LA JOLLA, CA—Recently, Scientists at The Scripps Research Institute (TSRI) discovered a new pathway in cells that promotes mitochondrial function during times of stress, a response that can guard against disease as we age. Rather than churn out misshapen proteins, the cells activate protective pathways that begin shutting down protein production altogether. Researchers show that along with this shutdown comes an odd change in the shape of mitochondria, which are responsible for generating cellular energy. Instead of having a kidney shape, mitochondria begin to stretch out like noodles.
“Just a couple hours of not making proteins seems to be enough to remodel the mitochondria, and they can stay that way for hours,” said Luke Wiseman, PhD, associate professor at TSRI and senior author of the new study. “That seems to be a protective way to promote mitochondrial function during the early stages of stress.”
“Blocking protein synthesis — and promoting cellular energy levels by regulating mitochondrial shape — seems to be an effective way of combatting stress over shorter time scales,” noted Aparajita Madhavan, graduate student at TSRI and co-first author of the study.
The study, “The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology During Acute Endoplasmic Reticulum Stress,” was published in the journal Cell Reports in March. Additional authors of the study were co-first authors Vivian W. R. Moraes and Jaclyn Saunders, as well as co-authors Nicole Madrazo and Mary C. Anthony of TSRI.
This research offers a closer look at a stress-response pathway in cells called the Unfolded Protein Response (UPR). The UPR has several “branches” that regulate different cellular functions. The Wiseman lab focused on how stress in the endoplasmic reticulum (ER) affects mitochondrial shape and function. An important player in this response is a sensor/initiator of the UPR called PERK.
Wiseman described the PERK branch as a finely tuned signaling pathway. Without enough PERK signaling, the mitochondria can go haywire in times of stress and significantly challenge cellular function. But if this pathway is hyperactivated, the cell self-destructs. As we age, it can become difficult for the system to maintain this balance. “When you’re older, little problems can become bigger problems because the PERK pathway isn’t as good at responding,” Wiseman said.
Previous research shows that in times of stress, PERK has an important role in regulating many aspects of mitochondrial function including preventing the mitochondrial accumulation of misshapen proteins in response to ER stress. This study shows that shutting down protein production through activation of PERK also influences mitochondrial shape by increasing its length. Changes in mitochondrial shape are known to influence mitochondrial function, indicating that this is a mechanism to adapt mitochondrial function during ER stress.
The next question for the team was whether this shutdown and remodeling was helping or hurting cells. The mitochondria’s main role is to produce energy for the cell, so the researchers measured energy output to see how well mitochondria were functioning after cells experienced ER stress. They found that shutting down protein production and remodeling the mitochondria did make a difference.
“We were able to able to show a protective effect, where mitochondrial energy production was protected due to increased mitochondrial length” commented Justine Lebeau, PhD, research associate at TSRI and co-first author of the study. Researchers suspect that this entire system evolved to give cells a way to respond to stress very quickly, when they don’t have time to make a batch of protective proteins.
Wiseman thinks that defects in PERK sensitivity/activation caused by aging or mutations might hinder this protective regulation of mitochondria. He pointed out that defects in PERK signaling are implicated in many diseases that also include mitochondrial dysfunction — diabetes, heart disease, and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Wiseman hopes the new work could point to a way to target this aspect of PERK signaling, in order to correct mitochondria defects that cause disease.