News release

From: University of Technology Sydney (UTS)

Researchers have developed experimental drugs that encourage the mitochondria in our cells to work a little harder and burn more calories. The findings could open the door to new treatments for obesity and improve metabolic health.

Obesity is a global epidemic and a risk factor for many diseases, including diabetes and cancer. Current obesity drugs require injections and can cause side effects, so a safe way to boost weight loss could deliver significant public health benefits.

The study, led by Associate Professor Tristan Rawling from the University of Technology Sydney (UTS), has just been published in Chemical Science, the UK Royal Society of Chemistry’s flagship journal, where it was highlighted as “pick of the week”.

The research team, from UTS and Memorial University of Newfoundland, Canada, focused on ‘mitochondrial uncouplers’. These are molecules that make cells burn energy less efficiently, and release fuel as heat instead of converting it into energy the body can use.

“Mitochondria are often called the powerhouses of the cell. They turn the food you eat into chemical energy, called ATP or adenosine triphosphate. Mitochondrial uncouplers disrupt this process, triggering cells to consume more fats to meet their energy needs,” said Associate Professor Rawling.

“It’s been described as a bit like a hydroelectric dam. Normally, water from the dam flows through turbines to generate electricity. Uncouplers act like a leak in the dam, letting some of that energy bypass the turbines, so it is lost as heat, rather than producing useful power.”

Compounds that induce mitochondrial uncoupling were first discovered around a century ago, however these early drugs were lethal poisons that induced overheating and death.

“During World War I, munitions workers in France lost weight, had high temperatures and some died. Scientists discovered this was caused by a chemical used at the factory, called 2,4-Dinitrophenol or DNP,” said Associate Professor Rawling.

“DNP disrupts mitochondrial energy production and increases metabolism. It was briefly marketed in the 1930’s as one of the first weight-loss drugs. It was remarkably effective but was eventually banned due to its severe toxic effects. The dose required for weight loss and the lethal dose are dangerously close,” he said.

In the new study, researchers created safer “mild” mitochondrial uncouplers by precisely adjusting the chemical structure of experimental molecules, allowing them to fine-tune how strongly the molecules boost cellular energy use.

While some of the experimental drugs increased the activity of mitochondria without harming cells or disrupting their ability to produce ATP, others created the same risky uncoupling seen with the older, toxic compounds.

This discovery allowed the researchers to better understand why the safer molecules behave differently. The mild mitochondrial uncouplers slow the process to a level that cells can handle, protecting against adverse effects.

Another advantage of mild mitochondrial uncouplers is that they reduce oxidative stress in the cell. This could improve metabolic health, provide anti-aging effects and protect against neurodegenerative diseases such as dementia.

While the work is still at an early stage, the research offers a framework for designing a new generation of drugs that could induce mild mitochondrial uncoupling and harness the benefits without the dangers.