Bak Protein Sets Stressed Cells On Suicide Path, Researchers Show

In a deadly double whammy, Bak helps  chop the finger-like filament shape of the cell's powerhouse, or mitochondrion,  into vulnerable little spheres. Another protein Bax then pokes countless holes  in those spheres, spilling their pro-death contents into the cell.

"We found out Bak has a distinct function in regulation of the  mitochondrial morphology," says Dr. Zheng Dong, cell biologist at the Medical  College of Georgia and the Veterans Affairs Medical Center in Augusta and  corresponding author on a paper published this week in Proceedings of the National Academy of Sciences. "Bax, on the other  hand, is not involved in morphological regulation but needs to be there to  puncture holes."

"One has to break up, kind of soften, the mitochondria for injury, and the  other one actually punches the holes to kill it," says Craig Brooks, MCG  graduate student and the paper's first author.

Bak and Bax have similar structures and scientists have long suspected they  play major, similar roles in programmed cell death, or apoptosis.  "These two proteins are very important for  mitochondrial injury and subsequent apoptosis," says Dr. Dong.

To stress cells, they blocked oxygen  supplies and used the common chemotherapeutic agent cisplatin, then documented  that filamentous mitochondria became fragmented very early and quickly in  apoptosis.  Ironically they also found  the deadly fragmentation results from Bak's interaction with mitochondria-shaping  proteins called mitofusins, which help mitochondria keep their filamentous  shape in non-stressed cells. Dr. Dong suspects Bak may also play a role in  mitofusin regulation in normal, non-stressful conditions.

In fact, the researchers suspect Bak, Bax and the contents they spill into  the cell all have roles in keeping a cell functioning until a stressor kicks in.

"They probably are both kept in  check normally in the cell by other proteins, and when something happens that  overwhelms the cell, it activates Bak and Bax to start cell death," says Mr.  Brooks.  "Some of the same proteins,  cytochrome c is the big one, are needed for daily mitochondrial function like  making energy, but if they are released from the mitochondria, they activate a  cell killing or apoptotic pathway," says Dr. Dong, referencing the contents  that spill from punctured mitochondria.

Looking at kidney cells and neurons  in a Bak deficient mouse, they also showed that Bak and Bax need each other to  successfully spawn cell suicide. "If you have Bak but not Bax, the mitochondria  still fragment but they don't die; if you have Bax but not Bak, you still have  punctures in the mitochondria but with low efficiency," says Mr. Brooks.

Now they want to know exactly how  Bak interacts with mitofusins, how the interaction is regulated and how it  affects mitochondrial morphology, physiology and pathology. Their long-term  goal for better understanding the cell suicide mechanism is developing drugs to  block it in the case of a stroke, for example, or induce it to kill cancer.

Dr. Dong recently received a $1.1  million, four-year renewal grant from the National Institute of Diabetes &  Digestive & Kidney Diseases to further study the structural changes of  mitochondria during apoptosis and normal physiological conditions.