“That additional window of survival is extremely important because in the body, cytokines are limiting.” Ihle said. “The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl.”

Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria—tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell's cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.

In lymphocytes, members of the Bcl-2 family of proteins both protect and initiate apoptosis. For this reason, Ihle and the researchers explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. This led them to discover that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur. This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.

Other authors of this study include Jyh-Rong Chao, Kelli Boyd, Evan Parganas, Cheol Yi Hong and Joseph T. Opferman (all St. Jude).

This work was supported in part by grants from the National Institutes of Health and ALSAC.

stjude