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 (UPRmt). When proteins misfold in the mitochondria, which can be caused by external threats like pathogens or mitochondrial toxins, the UPRmt gets activated which helps restore protein shape and function. Past research on the microscopic worm C. elegans has demonstrated that boosting the UPRmt 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 UPRmt 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 UPRmt in adult C. elegans are caused indirectly—the UPRmt is initiated in response to the opening of the transition pore. While the UPRmt 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 UPRmt from initiating and restores their average lifespan. This supports the case that the pore and UPRmt 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 UPRmt 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 UPRmt 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 UPRmt .To push this research forward, Angeli plans to investigate how the UPRmt 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 UPRmt 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.
Citation: The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging
Additional collaborators: Other Buck authors on this study include Anna Foulger, Manish Chamoli, Tanuja Harshani Peiris, Akos Gerencser, Azar Asadi Shahmirzadi, Julie Andersen, and Gordon Lithgow.
Acknowledgements: Funding for the study was provided by NIH grants R01AG029631 and RF1A057358 and the Hillblom Foundation.
About the Buck Institute for Research on Aging
At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. Our goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, we are globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Our success will ultimately change healthcare. Learn more at: https://buckinstitute.org
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The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging
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