A new pathway can promote mitochondrial function when under stress

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.
An article entitled “The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology during Acute Endoplasmic Reticulum Stress” was published in the journal Cell Reports on 13 March 2018. The main points are as below.

a. Stress-induced mitochondrial hyperfusion (SIMH) is triggered by ER stress
b. ER-stress-induced SIMH is activated by PERK-dependent translation attenuation
c. PERK-regulated SIMH promotes electron transport chain activity during ER stress
d. PERK integrates transcriptional and translational signaling to protect mitochondria

When met stress, cells will activate protective pathways to shut down the production of proteins completely, rather than churn out misshapen proteins. Along with the process, an odd change happened on the shape of mitochondria, the energy factories of the cell. Mitochondria start 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,” 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.”

The new study offers a closer look at Unfolded Protein Response (UPR), a stress-response pathway in cells. The UPR has several “branches” that regulate different cellular functions. The Wiseman lab focuses on how stress in a compartment of cells called the endoplasmic reticulum (ER) affects mitochondrial shape and function.

PERK, a sensor/initiator of the UPR, play important role in this response. Wiseman describes 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. However, it becomes difficult for the system to maintain this balance as we age.

This new 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.

But there still a question to be solved, whether this shutdown and remodeling was helping or hurting cells. Researchers measured energy output to see how well mitochondria were functioning after cells experienced ER stress. Indeed, shutting down protein production and remodeling the mitochondria did make a difference.

The researchers suspect that this whole system evolved to give cells a way to respond to stress very quickly, when they just don’t have time to make a batch of protective proteins. 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.

Wiseman thinks defects in PERK sensitivity/activation caused by aging or mutations might hinder this protective regulation of mitochondria. He says defects in PERK signaling are implicated in many diseases that also include mitochondrial dysfunction, such as diabetes, heart disease, and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. He hopes the new work could point to a way to target this aspect of PERK signaling to correct mitochondria defects that cause disease.

Find more details, please click:https://www.scripps.edu/news/press/2018/20180314_aging_disease.html