A research team has discovered a new pathway that protects mitochondria during periods of cellular stress. Responsiveness of the protective signaling pathway slows down with age and contributes to mitochondrial dysfunction. These new findings lay the groundwork for studying specific areas of the pathway that could improve mitochondrial performance. The research was published in Cell Reports.
Previous research has shown that cells respond to stress by shutting down protein production for a period of time. While not producing proteins, a cell’s mitochondria stretches out to a longer, flatter shape rather than retaining its bean-like formation.
"Just a couple hours of not making proteins seems to be enough to remodel the mitochondria, and they can stay that way for hours," says 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."
This new study focuses on endoplasmic reticulum (ER) stress, a branch of the Unfolded Protein Response (UPR) stress-response pathway, and how ER stress impacts mitochondrial shape and function. The PERK signaling pathway is key to controlling mitochondrial function in response to ER stress. The research team demonstrated that activating PERK not only shuts down protein production but also leads to a change in mitochondrial shape. Elongated mitochondria are known to function differently indicating that PERK causes the mitochondria to adapt during periods of ER stress.
The investigators then measured mitochondrial energy output after ER stress to investigate whether these changes were negatively impacting the cells. They found that reshaping mitochondria and preventing protein production saved energy and had a protective effect on the cell. "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," says Aparajita Madhavan, graduate student at TSRI and co-first author of the study.
Several age-related diseases are associated with mitochondrial dysfunction such as diabetes, Alzheimer’s and Parkinson’s disease. The research team believes mutations or age-related defects in PERK signaling might prevent the protective effect on mitochondria during stress. More in-depth studies of PERK signaling could lead to treatments for diseases linked to mitochondrial dysfunction.