Aging: It’s More Complicated Than We Thought

Summary: A new study on aging reveals a surprising discovery about the connection between protein shape and mitochondrial health.

Source: Buck Institute

Every cell in the body goes through thousands of chemical reactions each day, and each reaction involves tiny protein molecules folded into precise shapes to perform their functions. Misfolded proteins underlie some of the most common and devastating diseases of aging, like Alzheimer’s and Parkinson’s. A major focus of aging research is discovering ways to maintain protein shape and prevent misfolded proteins from wreaking havoc on cellular function.

Another major focus of aging research is on mitochondria, those canonical powerhouses that turn out to do so much more than just fuel a cell’s energy level. Aged mitochondria don’t perform as well as their younger counterparts and contribute to aging and disease, both through declining energy production and by signaling poor health to the rest of the cell.

In an important new study from the Lithgow lab at the Buck Institute for Research on Aging, postdoc and lead author Suzanne Angeli, PhD made a surprising discovery about the connection between protein shape and mitochondrial health, providing a piece of evidence for yet another theme in aging research: it’s always more complicated than we thought.

Results are published in eLife.

Mitochondria are jellybean shaped organelles containing two membranes, allowing them to maintain their own microenvironment. Proteins within the mitochondria are intricately involved in mitochondrial function, and are protected by the mitochondrial unfolded protein response (UPR^mt).

When proteins misfold in the mitochondria, which can be caused by external threats like pathogens or mitochondrial toxins, the UPR^mt gets activated which helps restore protein shape and function.

Past research on the microscopic worm C. elegans has demonstrated that boosting the UPR^mt during development contributes to better mitochondrial health and a longer lifespan for the worms.

Consistently, pharmacologically boosting this response has been shown to slow down diseases with mitochondrial dysfunction, such as Alzheimer’s.

Dr. Angeli’s research has found that activating the UPR^mt in adult worms has the opposite effect: adult worms with a boosted unfolded protein response have worse health and a shorter lifespan.

Digging into the details of this surprising outcome led the team to examine a pore called the mitochondrial permeability transition pore. Most of the time this pore is closed, keeping the interior of the mitochondria separate from the rest of the cell. Under stress, though, it opens to release calcium into the rest of the cell, signaling that it’s time to cut its losses and induce cell death.

It turns out that methods to boost the UPR^mt in adult C. elegans are caused indirectly—the UPR^mt is initiated in response to the opening of the transition pore.

While the UPR^mt is busy trying to clean things up, the signals coming from the opened pore are too strong for the cell to ignore and result in cell death. Dr. Angeli thinks this is what contributes to the early death of the adult worms.

Treating the worms with cyclosporin A, a pharmacological method to keep the pore closed, also prevents the UPR^mt from initiating and restores their average lifespan. This supports the case that the pore and UPR^mt are connected. Going one step further, genetic manipulations to keep the pore closed actually resulted in longer average lifespan for the worms.

Research in C. elegans forms the basis of much aging research, but what does this mean for efforts to boost health and prevent disease in people? While the mitochondrial permeability transition pore is already implicated in conditions like stroke and heart attack, the role of the UPR^mt is not as well understood.

This new discovery that it is associated with poor outcomes in adult C. elegans leads Angeli to think that it might not always be helpful in humans.

Says Angeli, “It’s going to be really important moving forward to understand the mitoUPR in ischemia reperfusion injuries [stroke] to see if it’s contributing to the injuries”.

She likens it to inflammation, which has a specific purpose and is useful under some conditions, but causes damage under others. One possibility is that, in a stressed cell, the UPR^mt uses valuable cellular resources, hastening the already inevitable cell death.

This study is the first to find a connection between the “bad” process of pore opening and the “good” process of UPR^mt .To push this research forward, Angeli plans to investigate how the UPR^mt gets activated by the pore. Her hunch is that the calcium release triggers the process, but this is uncharted territory with lots of room for discovery.

It also unknown if the UPR^mt can be decoupled from the opening of the pore in adult C. elegans, like it is during development. If so, how does it affect C. elegans lifespan and how does it contribute to our understanding of the aging process? One thing for sure, it will be more complicated than we expect.

About this aging research news

Author: Kris Rebillot
Source: Buck Institute
Contact: Kris Rebillot – Buck Institute
Image: The image is credited to Suzanne Angeli, PhD, Buck Institute for Research on Aging

Original Research: Open access.
“The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging” by Suzanne Angeli et al. eLife

Abstract

The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging

Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear.

We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPR^mt). Pharmacological or genetic inhibition of the mPTP inhibits the UPR^mt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging.

Our findings reveal how an mPTP/UPR^mt nexus may contribute to aging and age-related diseases and how inhibition of the UPR^mt may be protective under certain conditions.