Researching Mitochondria's Role in Preventing Damage During Heart Attacks

“Everyone is the age of his heart.” -Guatemalan Proverb

Few words provoke more fear in people than the term “heart attack.”

It’s easy to see why — heart attacks are one of the most common causes of death for men and women in this country. How common? The American Heart Association estimates more than 1.2 million Americans will have their first or a recurrent heart attack this year. About 479,000 will die.

Scientists at the SDSU Heart Institute, however, are hard at work trying to change that.

The institute’s researchers are discovering exactly how and where the heart fails during a heart attack — and how the heart can be strengthened to resist damage and heal from within.

The institute’s prominence in this field helped it recently attract its largest and most significant research grant to-date. It’s a five-year, $9.5 million program project grant from the National Heart, Lung and Blood Institute (part of the National Institutes of Health) to study how protecting mitochondria can preserve heart cells during a heart attack.

A single adult rat cardiomyocyte, dyed red.
The cell's mitochondria are filaments that cross
the cell, creating a banded look.
Image by Nathan Brady

Mighty mitochondria

A heart attack (also called myocardial infarction, or MI) occurs when one or more of the coronary arteries is blocked, cutting off the supply of oxygen-rich blood to the heart. If isolated from the blood supply long enough, the heart muscle cells die. If a large area of the heart is damaged, sudden death can result.

“Mitochondria, a cell’s energy center, are key to a heart cell’s survival during a heart attack,” said grant director Mark Sussman, a professor in SDSU’s biology department. “This grant will determine the molecular mechanisms needed to enhance mitochondrial and cell survival and maintain cardiac function.”

Mark Sussman, grant director
Photo by Tom Farrington

Heart muscle cells, or cardiac myocytes, require tremendous amounts of energy to pump blood through the heart. They can achieve the highest sustained metabolic rate of all the tissues in the human body. To accomplish this, up to 40 percent of a cardiac myocyte’s volume may be occupied by mitochondria. When these critical organelles get damaged, diminished cell function and cell death can follow, reducing the heart’s capacity to pump blood to the body.

Forever young?

But there’s more at stake than just finding out how to keep the heart alive and beating when a heart attack occurs. If Sussman and his colleagues can crack this mystery at the molecular level, it can put them on track for literally discovering how to keep people young at heart indefinitely.

“Within the next couple of decades we can make real progress toward extending the lifespan of the heart,” Sussman said of research happening at SDSU and elsewhere.

“We’re transitioning into a new way of addressing heart disease. We’re moving beyond the idea of fixing heart failure by cutting people open to switch out damaged parts, or to prop people up with drugs that merely slow down the decline of the heart. We’re moving toward an era of regenerative medicine that’s buoyed by the ability to rebuild and repair the heart at a molecular level to make it as healthy as it was when a person was young,” Sussman said.

Team effort

The SDSU Heart Institute’s $9.5 million program project grant addresses one part of this complex puzzle, and the grant itself is divided into several pieces.

Program project grants are among the most competitive grants awarded by NIH, requiring several different research teams to collaborate to investigate a complex biomedical question. In this case, there will be four interrelated projects tied to studying cardiac mitochondria. SDSU is conducting three of the four projects, with more than 20 researchers — ranging from full-time faculty and staff scientists to doctoral, master’s and undergraduate students — currently involved. Researchers at the University of California, San Diego are tackling the fourth project.

Deciphering signals

Sussman’s team is studying novel “survival signaling cascades” that protect mitochondria from damage. When heart cells stress, the contents of mitochondria leak out, starting a downward spiral that leads to cell death. However, research by Sussman has shown that Akt, an enzyme with many functions, can be activated to trigger a series of biochemical signals in heart cells to deter that process. Now his team’s goal is to find out how that series — the survival signaling cascade — works.

A newly forming myocyte in a mouse heart two weeks
after an infarction
Image by Jenna Fransioli

“We’re trying to blunt that mitochondrial destabilization,” said Sussman, who came to SDSU in 2003 from the Cincinnati Children’s Hospital and Research Foundation, and also is recognized for his research into Akt’s ability to protect the heart by boosting the activity of cardiac stem cells. “Activation of survival signaling protects the mitochondria and makes the cell resistant to death.”

Revealing regulators

Akt is at the center of another project led by Joan Heller Brown, professor and chair of the department of pharmacology at UCSD.

Joan Heller Brown,
professor and chair of
UCSD's department of
pharmacology

Heller Brown’s research includes examining several proteins that influence or are influenced by Akt. One, a newly discovered enzyme named PHLPP, has been shown to inactivate Akt and may be critical to regulating the amount of Akt activity in a cell. Another molecule, hexokinase, has been shown in her lab to be a target for regulation by Akt that functions to protect mitochondria.

“The pathways responsible for Akt activation, deactivation and mitochondrial protection in the heart have not been fully explored,” Heller Brown said. “We’re looking at how Akt gets turned on and off, and are using probes to examine how it moves around the cell to turn on genes and to activate signaling cascades involved in cardiac cell survival.”

Examining autophagy

Dr. Roberta Gottlieb, SDSU BioScience
Center director

Another grant project will be led by Dr. Roberta Gottlieb, the new director of SDSU’s BioScience Center and Frederick G. Henry Chair in Life Sciences. Gottlieb and her research team, who will move from The Scripps Research Institute to SDSU full-time in January, are focusing on how heart cells use autophagy – a process where a cell closes off and consumes damaged or deformed parts – to purge damaged mitochondria.

“The role of autophagy in the heart is poorly understood at present,” said Gottlieb, a renowned heart researcher who served as associate professor in the Hematology Division of the Department of Molecular and Experimental Medicine at TSRI. “Our project will examine the role of autophagy in removing damaged mitochondria after ischemia (reduction or loss of blood supply) and reperfusion (the restoration of blood flow). We believe that the process of autophagy is a critical mechanism to maintain healthy cells.”

Pondering proteins

The other grant project at SDSU is being led by Christopher Glembotski, director of the SDSU Heart Institute. Glembotski’s team will focus on proteomics — studying families of proteins — with the goal of discovering new ones that are capable of protecting and maintaining mitochondria.

Christopher Glembotski, SDSU Heart Institute director
Photo by Lauren Radack

Glembotski’s lab has previously discovered that a special protein called Alpha B-crystallin (aBC) can bind to mitochondria in the hearts of mice during a heart attack, and that hearts without this protein are more susceptible to damage from the stresses of a heart attack.

“aBC relocates to the mitochondria in reaction to ischemia. It binds to other proteins, keeping them in their proper configuration so they can still do their job,” Glembotski said. “It works like a chaperone.”

Now the challenge is to find exactly how that chaperone binds to the surface of the mitochondria – what proteins are possible receptors for aBC.

“There are many of families of proteins on mitochondria to which aBC could bind. There could be 1,000 or more proteins involved,” he says. The hope is that the discovery of these proteins may lead to the eventual development of therapies that can specifically trigger or enhance aBC’s protective role, reducing the damaging effects of ischemia and helping the heart —and the whole person — live longer.

The beat goes on

While these heart mitochondria studies will keep many in the SDSU Heart Institute busy for years, its scientists envision even more ambitious and important cardiovascular studies in the future.

“This is an exciting time for the Heart Institute,” said Glembotski, whose lab also recently discovered a gene program that activates the stress response in a cardiac cell’s endoplasmic reticulum, a tool that may eventually be used to reduce or even prevent damage from heart attacks. “The next step in the institute’s evolution is to move beyond basic research projects to translational research – projects where we can convert basic science discoveries into actual treatments and therapies patients can use to beat heart disease and heart attacks. And when you consider the staggering number of people who suffer from cardiovascular disease, these solutions can’t come a moment too soon.”

Related information

• Heart Attack, Stroke and Cardiac Arrest Warning Signs
• Five Strategies You Can Adopt Today to Prevent Heart Disease



• American Heart Association
• National Heart, Lung and Blood Institute
• National Institutes of Health

Credits

• Story by Jason Foster
• Photographs by Tom Farrington, Instructional Technology Services
• Graphics by John Signer
• Edited by Happy Aston
• Additional images courtesy of Joan Heller Brown, Dr. Roberta Gottlieb and Natalie Gude