Mitochondria, often referred to as the powerhouses of the cell, are essential for maintaining the human body’s energy balance. However, when mitochondria malfunction, the effects can be devastating, contributing to many severe diseases. Researchers have now uncovered how cells attempt to combat the harmful effects of mitochondrial mutations and revealed that the body’s natural responses may inadvertently do more harm than good. These findings open the door to potential new treatments for many conditions tied to mitochondrial dysfunction.
Mitochondrial diseases affect about 1 in 5,000 people worldwide. These disorders can manifest at any stage of life and affect many tissues, often including skeletal muscle, the brain and the liver. Effective therapies, however, remain limited.
A new study, published in Nature Communications by researchers at the Karolinska Institutet in Stockholm, Sweden, explored how an organism responds to mitochondrial dysfunction. It highlights new possibilities for therapeutic intervention by targeting cellular processes that either worsen or compensate for this dysfunction.
Insight from fruit fly experiments
When mitochondria fail, cells activate a variety of compensatory processes to mitigate the damage. “We want to determine whether overactive or inactive cellular processes related to mitochondrial dysfunction can be manipulated. Knowing how the body itself responds when the mitochondria do not function properly is important,” explains Anna Wredenberg, Professor, lead researcher and specialist physician at Karolinska Institutet.
The team’s research sheds light on how certain cellular responses, although initially protective, can spiral out of control, exacerbating the damage caused by mitochondrial dysfunction.
To better understand these processes, the researchers turned to an established model organism: the fruit fly (Drosophila melanogaster). They studied mutant flies that accumulate mutations in their mitochondrial genome, leading to mitochondrial dysfunction so severe that the flies fail to develop beyond the larval stage.
Using large-scale genetic screening, the researchers silenced genes on chromosome 3, corresponding to 40% of all fly genes, to identify those that could influence survival. This approach enabled them to pinpoint processes that were overactive in response to mitochondrial dysfunction and investigate whether turning them off could help the flies to survive and develop.
“We approached this study with an open mind, screening genes broadly without prior expectations. Our goal was simply to identify processes that might either protect or harm these flies,” says Anna Wredenberg.
Switching off signalling pathways
One key finding involves autophagy, a cellular process that removes damaged components and proteins. Although autophagy is typically beneficial, the researchers found that mitochondrial dysfunction caused it to become overactive, leading to harmful effects.
“In our experiments, fruit flies with overactive autophagy failed to develop beyond the larval stage,” Anna Wredenberg explains. “However, when we inhibited this process by reducing the copy number of specific genes, the flies managed much better, surviving and developing into adults.”
Beyond autophagy, the researchers identified additional pathways involved in how the body responds to mitochondrial dysfunction. These included pathways related to nutrient sensing, insulin sensitivity and protein import into mitochondria.
The study showed that these pathways are strongly activated in response to the accumulation of mitochondrial DNA mutations, likely contributing to the cellular dysfunction. By experimentally turning off specific genes, the researchers mitigated the negative effects of mitochondrial mutations.
“In total, we identified 11 genes that play a role in the cellular response to mitochondrial dysfunction,” notes Anna Wredenberg. “Silencing these genes helped the cells to counteract the damaging effects of mitochondrial mutations.”
Towards new therapeutic strategies
Anna Wredenberg explains that when the researchers began their experiments, they did not know whether manipulating other genes could positively affect mitochondrial dysfunction. The new results indicate that decreasing overactive cellular responses, such as autophagy, may be able to reduce the impact of mitochondrial dysfunction on people, an interesting direction for further research.
The next steps, according to Anna Wredenberg, involve testing these findings in mammals and exploring whether similar excessive processes occur in biopsies from people with mitochondrial diseases. If this is confirmed, it could pave the way for developing treatments aimed at modulating cellular responses to mitochondrial dysfunction.
“When mitochondrial dysfunction occurs, the cells’ attempts to compensate are often helpful – but not always. Sometimes, their overreaction or chronic activation can cause more harm than good,” Anna Wredenberg concludes. “Our research offers a promising path forward to better understand these processes and, ultimately, to develop treatments that can improve outcomes for people with mitochondrial diseases.”
