Uncovering the molecular causes of heart failure

By Bruce Lieberman
January 27, 2014
0

The cells in your body need to produce chemical energy in order to work properly. And there’s probably no other place in the human body where this is more important than in the heart, where cardiac cells are always in motion, constantly drawing on energy and expending it.

That may seem obvious, but exactly what’s going on when energy production inside your cells breaks down is complex. Now, however, researchers at Sanford-Burnham’s Lake Nona campus in Orlando, Florida, have discovered what happens when there’s not enough of a key player in this process.

A research paper by Daniel P. Kelly, M.D., professor and scientific director of Sanford-Burnham’s Diabetes and Obesity Research Center, reveals how and why heart defects occur when peroxisome proliferator-activated receptor gamma coactivator (PGC-1)—a needed molecular regulator of mitochondrial metabolism—is deficient. The paper, titled “A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis,” was published online in the Journal of Biological Chemistry.

Mitochondria are organelles within cells that are often referred to as “cellular power plants” because they generate most of a molecule called adenosine triphosphate, or ATP, which is used as a source of chemical energy.

In animal studies in the lab, Kelly’s research team found that a deficiency in PGC-1 causes a defect in the biosynthesis of phospholipids. Phospholipids are important components in membrane structures inside mitochondria called cristae. Cristae provide a labyrinth membrane system that maximizes the surface area inside mitochondria—which in turn supports full capacity in the production of ATP.

Where PGC-1 is deficient, the cristae structure inside mitochondria collapse, and ATP production is compromised. The result is that cells don’t produce chemical energy as they should. In the heart, where cells rely on a high density of mitochondria—and therefore ATP production– the outcome can be no less than heart failure.

“There has been a lot published about PGC-1, and there’s a lot known about it in terms of mitochondrial function and mitochondrial biogenesis,” said Rick Vega, Ph.D., research assistant professor in the Diabetes and Obesity Research Center, and co-author of the paper. “But this is the first instance in which it’s really been shown to have an impact on phospholipid content and production in the cell.”

Heart cells contain a particular class of phospholipids called cardiolipin that is critical for cristae formation and structure. In humans, it’s been shown that a defect in the production of cardiolipin can lead to a devastating disease called Barth syndrome. A rare genetic disorder, Barth syndrome is actually caused by an unrelated gene defect that, like the deficiency of PGC-1, short-circuits the biosynthesis of cardiolipin.

“Our discovery does provide an interesting link to Barth syndrome,” Vega said. “It has a lot of the same features. Even though we don’t think PGC-1 defects are involved in Barth syndrome, there’s a parallel between what we found and this devastating human disease.”

Ling Lai, M.D., Ph.D., a staff scientist and co-author of the paper, has been working with her colleagues to develop ways for physicians to intervene when their patients are suffering from heart failure—whatever the original cause. One key avenue is boosting energy production within heart cells. Numerous research groups and pharmaceutical companies have studied ways to boost the activity of PGC-1, but so far experiments have not been fruitful, Vega said.

“We know that PGC-1 activities and levels go down in the setting of heart failure, and we will continue to study the consequences,” Lai said. “For now, we’re very interested in understanding the molecular changes within mitochondria and energy production in the failing heart.”

This latest Sanford-Burnham study provides insight to develop targeted therapeutic approaches to boost energy production in the failing heart.

The study was performed in collaboration with Xianlin Han, Ph.D., professor in the Diabetes and Obesity Research Center.

Facebook Comments

About Author

Share.

Leave A Reply

CAPTCHA Image

*

* Copy This Password *

* Type Or Paste Password Here *

17,833 Spam Comments Blocked so far by Spam Free Wordpress