By studying mutations in yeast and human cells, Johns Hopkins Medicine scientists say they have discovered that biochemical bonds between fats and proteins in the mitochondria, the powerhouse of the cell, play a crucial role in how our cells they produce energy.
The results of the study, published June 5 in EMBO MagazineThey shed new light, researchers say, on how altered mitochondrial membranes found in people with metabolic diseases such as Barth syndrome, a rare genetic disorder that weakens the heart, do not allow cellular energy production.
Metabolism is a set of biochemical reactions fundamental to producing energy that fuels life and to get rid of substances that the body no longer needs. Metabolic diseases include forms of high cholesterol that run in families. About one in three adults has some type of metabolic syndrome, according to the National Heart, Lung, and Blood Institute.
Building on previous research, Johns Hopkins scientists sought to better understand the interaction of two components of the mitochondrial membrane: cardiolipin, a fatty compound or lipid, and proteins that transport the building blocks of adenosine triphosphate, or ATP, a molecule of energy produced by the mitochondria that fuel cellular metabolism.
“In the future, a better understanding of protein-lipid interactions could help researchers find new therapeutic targets for a wide range of metabolic diseases, including Barth syndrome,” says senior author Steven Claypool, Ph.D. , professor of physiology at Johns University. Hopkins University School of Medicine.
He says previous studies suggested that protein-lipid interactions in mitochondrial membranes are likely to play an important role in regulating the core activities of mitochondria.
The researchers carried out their experiments on yeast samples with mutations or alterations in a mitochondrial membrane protein called AAC and human cell samples that modeled a person with a mutation of the ANT1 protein who was diagnosed with a metabolic disease. , whose symptoms include weakness. in the heart and skeletal muscles, exercise intolerance and hyperlactatemia, or high levels of lactate in the blood.
The yeast protein, AAC, is the equivalent of ANT in humans, Claypool says.
By looking at three areas where cardiolipin binds to AAC proteins in yeast, Claypool and his colleagues found that when they introduced mutations in AAC2 to disrupt these interactions, cardiolipin could no longer bind to the protein, weakening its structure and reducing its function.
Similarly, in the cellular model of the person with ANT1 mutations, the structure of the protein was weakened, limiting its ability to transport ATP across the mitochondrial membrane.
“These findings indicate that when the interaction between cardiolipin and proteins is broken, the entire process that makes mitochondria our energy source is disrupted,” says first author Nanami Senoo, Ph.D., a postdoctoral fellow at the Claypool laboratory.
Claypool says that few studies have detailed the individual interactions between proteins and lipids, and that many more experiments will be needed to “understand the full set of mechanisms and functions that these interactions have in the membrane.”
Mitochondrial membranes contain many proteins, many of which are associated with lipids.
“This discovery opens up new possibilities for understanding the complexities of how our cells produce energy,” says Claypool. “In the future, we plan to explore how other protein-lipid interactions contribute to energy production.”
Other scientists who contributed to the study include Matthew G. Baile, Oluwaseun B. Ogunbona, James A. Saba, Teona Munteanu, Yllka Valdez, Kevin Whited and Macie S. Sheridan of Johns Hopkins; Dinesh K. Chinthapalli, Bodhisattwa Saha, Abraham O. Oluwole, Dror Chorev and Carol V. Robinson of the University of Oxford; Vinaya K. Golla, Nathan N. Alder, and Eric R. May of the University of Connecticut.
Funding for this study was provided by the National Institutes of Health (R01HL108882, R01HL165729, R35GM119762, T32GM007445, and T32GM136577), the American Heart Association, the Uehara Memorial Foundation, the Barth Syndrome Foundation, and the Royal Society Newton International Fellowship.