Mitochondrial Quality Control: New Drug Targets for Heart Disease

Cardiovascular disease (CVD) remains the leading cause of death worldwide, and recent research is increasingly focusing on the role of mitochondria in heart health. In the scientific paper Mitochondrial Quality Control in the Heart: New Drug Targets for Cardiovascular Disease, Oh et al. review the critical importance of mitochondrial quality control (MQC) systems—specifically, the mitochondrial unfolded protein response (UPR_mt) and mitophagy—in maintaining cardiac function. These systems help protect heart cells from stress-induced damage and dysfunction. The authors also highlight promising therapeutic strategies involving naturally derived compounds, such as urolithin A and spermidine, that have shown potential in restoring mitochondrial health and preventing heart failure. This paper underscores the growing interest in targeting mitochondria as a novel approach to treating heart disease.

The heart is one of the most energy-hungry organs in the body. It needs a constant supply of energy to keep beating and pumping blood. That energy comes from tiny structures inside cells called mitochondria. They act like power plants, making a molecule called ATP that fuels every heartbeat.

But when mitochondria stop working properly—due to stress, aging, or disease—the heart can suffer. Poor mitochondrial function can lead to problems like oxidative stress, cell death, and heart failure. To prevent this, heart cells rely on a system called mitochondrial quality control (MQC). This system includes ways to fix damaged mitochondria, clean them up, or make new ones.

This scientific paper focuses on how the MQC system works, how it’s connected to heart disease, and how certain natural compounds like urolithin A and spermidine may help protect the heart by supporting healthy mitochondria.

This paper is a scientific review. That means the authors did not run new experiments but carefully examined and summarized findings from many other published studies. They focused on studies about:

• How the MQC system protects heart cells
• What happens when this system fails
• How specific compounds (urolithin A and spermidine) help restore mitochondrial function in both animals and humans

The paper included evidence from cell cultures, mouse models, and some early human clinical trials.

Heart cells are under constant stress and need a system to keep proteins inside mitochondria healthy. This is called mitochondrial proteostasis. Special proteins called chaperones and proteases help fold new proteins and break down damaged ones.

When too much stress builds up, a signal called the mitochondrial unfolded protein response (UPR_mt) kicks in. This response sends messages from the mitochondria to the cell’s nucleus to activate genes that help protect the cell.

The study explains, “Disrupted mitochondrial proteostasis and dysfunction initiates a retrograde signaling pathway… known as UPR_mt.” In mammals, ATF5 and ATF4 are the main proteins that help carry out this response.

In mouse models, activating UPR_mt helped protect heart function after injuries like lack of blood flow (ischemia-reperfusion or I/R injury). However, when ATF5 was missing, the protective effects were gone. This shows that ATF5 is key for UPR_mt to help the heart recover from stress.

Another major MQC process is mitophagy, which is how cells break down and remove damaged mitochondria. This prevents them from harming the rest of the cell.

PINK1, a protein that builds up on damaged mitochondria, is a key player in this process. It brings in another protein called Parkin, which helps mark the bad mitochondria for removal.

The paper says, “Mitophagy is a critical MQC mechanism in cardiac myocytes. Impaired mitophagy leads to accumulation of aberrant mitochondria, loss of myocytes, and contractile dysfunction.”

In studies, mice without PINK1 or Parkin developed worse heart disease and had more damaged mitochondria. Other proteins like BNIP3, FUNDC1, and cardiolipin also help mitophagy work, especially when oxygen levels are low.

Problems in the MQC system are linked to many heart conditions:

• In heart failure models, activating UPR_mt with nicotinamide riboside (NR) improved heart function and reduced cell death.
• In diabetes-related heart disease, damaged mitochondria were a significant problem. Activating mitophagy helped improve heart health in these models.
• Mice with faulty mitophagy genes had more heart damage after stress or aging.

This shows that both UPR_mt and mitophagy are essential for preventing or slowing heart disease.

Urolithin A is a natural compound made in the gut from pomegranate juice. Studies in mice and worms have shown it can activate mitophagy, protect mitochondria, and even extend lifespan.

The paper highlights one study where “urolithin A activates mitophagy signal in cardiac myocytes and suppresses cardiac fibrosis.” In rats with diabetes, it reduced inflammation and improved heart function. In humans, it enhanced mitochondrial function in muscles.

These results suggest that urolithin A may one day help people with heart disease by supporting their mitochondria.

Spermidine is another natural compound in foods like soybeans, mushrooms, and aged cheese. It’s part of a group called polyamines that help with cell growth and survival.

Studies show that spermidine:

• Boosts mitochondrial energy production
• Helps clear damaged mitochondria (via mitophagy)
• Reduces heart inflammation
• Protects against aging in the heart

In one study, feeding mice spermidine “led to a 10% increase in the median lifespan” and delayed heart failure. In humans, higher spermidine intake is linked with a lower risk of heart attacks, strokes, and heart failure.

This scientific paper highlights how keeping mitochondria healthy is essential for protecting the heart, especially as we age or face diseases like diabetes and heart failure. The two key systems—UPR_mt and mitophagy—act like emergency repair crews and waste removal teams for mitochondria. When these systems break down, the heart becomes more vulnerable.

Natural compounds like urolithin A and spermidine offer exciting potential as new treatments. These compounds could one day prevent or reverse heart damage by supporting mitochondrial cleanup and stress responses.

As the paper notes, “Further researches aimed at identifying new compounds enhancing mitochondrial proteostasis and long-term clinical studies are needed.” If future studies confirm these early findings, targeting mitochondrial quality control may become a powerful strategy for fighting heart disease.