PHD3 enzyme plays a unique role in fat metabolism

Sugars and fats are the primary fuels of every cell, tissue, and organ. Sugar is the main energy source for most cells. During the time of starvation or extreme exertion, the nutrients are scarce, and the cells will switch to breaking down fat instead. Cell Metabolism published this study.

The mechanisms of how a cells’ metabolism works during the changes in resource availability are not yet fully understood. But new research provides a surprising consequence when one of the mechanisms is turned off: an increased capacity for endurance exercise.

phd3 enzyme

Prolyl hydroxylase 3 (PHD3) enzyme

Harvard Medical School researchers identified an enzyme, prolyl-hydroxylase 3 (PDH3). This enzyme is responsible for sensing nutrient availability and regulating the ability of muscle cells to break down fats. When there are more nutrients in the body, PHD3 acts as a brake that inhibits unnecessary fat metabolism. The brake gets released at the time when fuel is low and more energy needed, such as during exercise.

The research showed that blocking this enzyme production in mice leads to dramatic improvements in specific measures of fitness. When compared with normal mice, the mice lacking PHD3 enzyme ran 40% longer and 50% farther on treadmills. Moreover, they also showed a higher VO2 max, a marker of aerobic endurance that measures the maximum oxygen uptake during exercise.

The authors said that their findings led to know a key mechanism behind how cells metabolize fuels. Furthermore, it also offers clues toward a better understanding of muscle function and fitness.


Marcia Haigis is a senior author and professor of cell biology in the Blavatnik Institute at HMS. Haigis said that PHD3 inhibition in the whole body or skeletal muscle is beneficial for fitness in terms of endurance exercise capacity. Moreover, understanding this pathway and the energy metabolism of our cells has broad applications in biology. It ranges from cancer control to exercise physiology.

However, it requires more study to elucidate whether this pathway can manipulate in humans to improve muscle function in disease settings, said the authors.

How PHD3 works?

In previous studies, Haigis and her colleagues investigated the function of PHD3, which plays a role in fat metabolism regulation in specific types of cancer. Under normal conditions, PHD3 chemically modifies ACC2, another enzyme. This modification, in turn, prevents fatty acids from entering mitochondria to broken down into energy.

Now, the researchers revealed that PHD3 and AMPK enzyme simultaneously controls the activity of ACC2 to regulate fat metabolism. Moreover, this control depends on energy availability.

PHD3 in mice

Impact of PHD3 and AMPK on ACC2

If we put mice cells in sugar-rich conditions, PHD3 chemically modifies ACC2 to inhibit fat metabolism. However, under low-sugar conditions, AMPK gets activated and places a different opposing chemical modification on ACC2 to repress PHD3 activity. This modification allows fatty acids to enter into the mitochondria to get broken down for energy.

Moreover, live mice when allowed to fasting to induce energy-deficient conditions confirmed these observations. In fasted mice, the PHD3-dependent chemical modification to ACC2 reduced in skeletal and heart muscle in comparison with the fed mice. In contrast, AMPK-dependent change in ACC2 increased.

Further study

In the next step, the researchers used genetically modified mice that do not express the PHD3 enzyme. So that AMPK expression will be high, which plays a role in energy expenditure and exercise tolerance. Then the team carried out a series of endurance exercise experiments.

phd3 deficiency

Haigis said that if they could knock out PHD3, would that increase fat-burning capacity and energy production? And have a beneficial effect on skeletal muscle, which relies on energy for function and exercise.

To investigate this, the team used young mice which have PHD3 deficiency to run on an inclined treadmill. In comparison with normal mice, this mouse ran longer and further before reaching the exhaustion point. Moreover, these PHD3 deficient mice also had higher oxygen consumption rates.

After the endurance exercise, the mice showed increased fat metabolism and an altered fatty acid composition and metabolic profile. Moreover, PHD3 dependent modification to ACC2 was undetectable, whereas AMPK-dependent change increased. This change suggested that fat metabolism changes play a role in improving exercise capacity.

Haigis said that a better understanding of PHD3 mechanisms could someday help unlock new applications in humans, such as novel ways for treating muscle disorders.

To know further read the article, “PHD3 loss promotes exercise capacity and fat oxidation in skeletal muscle.”

Don’t miss – Controlling Brain with Light.