. Under hypoxic conditions, Siah2-deficient mice fared better than their normal counterparts did.

“Our work reveals key aspects to controlling mitochondrial dynamics in response to low oxygen tension,” said senior author Dr. Ze'ev A. Ronai, associate director the cancer center at the Sanford-Burnham Medical Research Institute. “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 have experienced a heart attack.”

Research efforts are now focused on the pursuit of chemical compounds to inhibit Siah2 that can be further developed into new therapies to prevent or reverse cardiac damage.

Related Links:
Sanford-Burnham Medical Research Institute