If your car’s engine develops a stutter, that’s generally a sign that you should go to a mechanic before it stops running. We tend to think the same way about our bodies: When something’s broken, something bad usually follows. There might be, however, at least one exception to this rule.
Mutations in the energy-production pathways of mitochondria, the organelles responsible for making the energy cells need to function and survive, are normally associated with aging and several disease states. However, there’s a decades-old paradox in aging biology in which certain disturbances in mitochondrial function can counterintuitively help extend an organism’s lifespan.
This effect has not just been observed in Caenorhabditis elegans, the transparent worm in which this phenomenon was discovered, it’s also been observed across evolution and even in humans. In fact, metformin, a drug approved for the treatment of diabetes type 2, is a mild mitochondrial inhibitor that is currently being developed as a potential anti-aging drug.
And yet—scientists have not yet been able to parse what makes mitochondrial inhibition beneficial in some contexts, but pathological in others.
Kris Burkewitz, an assistant professor of cell and developmental biology, has been working to understand how cells respond and adapt to mitochondrial impairment. In a recent paper in Nature Communications, the Burkewitz lab explored how communication between the mitochondria and other organelles might be helping cells adapt to mitochondrial dysfunction.
“Much of the past research has focused on understanding how mitochondria themselves adapt to stress, but really the cell operates as a community of many different organelles,” Burkewitz said. “One of our goals was to take a more holistic approach and ask how other parts of the cell might be involved in adapting to mitochondrial dysfunction.”
Emerging research has shown that the endoplasmic reticulum, a second essential metabolic hub of the cell, interacts closely with mitochondria and regulates their functions through calcium signals, among other pathways.
True to the research team’s goal of understanding connections between different parts of the cell, they found that the major player in ER calcium signaling, a conserved ion channel called the IP3 receptor, is essential for the ability of a specific mitochondrial mutation to extend lifespan. Mutations in energy production pathways trigger mitochondria to grow and expand as a way to overcome their reduced function. The study showed that an essential aspect of successful adaptation to mitochondrial stress in the long-lived worms is the ability to keep these dysfunctional mitochondrial networks from growing excessively large and interconnected. The team demonstrated that, to prevent the uncontrolled expansion of mitochondria, calcium released by the ER activates the remodeling of the actin cytoskeleton, which earlier research had shown can act as restricting mitochondrial “cages.”
“We’ve identified new genetic links between ER calcium signaling, actin remodeling, and the turnover dynamics of mitochondrial networks in these aging contexts, but there are many molecular details to fill in before we fully understand how these pathways are connected,” Burkewitz said. His group used “simple genetic tools” with large impacts on calcium signals in the study, and he believes that a good next step is to more delicately decipher how cells change the timing and pattern of calcium release to convert certain forms of mitochondrial stress into a life-prolonging response.
The findings from this paper may also shed more light on why mitochondrial dysfunction and defects in calcium signaling frequently co-occur in several diseases associated with advanced age, most notably in neurodegenerative diseases. If calcium signaling is supporting mitochondrial functions, as this study shows, then cells can fall into a vicious cycle when both processes become impaired during normal aging, resulting in overt disease.
Ultimately, an improved understanding of the complex dynamics surrounding the mitochondria and the ER (and, possibly, other organelles) may help unlock new therapeutics that extend our healthy years of life.
In the meantime, if my mechanic could figure out how to keep my car running for many more years by precisely breaking a thing here or there, I’d bring him a mallot myself.
Go deeper
The paper “InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity” was published in Nature Communications in August 2026. Gaomin Feng and Elizabeth Ruark are co-first authors.
Funding
This research used funds from the Glenn Foundation for Medical Research/American Federation for Aging Research and the National Institute on Aging.
School of Medicine Basic Sciences shared resources
This research made use of the Cell Imaging Shared Resource.
Open access
The study was published open access through a transformative agreement negotiated by Vanderbilt University’s Jean and Alexander Heard Libraries. Transformative agreements eliminate traditional paywalls and remove the obstacle of article processing charges, ensuring immediate and unrestricted access to research worldwide. Vanderbilt authors can learn more about the Heard Libraries’ agreements supporting open access publishing in this research guide.