Within nearly every cell in the human body are mitochondria — tiny power plants that produce the chemical energy our bodies need to function. When these powerhouses don’t work properly, the consequences can be far-reaching. Mitochondrial dysfunction has been linked to a wide range of conditions, from neurodegenerative diseases like Parkinson’s and Alzheimer’s to inherited metabolic disorders and age-related decline.
Yet one central question has continued to confound scientists: how do cells know their powerhouses are in trouble?
Now, researchers at the UBC Faculty of Medicine have discovered a molecular “distress signal” that sounds the alarm when mitochondria start to falter, triggering the cell to take corrective action.
“If we can harness this mechanism, we may be able to develop treatments that boost the cell’s own protective responses.”
Dr. Hilla Weidberg
The study, published in Nature, describes a never-before-seen signalling mechanism that sheds new light on health, disease and aging.
“Cells can’t survive without healthy mitochondria,” says Dr. Hilla Weidberg, senior author of the study and a professor of cellular and physiological sciences at the UBC Faculty of Medicine. “This work reveals one way that cells monitor the health of these essential organelles. This new insight will help us better understand mitochondria-related diseases and potentially provide new avenues to treat them.”
A cellular 911 call
To generate energy, Mitochondria depend on a constant flow of incoming proteins. Each of these proteins is tagged with instructions that tell the cell where to deliver it, and under healthy conditions, they are efficiently imported into mitochondria to keep the powerhouses running smoothly.
“It’s an incredibly complex system, like a package delivery service where each protein carries a shipping label that guides it to the mitochondria,” explains Dr. Weidberg. “When the import system stops working, proteins begin to pile up outside the mitochondria — like a warehouse whose loading dock is suddenly blocked.”
Dr. Weidberg and her team at UBC’s Life Sciences Institute have been studying how cells manage these breakdowns and restore mitochondrial function.
In the new study, they identified one protein in particular (Mge1) that behaves very differently when stranded outside the mitochondria. Instead of remaining adrift in the cell’s cytoplasm, the protein travels directly to the nucleus — the cell’s command centre — to deliver an urgent call for help.
Once there, the protein activates the cell’s built-in emergency response program, helping clear the import blockage to restore mitochondrial function and prevent further damage.
“It turns out the secret to this process is in the shipping label,” says Zixuan (Christina) Yuan, the study’s first author and a PhD student in the Weidberg Lab. “The tag that normally guides the protein to the mitochondria serves a dual purpose, becoming a distress signal that triggers a protective response.”
A path toward new therapeutics
While the researchers performed the current study in yeast, they say similar processes playout in human cells, which could have important implications for the many human diseases linked to mitochondrial dysfunction.
“This discovery gives us a blueprint for how cells detect mitochondrial damage,” says Dr. Weidberg. “If we can harness this mechanism, we may be able to develop treatments that boost the cell’s own protective responses before damage occurs.”
The team is now working to identify the human proteins that act in a similar way. Those pathways could provide new targets for drugs aimed at stabilizing mitochondrial function or preventing the cascade of cellular stress that contributes to aging and disease.
“Our hope is that by understanding how cells manage the health of mitochondria, we can begin to devise new strategies to keep these organelles functioning longer and more reliably,” says Dr. Weidberg.