Advances in Mitochondrial Modulation: How Infrared Light is Changing Brain Injury Recovery
A recent study has spotlighted the transformative role of near-infrared (NIR) light in improving mitochondrial dynamics and quality control, offering new hope for brain injury recovery following cardiac arrest. Dr. Maik Hüttemann, Wayne State University (USA) and active member of the WMS Scientific Board will join Targeting Mitochondria 2024 Congress in Berlin, where he will delve deeper into these findings and discuss the advances in infrared light treatment.
Brain injury remains a significant challenge following cardiac arrest, with mitochondrial dysfunction playing a pivotal role in exacerbating neurological damage. The study investigates how targeting mitochondrial dysfunction with near-infrared light (NIR) wavelengths can mitigate brain injury following cardiac arrest. By employing various models, including isolated porcine brain cytochrome c oxidase (COX), primary mouse neurons, and large animal models, the research provides new insights into NIR-induced mitochondrial modulation.
The research demonstrates that NIR treatment reduces COX activity in an intensity-dependent manner, achieving a controlled modulation of mitochondrial function. This approach results in a moderate reduction of enzyme activity without complete inhibition. Additionally, in neuronal cells, NIR therapy has been shown to decrease mitochondrial swelling and enhance mitophagy, indicating improved mitochondrial health and quality control.
Practical application of NIR therapy has also been investigated. In anesthetized pigs, NIR was found to penetrate deep into the brain with minimal tissue heating, making it a feasible noninvasive treatment option. Moreover, in a model of out-of-hospital cardiac arrest, NIR treatment applied during resuscitation resulted in significantly improved neurological outcomes and reduced brain injury.
The study concludes that NIR effectively modulates mitochondrial function, enhancing mitochondrial dynamics and quality control after ischemia/reperfusion. This noninvasive technique offers promising potential for improving neurological recovery in patients resuscitated from cardiac arrest.
Join Dr. Hüttemann at the Targeting Mitochondria 2024 Congress in Berlin to know more about these findings and explore the future of mitochondria and photomedicine.
Image credits: Wider, J.M., Gruley, E., Morse, P.T. et al. Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest. Crit Care27, 491 (2023).
New Treatment Shows Promise for POLG-Related Mitochondrial Disorders
A clinical trial led by the Research Institute of the McGill University Health Centre (RI-MUHC) has identified Deoxycytidine/Deoxythymidine Combination Therapy as a safe and potentially effective treatment for POLG-related mitochondrial disorders. These disorders cause severe neurological decline, with patients typically surviving only five months after symptom onset. The preliminary results, published in eClinicalMedicine, were largely funded by the Liam Foundation, established after a patient’s diagnosis at the Montreal Children’s Hospital (MCH).
Dr. Kenneth Myers, a pediatric neurologist at MCH, noted, “Our study offers new hope, transforming what was once a death sentence into a chance for a better life. While not a cure, the treatment has significantly improved patients' conditions”.
Understanding the Condition
Mitochondrial diseases, affecting one in 5,000 people, result from dysfunctional mitochondria, the energy-producing parts of cells. In POLG-related disorders, mutations in the POLG gene reduce mitochondrial DNA (mtDNA), leading to seizures, vision loss, muscle issues, nerve damage, developmental delays, and liver failure. The therapy aims to replenish the mtDNA, enhancing mitochondrial function.
After six months, patients showed improved scores on the Newcastle Mitochondrial Disease Scale and lower levels of GDF-15, a marker of mitochondrial dysfunction. Caregivers reported better energy, motor skills, cognition, and communication. No serious side effects were observed.
Dr. Myers highlighted, “Many patients regress dramatically after infections or other triggers. This treatment supplies the mitochondrial DNA they need to function normally.”
Expanding the Trial
The trial included 10 children and adolescents with POLG mutations from the US, Brazil, and India. They received the treatment for six months, with some continuing for 24 months due to significant improvements. Another 14 patients have joined, and a follow-up study on long-term effects is underway.
Liam’s Story: From Despair to Hope
Liam, a ten-year-old with POLG-related mitochondrial disease, began having seizures in 2019. His father, Kevin Reason, started the Liam Foundation after learning about the potential of Deoxycytidine/Deoxythymidine. “Liam is now walking, communicating, and smiling. This treatment gives us hope and vital time to find a cure”, Kevin said.
Liam was the first North American patient in the trial. Thanks to the Liam Foundation and other supporters, 23 more POLG patients have since enrolled.
Bridging In Vitro and In Vivo for Mitochondrial Transplantation in Acute Diseases
Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. Current clinical applications focus on the delivery of autologous mitochondria to limit immune responses and rejection.
A Mitochondrial Transplant Convergent Working Group (CWG) was recently convened to explore three key issues limiting clinical translation:
- Storage of mitochondria
- Biomaterials to enhance mitochondrial uptake
- Dynamic models to mimic the recipient tissue environment
Anna C. Andreazza and her team presented a summary of CWG conclusions related to these three issues and provided an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.
While mitochondrial transplants show promise in animal and early clinical trials, many questions remain. The CWG identified priorities to accelerate progress, including the need for improved storage and delivery of isolated mitochondria, and accurate in vitro models to mimic human tissue complexity.
A research plan was developed to evaluate the stabilization and short-term storage of mitochondria encapsulated in hyaluronic acid, methyl cellulose, and poly(L-lysine). Storing isolated mitochondria enables comprehensive quality control, ensuring healthy and pure transplants, reducing adverse events, and allowing for procedures requiring multiple transplants without repeated isolations.
Organ-on-a-chip models for brain, cardiac, muscle, joint, lung, and liver tissues will be used to evaluate mitochondrial transplants in acute and chronic disease states. This approach allows accurate assessment of clinical applicability and therapeutic mechanisms in vitro, advancing mitochondrial transplant translation across various diseases.
Anna C. Andreazza will be a speaker at the 15th WMS Annual Meeting this October in Berlin. She will discuss advances in mood disorders and mitochondrial-organ transplantation.
Image Credits: Bodenstein, D.F., Siebiger, G., Zhao, Y. et al. Stem Cell Res Ther15, 157 (2024)
Prof. Volkmar Weissig's Interview: Is it time for mitochondria to take centre stage?
It is a great pleasure to announce that the interview of Professor Volkmar Weissig, president of the World Mitochondria Society, has been published in Presciber Journal.
In his interview, Prof. Weissig discusses the profound impact of mitochondrial dysfunction on human health. He highlights a landmark case from the 1950s that first linked malfunctioning mitochondria to human disease, spurring extensive research over subsequent decades.
"There may not be any disease that does not, in one way or another, involve dysfunctional mitochondria".
Prof. Weissig elaborates on the widespread prevalence of primary mitochondrial disorders (PMDs) and the role of dysfunctional mitochondria in common diseases such as diabetes, cardiovascular disease, cancer, and Alzheimer's disease. He emphasizes the critical importance of mitochondria in cellular energy production and their involvement in numerous physiological and pathological processes.
The interview also highlights the historical evolution of mitochondrial research, from their identification as the "powerhouse of the cell" to their recent recognition as crucial players in immunity and cellular signaling. Prof. Weissig shares insights into innovative therapeutic approaches, including gene therapy and mitochondrial transplantation, that hold promise for treating mitochondrial diseases.
This interview sheds light on the essential role of mitochondria in health and disease and highlights ongoing efforts to translate mitochondrial research into clinical therapies, aiming to improve the quality of life for patients with mitochondrial disorders.
Read the full interview: https://doi.org/10.1002/psb.2128.
Mitochondrial DNA: A Key Player in Cell Death and Inflammation
Overview of factors inducing mtDNA release
Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP–AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. This inflammation can engage anti-tumor immunity, offering a potential avenue for cancer therapy.
Stephen W.G. Tait explained that various studies have described mtDNA leakage independent of cell death, triggered by pathogenic infections, changes in mtDNA packaging, mtDNA stress, or reduced mitochondrial clearance. While the interferon response in these scenarios can be beneficial, it may also contribute to disease phenotypes. Understanding the cues and factors inducing mtDNA leakage into the cytosol during cell death and beyond is crucial to purposely promote (e.g., in cancer, infections) or hinder (e.g., mtDNA-associated disease phenotypes) mtDNA release pharmacologically.
During apoptosis, mtDNA is released upon mitochondrial outer membrane permeabilization (MOMP) in caspase-deficient conditions. The cytosolic mtDNA activates the DNA sensor cGAS, inducing an NFκB and type I interferon response, thereby promoting inflammation. Beyond apoptosis, other cues such as mitochondrial stress, mtDNA stress, and pathogenic infections induce mtDNA release through distinct mechanisms, causing inflammation via activation of DNA sensors (cGAS) and receptors (NLRP3, AIM2, or TLR9).
To date, mtDNA release has been observed in a variety of systems and circumstances, resulting in inflammatory gene expression. However, the mechanistic insight into how mtDNA reaches the cytosol and how its recognition is regulated remains ambiguous and requires further research. Moreover, understanding the impact of mtDNA-driven inflammation in health and disease is vital for pharmacological intervention and necessitates in-depth knowledge of the pathway.
Dr. Stephen Tait will present his latest findings on mitochondria and inflammation at the Targeting Mitochondria 2024 conference on October 29-31 in Berlin.
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