Heart mitochondria without Bid proteins. Image credit: Zinkel et al. 2018 (CC BY 4.0)
Cells contain specialized structures called mitochondria, which help to convert fuel into energy. These tiny energy factories have a unique double membrane, with a smooth outer and a folded inner lining. The folds, called cristae, provide a scaffold for the molecular machinery that produces chemical energy that the cell can use. The cristae are dynamic, and can change shape, condensing to increase energy output.
Mitochondria also play a role in cell death. In certain situations, cristae can widen and release the proteins held within their folds. This can trigger a program of self-destruction in the cell. A family of proteins called Bcl-2 control such a ‘programmed cell death’ through the release of mitochondrial proteins. Some family members, including a protein called Bid, can reorganize cristae to regulate this cell-death program. When cells die, Bid proteins that had been split move to the mitochondria. But, even when cells are healthy, Bid molecules that are intact are always there, suggesting that this form of the protein may have another purpose.
To investigate this further, Salisbury-Ruf, Bertram et al. used mice with Bid, and mice that lacked the protein. Without Bid, cells – including heart cells – struggled to work properly and used less oxygen than their normal counterparts. A closer look using electron microscopy revealed abnormalities in the cristae. However, adding ‘intact’ Bid proteins back in to the deficient cells restored them to normal.
Moreover, without Bid, the mice hearts were less able to respond to an increased demand for energy. This decreased their performance and caused the formation of scars in the heart muscle called fibrosis, similar to a pattern observed in human patients following a heart attack.
DNA data from an electronic health record database revealed a link between low levels of Bid genes and heart attack in humans, which was confirmed in further studies. In addition, a specific mutation in the Bid gene was found to affect its ability to regulate the formation of proper cristae.
Combining evidence from mice with human genetics revealed new information about heart diseases. Mitochondrial health may be affected by a combination of specific variations in genes and changes in the Bid protein, which could affect heart attack risk. Understanding more about this association could help to identify and potentially reduce certain risk factors for heart attack.
