ROCHESTER, Minn. — Researchers have uncovered a previously unknown mechanism that helps aging cells drive the chronic inflammation linked to many age-related diseases. The findings reveal how dysfunctional mitochondria — the cell’s energy-producing structures — work with the cell’s epigenetic machinery to switch on inflammatory genes, opening the door to a new therapeutic approach for promoting healthier aging.

The study, published in Nature, builds upon years of research showing that senescent, or “zombie,” cells accumulate with age. While these cells no longer divide, they remain metabolically active and release a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP.

This persistent inflammation is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration and other disorders of aging.

“For years, the field has focused on getting rid of senescent cells,” says João Passos, Ph.D., a Mayo Clinic researcher and senior author of the study conducted in collaboration with Sanford Burnham Prebys Medical Discovery Institute. “Our strategy has been different. Instead of killing the cells, we asked whether we could switch off the inflammation that makes them harmful.”

Previous work from the Passos laboratory demonstrated that damaged mitochondria leak mitochondrial DNA and RNA into the cell, activating immune pathways that trigger inflammation. The new study identifies a second, independent pathway that is equally essential.

“We found that inflammatory signaling alone isn’t enough,” says Helene Martini, Pharm.D., Ph.D., a Mayo Clinic researcher and first author of the study. “The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on.”

The researchers discovered that senescent cells increase production of acetyl-CoA, a molecule generated through mitochondrial metabolism. Acetyl-CoA enables epigenetic modifications — chemical changes that regulate whether genes are switched on or off without altering the DNA sequence itself. These modifications make inflammatory genes more accessible, allowing them to be robustly expressed.

In other words, mitochondrial DNA and RNA provide the inflammatory alarm, while mitochondrial metabolism grants the molecular “permission” needed to fully activate inflammatory genes.

“This is a completely new pathway,” says Dr. Martini. “We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on.”

The team also identified a promising therapeutic target: a mitochondrial citrate transporter known as SLC25A1. Blocking this transporter reduced the supply of acetyl-CoA, limiting activation of inflammatory genes even though the initial immune signals remained present. Together, these findings reveal a previously unrecognized control point that could be exploited to promote healthier aging.

The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding.

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The study’s focal point is the pathophysiological phenomenon of OGD/R injury, an in vitro reproduction of ischemia-reperfusion events that critically impair intestinal cell viability and function. OGD/R injury induces mitochondrial perturbations leading to the release of mitochondrial DNA (mtDNA) into the cytosol and extracellular milieu. This mtDNA acts as a potent danger-associated molecular pattern (DAMP), inciting inflammatory signaling pathways that exacerbate cellular damage. By infiltrating this vicious cycle, tranexamic acid emerges as a potent modulator of both mitochondrial stability and inflammation, offering unprecedented implications for therapeutic strategies targeting ischemia-reperfusion injuries in gastrointestinal contexts.

Mitochondria, the energy-producing powerhouses of the cell, serve a dual role as arbiters of apoptosis and coordinators of innate immune responses. Under stress, particularly during ischemic insults with subsequent reperfusion, mitochondrial membranes become permeabilized, releasing intermembrane constituents such as mtDNA into the cytoplasm. This liberation triggers pattern recognition receptors, including Toll-like receptor 9 (TLR9), which in turn activate nuclear factor kappa B (NF-κB) pathways, culminating in the synthesis and secretion of proinflammatory cytokines that perpetuate tissue injury.

Tranexamic acid’s well-documented role in inhibiting fibrinolysis by blocking plasminogen activation has recently been expanded by evidence indicating its capacity to stabilize mitochondrial integrity. The researchers demonstrated that treatment with tranexamic acid during OGD/R insult significantly diminished the release of mtDNA from damaged Caco-2 cells. This reduction in mtDNA release was accompanied by a marked decrease in downstream activation of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), underscoring the drug’s capacity to attenuate sterile inflammation triggered by cellular stress.

The research team employed a robust in vitro model using human colorectal adenocarcinoma-derived Caco-2 cells, which differentiate to form tight junctions and microvilli resembling intestinal epithelial cells, thus serving as an invaluable platform to study gastrointestinal pathophysiology. Cells were subjected to OGD to mimic ischemia, followed by reoxygenation and glucose restoration to simulate reperfusion injury. Employing precise molecular assays and fluorescence microscopy, the investigators quantitatively and qualitatively assessed mtDNA release and inflammatory markers in treated versus untreated cohorts, evidencing tranexamic acid’s protective properties.

Beyond merely demonstrating significant reductions in mtDNA release and inflammatory cytokine expression, the study elucidated the potential mechanisms of tranexamic acid’s mitochondrial protection. The drug appears to modulate the mitochondrial permeability transition pore (mPTP), a key channel implicated in mitochondrial swelling and outer membrane rupture during ischemic insults. By inhibiting mPTP opening, tranexamic acid preserves mitochondrial membrane potential, enhances ATP synthesis, and curtails apoptotic signaling pathways, thus fostering cytoprotection within the OGD/R-injured epithelium.

The implications of these findings extend far beyond the gastrointestinal tract, shedding light on a potentially universal protective paradigm applicable to multiple ischemia-reperfusion injury models, including cerebral stroke, myocardial infarction, and acute kidney injury. The research team emphasizes that tranexamic acid’s dual role as both an antifibrinolytic agent and a mitochondrial stabilizer offers an unsurpassed therapeutic versatility, spurring interest in repurposing this clinically accessible drug across diverse pathological domains characterized by ischemia and inflammation.

A particularly intriguing dimension of this study lies in its challenge to conventional perspectives on tranexamic acid, traditionally confined to hemostatic contexts. By unveiling its anti-inflammatory properties mediated through mitochondrial preservation and mtDNA release inhibition, the research expands the pharmacological repertoire of tranexamic acid, sparking a paradigm shift in therapeutic strategies aimed at ameliorating the deleterious sequelae of reperfusion injury.

The researchers caution, however, that despite the compelling in vitro results, translation to clinical settings necessitates further probing through rigorous in vivo studies and randomized controlled trials. Elucidating tranexamic acid’s pharmacokinetics and mitochondrial-targeted mechanisms within live organisms will be pivotal for harnessing its full therapeutic potential. Moreover, understanding the optimal dosing regimens, potential off-target effects, and long-term safety profiles represents vital next steps in the drug’s repurposing journey.

At a cellular signaling level, this study intersects with burgeoning research into the cGAS-STING axis, which senses cytosolic DNA, including mtDNA, initiating interferon-related inflammatory cascades. While the current study centered on TLR9-mediated pathways, future investigations could explore tranexamic acid’s effects on these parallel signaling mechanisms, potentially revealing a broader anti-inflammatory spectrum and offering synergistic therapeutic opportunities.

The burgeoning field of mitochondrial medicine stands at the forefront of this research advancement, highlighting mitochondria not merely as metabolic centers but as critical culprits and targets in cell injury and inflammation. This study places tranexamic acid within this transformative context, positioning it as a novel mitochondrial protector with the capacity to mitigate inflammatory injury via modulation of DAMP release and receptor signaling.

These revelations bear consequential significance for patients suffering from intestinal ischemic conditions such as mesenteric ischemia, inflammatory bowel disease exacerbations, and gastrointestinal graft-versus-host disease, where OGD/R insult and resultant inflammatory vicious circles drive morbidity. Integrating tranexamic acid into therapeutic protocols could ameliorate epithelial barrier dysfunction, reduce systemic inflammation, and potentially improve clinical outcomes in these challenging scenarios.

In summary, this pioneering research unpacks a previously unrecognized dimension of tranexamic acid’s pharmacodynamics, demonstrating its capacity to inhibit mtDNA release and suppress inflammatory responses in an OGD/R-induced in vitro injury model of human intestinal epithelial cells. The strategic targeting of mitochondrial distress and DAMP-mediated inflammation heralds a novel therapeutic avenue with extensive cross-disciplinary applications spanning gastroenterology, neurology, cardiology, and critical care medicine.

As the scientific community digests these insights, the emphasis on mitochondria as therapeutic targets continues to gain momentum. Tranexamic acid’s repositioning offers a compelling testament to the untapped potential residing within established drugs when explored through innovative mechanistic lenses. The convergence of mitochondrial biology, inflammation research, and pharmacology embodied by this study holds promise for future breakthroughs in managing ischemia-reperfusion injury and beyond.

This revelation affirms the centrality of mitochondrial health in maintaining cellular resilience and underscores the importance of anti-inflammatory interventions that extend beyond symptomatic relief to address root causes of cellular demise. Tranexamic acid thus emerges not only as a hemostatic agent but as a molecular sentinel guarding against inflammatory destruction when the cells endure ischemic stress.

Given the global burden of ischemia-associated diseases, these findings propel tranexamic acid into the spotlight as a versatile and promising candidate in the arsenal against mitochondrial and inflammatory dysfunction. The continued exploration of its mechanisms and therapeutic boundaries will undeniably enrich the evolving landscape of molecular medicine and patient care.

Subject of Research: Tranexamic acid’s role in inhibiting mitochondrial DNA release and reducing inflammation in an OGD/R-induced cell injury model.

Article Title: Tranexamic acid inhibits mitochondrial DNA release and reduces inflammatory response in an in vitro model of OGD/R-induced Caco-2 cell injury.

Article References:
Wang, Z., Huo, L., Liu, H. et al. Tranexamic acid inhibits mitochondrial DNA release and reduces inflammatory response in an in vitro model of OGD/R-induced Caco-2 cell injury. BMC Pharmacol Toxicol (2026). https://doi.org/10.1186/s40360-026-01160-w

Image Credits: AI Generated

In the evolving landscape of regenerative medicine, mitochondrial transplantation emerges as a startlingly promising approach. This novel concept involves isolating intact, functional mitochondria and delivering them into cells experiencing mitochondrial insufficiency. Unlike gene or stem cell therapies, mitochondrial transplantation aims to rapidly reconstitute bioenergetics without genetically altering the host cell. However, despite encouraging preliminary findings in animal and cellular models, a fundamental understanding of how transplanted mitochondria interface with recipient cells remains elusive. Do these organelles penetrate the cellular membrane and integrate functionally? If so, through which cellular uptake mechanisms? And critically, can they sustain their bioenergetic roles once internalized?

A landmark study recently addressed these pivotal questions with unprecedented rigor. Led by Associate Professor Kosuke Kusamori at Tokyo University of Science, the research employed mesenchymal stromal cells (MSCs)—a cell type renowned for regenerative potential—as recipients for isolated mitochondria. By amalgamating advanced imaging modalities—including fluorescence microscopy, confocal imaging, flow cytometry, and electron microscopy—with comprehensive biochemical assays, the investigators mapped the trajectory and function of exogenous mitochondria within MSCs. This multifaceted approach allowed precise visualization and quantification of mitochondrial uptake, as well as functional assessments post internalization.

Initial experiments focused on the isolation of mitochondria while preserving their ultrastructure and functional capacity. The mitochondria extracted from MSCs demonstrated high purity, devoid of contaminants such as other cellular organelles or debris. Importantly, these isolated mitochondria retained robust ATP synthesis ability, indicating preserved bioenergetic integrity during the isolation process. Subsequent provision of these mitochondria to living MSCs and hepatocytes yielded remarkable enhancements in cellular health. Notable outcomes included increased cell proliferation rates and improved resistance to oxidative and chemical stressors, reflecting the mitochondria’s cytoprotective effect.

A central question was whether these beneficial effects required actual mitochondrial internalization by recipient cells. Time-course studies revealed a gradual, time-dependent uptake of mitochondria by MSCs, reaching significant intracellular accumulation over several hours. Electron microscopic analysis showcased mitochondria entrapped within membrane-bound vesicles inside the cytoplasm, confirming true internalization rather than superficial adherence. By employing specific pharmacological inhibitors to block clathrin-, caveolin-, CLIC/GEEC-, and actin-mediated endocytic pathways, the research uncovered that MSCs utilize multiple, overlapping mechanisms to engulf transplanted mitochondria. This multiplicity underscores a complex, multifaceted cellular uptake process differing from single-pathway endocytosis found in many other biological processes.

Functional assays corroborated that the internalized mitochondria remained bioenergetically active. MSCs receiving mitochondrial transplants demonstrated enhanced mitochondrial respiration, evaluated by oxygen consumption rate measurements, alongside increased ATP production. These effects displayed a dose-responsive relationship to mitochondrial concentration, emphasizing the therapeutic potential of modulating mitochondrial doses. The enhanced respiratory capacity, coupled with heightened proliferation and stress resistance, suggests that transplanted mitochondria can more than simply survive within host cells—they actively improve cellular metabolic competence.

The elucidation of these uptake pathways and their biological consequences lays a crucial foundation for advancing mitochondrial transplantation from bench to bedside. By harnessing natural endocytic routes, therapeutic protocols can be optimized to maximize mitochondrial delivery efficiency. Such precision could enable tailored approaches adapted to the unique endocytic profiles of different cell types or pathological states. Moreover, confirming that transplanted mitochondria retain functionality challenges previous skepticism regarding their intracellular fate and offers compelling evidence for mitochondrial therapy as a distinct biomedical field.

Currently, mitochondrial transplantation remains in preclinical research, with many regulatory, safety, and efficacy hurdles to overcome. Long-term studies are needed to assess the persistence and integration of transplanted mitochondria, potential immune responses, and effects on tissue homeostasis across diverse disease models. Ensuring the purity, consistency, and biological activity of isolated mitochondria is paramount for clinical translation. Nonetheless, the non-genetic nature of this approach could provide rapid interventions for acute mitochondrial failure, circumventing complexities linked to gene editing or stem cell integration.

The therapeutic applications of mitochondrial transplantation are vast and especially poignant in diseases marked by mitochondrial defects. Ischemia–reperfusion injury following heart attacks or strokes, neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases, and toxin-induced hepatic injury are all promising targets. Furthermore, mitochondrial therapy could revolutionize treatment paradigms in aging—a state intimately linked to mitochondrial decline—and other chronic conditions characterized by compromised cellular energetics.

Ultimately, this innovative research represents a leap forward in regenerative medicine and cellular bioengineering. Dr. Kusamori and his team’s work provides a rigorous scientific blueprint for developing mitochondrial therapy as a novel, precise, and powerful modality to restore cellular energy homeostasis. With continued investigation and refinement, mitochondrial transplantation holds the potential to transform clinical care for a spectrum of debilitating diseases, offering hope for treatments rooted in the restoration of life’s fundamental energy processes.

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Subject of Research: Cells
Article Title: Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells
News Publication Date: 29-Dec-2025
References: DOI: 10.1038/s41598-025-28494-5
Image Credits: Associate Professor Kosuke Kusamori, Tokyo University of Science, Japan
Keywords: Mitochondria, Mesenchymal stromal cells, Mitochondrial transplantation, Cellular bioenergetics, Endocytosis, Regenerative medicine, Oxidative phosphorylation, Cellular respiration, Cell proliferation, Mitochondrial therapy, Neurodegenerative diseases, Mitochondrial dysfunction

Mitochondria, traditionally known as the cell’s “powerhouses,” have long been recognized for their role in generating adenosine triphosphate (ATP), the cellular energy currency. However, emerging research over the past decade has revolutionized this view, highlighting mitochondria’s pivotal roles in immunity and inflammation. The recent study led by JAX Associate Professor Phillip West, published in Nature Communications, reveals how the malfunction of mitochondria at the cellular level hyperactivates the innate immune response through a cascade involving the inflammatory protease caspase-11. This hyperactivation leads to excessive inflammation and consequent tissue injury, particularly during bacterial infections.

At the heart of the investigation is polymerase gamma (PolG) disease, a rare inherited mitochondrial disorder characterized by progressive defects in mitochondrial DNA replication and repair. Using a novel mouse model harboring the same PolG mutations found in affected human patients, the team simulated conditions that closely mirror the human disease state. These genetically engineered mice provided an unprecedented window into the cellular and molecular defects driving immune dysregulation in mitochondrial disease – a subject that has long confounded clinicians and researchers alike.

When these PolG mutant mice were exposed to Pseudomonas aeruginosa, a ubiquitous and opportunistic pathogen notorious for causing severe lung and skin infections especially among hospitalized and immunocompromised individuals, the researchers observed devastating immune responses. Instead of mounting a protective defense, the mutant mice exhibited an overwhelming inflammatory reaction marked by extensive lung tissue damage. This intense inflammation was disproportionate to the bacterial load, signaling that the immune response itself contributed substantially to pathology rather than the pathogen alone.

Delving into the molecular underpinnings of this phenomenon, the scientists identified a continuous baseline activation of type I interferons, a class of cytokines critical for antiviral and antibacterial defense. The chronically elevated interferon signaling in PolG immune cells acted as a primer for the activation of caspase-11, a protease that ordinarily functions as a cytosolic sensor for bacterial lipopolysaccharide (LPS) – a key component of Gram-negative bacterial cell walls. In healthy conditions, caspase-11’s role is to detect invading bacteria and initiate pyroptosis, a form of programmed cell death that limits infection spread. However, in the PolG mice, caspase-11 was excessively active even in the absence of bacterial challenge, setting the stage for runaway inflammation.

This pathological state triggers immune cells, particularly macrophages, to undergo pyroptosis more frequently than normal. The lytic death of these cells releases potent inflammatory mediators that further amplify tissue damage and immune system dysregulation. The researchers vividly describe this phenomenon as the immune cells effectively “self-destructing” and fueling a vicious cycle of inflammation. Importantly, this immune hyperactivation bears striking resemblance to the dysregulated immune responses observed in critical illness contexts such as severe COVID-19, where excessive cytokine storms cause collateral organ injury.

Extending their findings beyond animal models, West and colleagues collaborated with the National Human Genome Research Institute to analyze white blood cells from human patients with various mitochondrial diseases. These cells exhibited a comparable inflammatory signature featuring elevated caspase-11 activity and type I interferon production, suggesting a common underlying mechanism that may exacerbate infection susceptibility across different mitochondrial pathologies. This convergence of murine and human data adds robust translational weight to the study’s conclusions.

The implications of these findings are profound, offering a potential paradigm shift in how mitochondrial disease-related infections might be treated. Traditional approaches that broadly suppress immune function risk leaving patients defenseless against infections. By contrast, selectively targeting the caspase-11 signaling axis could modulate the immune response to mitigate harmful inflammation without compromising host defenses. This nuanced, targeted approach offers hope for developing disease-modifying therapies that address the root cause of immune dysfunction in mitochondrial diseases.

Jordyn Van Portfliet, the study’s lead author, emphasizes the transformative potential of these discoveries: “If we can dial down this hyperactive immune response without shutting down the immune system entirely, it could be a game-changer for patients with mitochondrial disorders.” Such therapeutics, if realized, might not only reduce infection severity but also prevent the often fatal inflammatory cascades that follow bacterial insult in this vulnerable population.

Beyond the immediate clinical relevance for mitochondrial disorder patients, the study highlights broader biological insights. The link between mitochondrial integrity and immune regulation may also illuminate pathways relevant to a spectrum of inflammatory diseases, including neurodegenerative conditions and acute viral syndromes like COVID-19. This intersection of mitochondrial biology and immunology is rapidly emerging as a fertile ground for novel interventions across multiple disciplines of medicine.

The journey to this discovery was bolstered by collaborations with the PolG Foundation, an organization supporting research and patients affected by polymerase gamma disease. Founded by the family of Prince Frederik de Nassau of Luxembourg, who succumbed to complications of PolG disease, the foundation’s support underscores the human significance of this research. It is a poignant reminder of how bench science, patient experience, and advocacy can synergize toward breakthroughs with tangible clinical impact.

In conclusion, this study by West and colleagues marks a significant leap forward in decoding the complex immune dysfunction afflicting patients with mitochondrial diseases. By unveiling caspase-11-driven macrophage hyperinflammation as a key player in PolG-associated pathology, their work opens promising vistas for targeted therapeutics. As the field further explores mitochondrial-immunity dynamics, hopes are high that these insights will translate into life-saving treatments for mitochondrial disease patients and others suffering from inflammatory disorders linked to mitochondrial damage.

Subject of Research: Animals
Article Title: Caspase-11 drives macrophage hyperinflammation in PolG-related mitochondrial disease
News Publication Date: 20-May-2025
Web References:

• https://www.nature.com/articles/s41467-025-59907-8
• http://dx.doi.org/10.1038/s41467-025-59907-8
  References: Included within article citations in text
  Image Credits: The Jackson Laboratory
  Keywords: Diseases and disorders, Genetics, Immunology, Molecular biology