After a century of false starts, scientists believe they have found a way to make cells burn more energy without the dangerous side effects – and it could be a breakthrough that reshapes weight-loss and anti-aging medicine as we know it.
Researchers from the University of Technology Sydney (UTS) have found ideal “mitochondrial uncoupling” molecules that are able to gently coax these cellular organelles to let go of some of their energy supplies, without setting off a dangerous system-wide shutdown.
While we might know mitochondria as the powerhouses of our cells, they’re incredibly complex and varied throughout our bodies. They constantly split, fuse, move and are recycled in response to our cells’ energy needs, stress levels and what stage of life we’re at. But this is also why even subtle changes to their function can trigger serious health problems.
For decades, scientists have known that reducing the energy efficiency of mitochondria has the potential to boost metabolism and shield cells from damage – making any drug that could facilitate this a potential weight-loss and anti-aging breakthrough. However, forcing mitochondria to waste energy instead of storing it also results in a dangerous level of heat production throughout the body, leading to hyperthermia and cell death. Because of this, developing novel mitochondrial uncouplers has been slow work.
Now, the UTS team, along with scientists from the Memorial University of Newfoundland in Canada, believe they have found the mitochondrial-uncoupling molecules that can work as a kind of release valve, allowing some energy to leak away as heat, instead of it being stored up, without any harmful side-effects.
“Mitochondria are often called the powerhouses of the cell,” said Tristan Rawling, an associate professor at UTS. “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.
“It’s been described as a bit like a hydroelectric dam,” he added. “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.”
In this study, the researchers landed on a new class of experimental molecules – arylamide-substituted fatty acids – that act as mitochondrial uncouplers. Unlike older uncoupling drugs, they are able to increase energy use without shutting down ATP production. In lab-grown human tissue, the most promising drug candidates encouraged cells to burn more fuel, while still maintaining normal levels of ATP. What’s more, the cells remained healthy and viable – a key difference from the first known uncoupling agents, which were discovered a century ago, that rapidly drained ATP and killed cells, resulting in death.
“During World War I, munitions workers in France lost weight, had high temperatures and some died,” said Rawling. “Scientists discovered this was caused by a chemical used at the factory, called 2,4-Dinitrophenol or DNP.
“DNP disrupts mitochondrial energy production and increases metabolism,” he added. “It was briefly marketed in the 1930s 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.”
These new molecules, however, are able to “interfere” with mitochondria more delicately, so the organelle essentially functions as normal but needs to work a bit harder – which translates to burning more calories without the side effects. In addition to this, the molecules help to reduce oxidative stress, offer anti-aging benefits and can even protect against neurodegenerative diseases like dementia.
While the research is still in its early stages and these proof-of-concept molecules have so far only been tested in lab-grown cells, they open the door to the development of a new class of drugs that can harness mitochondrial inefficiency – through mild uncoupling – to safely boost metabolism and cell health.
“This work represents the first exploration of how proton transport rates influence mitochondrial uncoupling and provides a new conceptual framework for the rational design of mild uncouplers,” the researchers noted.
The study was published in the journal Chemical Science.
Source: University of Technology Sydney
