Associate Professor Tristan Rawling of the University of Technology Sydney is leading new research into compounds that encourage cells to burn more calories by subtly changing how mitochondria generate energy. The work, carried out in collaboration with researchers at Memorial University of Newfoundland, explores a class of experimental molecules designed to increase metabolic activity without the severe risks associated with earlier weight loss drugs.
Pacchini, E., McNaughton, D. A., Pye, A., Wilson, K. A., Gale, P. A., & Rawling, T. (2026). The role of transmembrane proton transport rates in mild mitochondrial uncoupling by arylamide substituted fatty acids. Chemical Science. https://doi.org/10.1039/D5SC06530E
Mitochondria are responsible for converting nutrients into adenosine triphosphate, the chemical energy that powers most cellular processes. Under normal conditions, this conversion is highly efficient. The research team focused on compounds known as mitochondrial uncouplers, which reduce this efficiency by allowing some of the energy from food to be released as heat rather than stored as ATP. As a result, cells must burn more fuel to meet their energy demands.
Associate Professor Tristan Rawling of the University of Technology Sydney stated,
“DNP disrupts mitochondrial energy production and increases metabolism. 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.”
This concept is not new. Mitochondrial uncoupling was first identified nearly a century ago, most notably through the compound 2,4-dinitrophenol. While effective at increasing metabolism and promoting weight loss, such early uncouplers proved highly dangerous. The difference between a dose that increased calorie burning and one that caused overheating or death was small, leading to their withdrawal from medical use. These historical risks have long limited further development in this area.
The new study takes a more controlled approach. By carefully modifying the chemical structure of experimental molecules, the researchers were able to adjust how strongly each compound disrupted mitochondrial energy production. Some variants caused excessive uncoupling similar to older toxic compounds, while others produced a milder effect that increased energy use without damaging cells or fully blocking ATP generation.
Laboratory experiments showed that these milder uncouplers increase fat consumption at the cellular level while maintaining normal mitochondrial function. This distinction is critical. Instead of overwhelming the system, the compounds slow energy production just enough to raise metabolic demand, a level that cells appear able to tolerate.
Beyond calorie burning, the researchers observed additional cellular effects that may be relevant to long-term health. Mild mitochondrial uncoupling reduced oxidative stress, a process linked to aging and metabolic disease. Similar findings have been reported in other recent metabolic studies, suggesting that carefully regulated energy inefficiency could have benefits beyond weight management, including improved insulin sensitivity and protection against cellular damage.
The study also provides new insight into why some uncouplers are dangerous while others are not. By examining how quickly protons move across mitochondrial membranes, the team identified transport rates that distinguish mild, manageable uncoupling from harmful energy disruption. This mechanistic understanding offers a framework for designing safer compounds in the future.
While the research remains at an early stage, it addresses several limitations of current obesity treatments. Many existing drugs require injections and can produce unwanted side effects. A carefully designed oral compound that modestly increases energy expenditure could complement lifestyle changes rather than replace them. However, extensive testing will be required before any clinical use is considered.
From an engineering and drug design perspective, the work highlights the value of precision at the molecular level. Rather than seeking maximal metabolic stimulation, the researchers focused on fine control, balancing effectiveness with safety. This approach reflects a broader trend in biomedical engineering, where incremental changes in biological systems are often more viable than dramatic interventions.
The findings do not suggest an immediate solution to obesity, but they reopen a scientific pathway that was largely abandoned due to safety concerns. By revisiting mitochondrial uncoupling with modern chemical design and biological insight, the researchers have provided a clearer picture of how metabolism might be safely adjusted. For Engineeringness readers, the study illustrates how careful control of fundamental cellular processes can translate into new strategies for addressing complex health challenges.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
