First author Dr Kerstin Brinkmann said that while previous research in cell cultures had hinted at the metabolic role of MCL-1 in providing energy to cells, it was unclear whether this mattered in living organisms.

“This is the first time MCL-1’s metabolic function has been shown to be critical in a living organism,” said WEHI researcher Dr Brinkmann.

“It’s a fundamental shift in how we understand what this protein does.

“The findings open up a completely new way of thinking about the intersection between programmed cell death and metabolism – something that’s been speculated on for years but never been shown in a living organism until now.”

The research strengthens the potential of MCL-1 as a cancer drug target, which is currently the subject of clinical trials all over the world.

While drug compounds targeting MCL-1 that have been developed to date are considered extremely effective at combating cancer, they have unfortunately also caused significant side effects in early clinical trials, particularly in the heart.

Co-senior researcher Professor Andreas Strasser said the findings could help resolve the safety issues of drugs targeting MCL-1 that have hindered these promising treatments.

“If we can direct MCL-1 inhibitors preferentially to tumour cells and away from the cells of the heart and other healthy tissues, we may be able to selectively kill cancer cells while sparing healthy tissues,” Prof Strasser, a WEHI laboratory head, said.

The study also lays the groundwork for better combination therapies. By understanding the distinct pathways the protein influences, researchers can design smarter dosing strategies and pair MCL-1 inhibitors with other treatments to reduce toxicity.

“This work exemplifies the power of discovery science,” said co-senior researcher Professor Marco Herold, CEO of the Olivia Newton-John Cancer Research Institute (ONJCRI).

“The sophisticated preclinical models we developed allow us to interrogate the precise function of MCL-1, and to address fundamental biological questions that have direct relevance to human disease.”

MCL-1’s role in energy production could help explain fatal metabolic diseases in infants, such as mitochondrial disorders. These rare conditions, often caused by mutations in genes that stop cells from generating enough energy, can be lethal in early life.

The study suggests MCL-1 may play a previously unrecognised role in these diseases, offering a potential new target for future therapies.

Another key outcome of the study is the creation of a system that allows researchers to compare the functions of pro-survival proteins like MCL-1, BCL-XL and BCL-2.

These new tools will help identify which roles are shared and which are unique – knowledge that could inform future drug development across multiple targets.

The project was made possible by WEHI’s collaborative research environment, bringing together experts in cancer biology, metabolism, developmental biology and gene editing.

Co-senior authors Prof Herold (from the ONJCRI), Professor Tim Thomas and Professor Anne Voss played key roles in the study.

“This kind of discovery only happens when you have the right mix of people and expertise,” said Prof Strasser.

“It’s a powerful example of how fundamental science drives future medical breakthroughs.

“This came from a simple biological question – not a drug development project. It shows why we need to support curiosity-driven science. That’s where the big insights come from.”

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Header image: The research team behind the discovery, L–R: Professor Tim Thomas, Dr Kerstin Brinkmann, Professor Marco Herald (from the ONJCRI), Professor Anne Voss and Professor Andreas Strasser.