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Exploring Age-Related Changes in Mitochondrial Structure and Function

2024-04-22T17:32:17+02:00

Mitochondria, essential organelles with dual membranes, are the energy powerhouses of cells. Their inner membrane folds, known as cristae, are crucial for enhancing the organelle’s energy production capabilities.

While oxidative stress is a natural byproduct of mitochondrial activity, excessive stress can lead to dysfunction, aging, and diseases. The structural and functional changes in mitochondria vary significantly across different tissues.

The study, published in Advanced Biology, revealed that while overall mitochondrial size increases with age, the surface area, volume, and complexity of cristae decrease, which affects thermogenic capacity and overall metabolic health.

Changes in Cristae and Mitochondrial Structure

The study discovered that while the overall size of mitochondria increases with age, the surface area, volume, and complexity of cristae diminish. This structural change impacts the mitochondria's efficiency and functionality in energy production.

Influence on Thermogenic Capacity

Mitochondrial shape was found to significantly affect the thermogenic capability of brown adipose tissue (BAT). Round or spherical mitochondria were associated with higher thermogenic function, whereas elongated mitochondria showed reduced thermogenic capacity and were more common in older subjects.

Future Perspectives

- Exploration of Sex-Dependent Differences: The research team plans to investigate whether there are differences in mitochondrial structure and function that are dependent on sex as individuals age.
- Broader Implications for Aging and Metabolic Health: By studying mitochondrial structure across different tissues and species, the team hopes to gain a deeper understanding of aging mechanisms and identify potential therapeutic targets for treating age-related ailments and mitochondrial dysfunctions.

Stay tuned for Targeting Mitochondria 2024 this October for more updates mitochondria reseacrh and aging.

Read the full paper.

HDL-C and Ferritin: Key Metabolic Indicators of Long COVID-19 Severity Revealed, Opening New Avenues for Treatment Strategies

2024-04-15T16:24:57+02:00

Study reveals HDL-C and ferritin as crucial markers for long COVID-19 severity, leading to novel treatment strategies.

Long COVID-19, or post-acute sequelae of SARS-CoV-2 infection (PASC), is a global health phenomenon characterized by persistent symptoms following the acute phase of COVID-19. Affecting millions worldwide, it leads to sustained healthcare needs and impacts workforce participation due to symptoms such as fatigue and cognitive impairments. The condition highlights the necessity for ongoing research, healthcare system adjustments, and the formulation of targeted treatments to address its prolonged effects on individuals and economies.

A recently published study in Clinics Journal (Elsevier) has shed light on significant metabolic changes in non-vaccinated individuals with Long COVID-19, offering key insights into disease severity. This study was led by Marvin Edeas, MD, PhD, Université de Paris, Institut Cochin, INSERM 1016, France, and a team of international researchers led by Jumana Saleh, PhD, Sultan Qaboos University Hospital, Oman.

Published under the title “Reduced HDL-cholesterol in Long COVID-19: A Key Metabolic Risk Factor Tied to Disease Severity”, the study examined 88 patients across varying degrees of initial disease severity (mild, moderate, and severe) compared to a control group comprising 29 healthy individuals.

Findings from the controlled study revealed major metabolic shifts, particularly a substantial reduction in HDL-cholesterol (HDL-C) levels, coupled with a twofold increase in ferritin levels and insulin resistance among severe Long COVID-19 cases, compared to milder cases and the control group. These metabolic markers emerged as leading predictors of disease severity, offering novel understandings of Long COVID-19 management and treatment.

Marvin Edeas explained, “Our research has, for the first time, established a direct correlation between HDL-C and ferritin levels and the severity of Long COVID-19. The decline in HDL-C levels and the rise in ferritin levels observed in patients, influenced by the severity of the initial infection, could potentially play a role in the persistence and progression of Long COVID-19 symptoms”. This study is critical in understanding Long COVID-19 and its long-term impacts on metabolic health.

The research findings suggest that HDL-C and ferritin levels could serve as crucial markers and therapeutic targets, opening new avenues for treatment strategies aimed at mitigating the long-term effects of the disease. By considering these metabolic markers, we can shape preventive strategies and significantly mitigate the long-term impacts of COVID-19 on patients’ health.

The Function of HDL-C in Immune Response Modulation

The observed correlation between diminished levels of HDL-cholesterol (HDL-C), the severity of COVID-19, and its prolonged course might be explained by HDL-C's function as a modulator of the immune response. This includes its roles as an anti-inflammatory, antioxidant, and antiatherogenic agent, particularly vital during the heightened inflammatory response triggered by the virus. Investigating HDL-C’s utility beyond its conventional role in cholesterol transport is crucial for a comprehensive understanding of COVID-19 and its secondary health effects, such as long-COVID.

Implications of Lipid Remodeling During SARS-CoV-2 Infection

Extensive research indicates that COVID-19 precipitates notable shifts in the host's lipid metabolism, leading to the accumulation of cellular lipid reserves. These alterations aid in the viral takeover of host cellular mechanisms, thus facilitating the progression of the infection. This theory gains support from laboratory evidence showing the cessation of viral replication upon the administration of small molecule lipid inhibitors, highlighting the critical dependence of the virus on host lipid resources for replication.

The Interrelation of Iron Dysregulation, HDL-C, and Ferroptosis in COVID-19

A notable aspect of the interplay between HDL-C functionality and iron homeostasis is the process of ferroptosis, induced by lipid peroxidation and disturbed iron balance, characterized by the buildup of iron and products of lipid oxidation. This leads to diminished antioxidant defense capabilities. HDL-C is influential in mitigating the detrimental effects associated with ferroptosis, underscoring the significance of maintaining balanced iron levels in COVID-19 management.

"Our findings highlight the exacerbating effect of impaired iron regulation on COVID-19 progression, further complicated by the disrupted protective functions of HDL-C", stated Jumana Saleh.

The Dynamic Competition Between Host Metabolic Processes and Viral Interference

The outcome of the "war", between the host's metabolic defenses and viral invasion strategies, axes on the control over iron and lipid resources. The virus strategically targets these metabolic reserves to support its replication and spread. For Marvin Edeas, this battle underscores the complex interaction between host metabolic pathways and viral mechanisms, emphasizing the strategic importance of iron and lipid regulation in determining the course and outcome of COVID-19 infection.

Marvin Edeas, Founder of the WMS

How does the strategic alteration of iron and HDL-C levels by a virus contribute to its underlying aim of targeting mitochondria to disrupt host defense mechanisms?

Marvin Edeas commented on the perspective of this study.

"In the intricate dance of viral infection, the virus employs a calculated strategy aimed directly at the heart of the host's cellular energy and defense systems — the mitochondria. By subtly manipulating and altering the host's iron metabolism and HDL-C levels, the virus orchestrates a multifaceted attack designed to undermine mitochondrial integrity and function. This strategic disruption serves to weaken the mitochondria, a crucial step in the virus's broader aim to compromise the host's ability to mount an effective defense. Through this sophisticated mechanism of action, the virus ensures its survival and proliferation within the host, highlighting the importance of understanding these viral tactics for the development of targeted therapeutic interventions".

The implications of this study are broad, providing a new understanding of Long COVID-19’s impact on metabolic health and laying the foundation for future research and therapeutic interventions aimed at improving patient outcomes.

Paper DOI.

Photo Credits: Freepik.

Transforming Transplantation: Real-Time Monitoring of Mitochondrial Health During Organ Perfusion

2024-03-29T12:01:31+01:00

A recent study published in Nature Scientific Reports journal addressed a significant challenge in the field of organ transplantation – ischemia reperfusion injury (IRI) – which can lead to post-transplantation complications and limit the use of organs from extended criteria donors.

Resonance Raman Spectroscopy predicts functional oxygenation of liver tissue during machine perfusion. Credits: Rohil Jain et al., 2024

A team of researchers from Harvard Medical School, Massachusetts General Hospital and Shriners Children’s Hospital in the USA has developed a novel, real-time, and non-invasive method to assess organ quality during machine perfusion. This innovative approach focuses on mitochondrial function and injury, using resonance Raman spectroscopy to quantify the oxidation state of mitochondrial cytochromes during perfusion.

The new technique, known as the index of mitochondrial oxidation or 3RMR, was employed to study the differences in mitochondrial recovery of cold ischemic rodent livers during machine perfusion at normothermic temperatures. The study compared acellular and cellular-based perfusates to understand their impact on organ quality.

The findings revealed that, following 24 hours of static cold storage, the 3RMR returned to baseline faster with a cellular-based perfusate. However, the 3RMR progressively increased during perfusion, indicating that injury may develop over time. These insights underscore the need for further refinement of reoxygenation strategies during normothermic machine perfusion, taking into account cold ischemia durations, gradual recovery/rewarming, and the risk of hemolysis.

These findings highlight an improved organ assessment during machine perfusion, ultimately enhancing transplantation outcomes and expanding the pool of viable organs for those in need.

Stay tuned for Targeting Mitochondria 2024 this October for more updates mitochondria and the future of organ transplantation.

Read the full paper.

Mitochondria and Powering the Mind: Secrets of Synaptic Energy with VAP

2024-03-21T13:42:54+01:00

VAP spatially stabilizes mitochondria to locally support synaptic plasticity.

WMS Analysis

The study highlights the essential role of VAP (vesicle-associated membrane protein-associated protein) in synaptic plasticity by stabilizing mitochondria near synapses through cytoskeletal tethering. VAP's ability to maintain mitochondrial stability is crucial for meeting the high energy demands of synaptic activity, facilitating memory formation and learning. This stabilization not only supports the immediate demands of synaptic plasticity but also acts as a determinant for the spatial extent of dendritic segments involved in these processes. The implications of these findings extend to understanding the mechanisms underlying neurodegenerative diseases like ALS, where disruptions in mitochondrial stability at synapses could contribute to disease pathology. Essentially, the research underscores the critical interplay between mitochondrial stability, synaptic plasticity, and the potential for targeted therapies in neurodegenerative diseases.

About the study

The study investigates the crucial role of synapses in plasticity and memory formation, highlighting that synapses, being energy consumption hotspots, depend on local energy supplies provided by mitochondria. These mitochondria are stabilized near synapses by the cytoskeleton, a necessary arrangement for supporting synaptic plasticity. The research identifies proteins that exclusively tether mitochondria to the actin near postsynaptic spines, with a focus on VAP (vesicle-associated membrane protein-associated protein), known for its implications in amyotrophic lateral sclerosis (ALS). VAP is shown to stabilize mitochondria via actin near the spines, playing a vital role in maintaining mitochondrial compartments that locally support synaptic plasticity.

The study elaborates on the necessity of local energy sources for synapses, given their distance from the neuron's cell body and high energy demands. It was previously established that mitochondria form temporally and spatially stable compartments by tethering to the cytoskeleton, which are crucial for fueling synaptic plasticity. However, the mechanisms enabling these stable mitochondrial compartments in dendrites were not fully understood.

This research provides significant insights by identifying the role of VAP in stabilizing dendritic mitochondria, ensuring their function during long durations of synaptic plasticity formation and maintenance. VAP's unique role includes acting as a spatial stabilizer and a ruler, determining the extent of dendritic segments supported during synaptic plasticity, crucial for clustered synaptic plasticity related to learning and development.

Furthermore, the study underscores the broader implications of mitochondrial dysfunction in neurodegenerative diseases like Alzheimer's, Parkinson's Disease (PD), and ALS. By leveraging advances in proteomic labeling and high-resolution imaging techniques, the research delineates the mechanisms dictating the spatial organization of dendritic mitochondria and their pivotal role in sustaining synaptic plasticity. The findings emphasize VAP's distinct role in spatially stabilizing mitochondria in dendrites, influencing both the formation and maintenance of synaptic plasticity and potentially offering new avenues for understanding and treating neurodegenerative diseases.

Article DOI.

Photo Credits: Bapat, O., Purimetla, T., Kruessel, S. et al. Nat Commun15, 205 (2024).

Mitochondrial Dynamics Crucial in Determining Muscle Fiber Type, Study Finds

2024-03-20T12:02:00+01:00

In a recent study published in Cell Reports, researchers led by Naotada Ishihara from Osaka University, Japan, shed light on the intricate relationship between mitochondrial dynamics and muscle fiber type differentiation.

The study uncovered that the loss of mitochondrial fission, a process controlled by dynamin-related protein 1 (Drp1), specifically hampers the differentiation of fast-twitch muscle fibers. This finding challenges previous notions, emphasizing the pivotal role of mitochondrial dynamics in shaping muscle composition post-birth.

By depleting Drp1 in both mouse skeletal muscle and cultured myotubes, the researchers observed a distinct reduction in fast-twitch fibers, independent of respiratory function. This shift in fiber type was accompanied by the activation of the Akt/mammalian target of rapamycin (mTOR) pathway, facilitated by the accumulation of mTOR complex 2 (mTORC2) on elongated and bulb-like mitochondria.

Excitingly, intervention through rapamycin administration effectively rescued the decline in fast-twitch fibers both in vivo and in vitro, highlighting the potential for targeted therapies in muscle-related disorders.

Furthermore, the study identified the upregulation of growth differentiation factor 15 (GDF-15), a mitochondria-related cytokine, under Akt/mTOR activation. This upregulation, in turn, suppressed the differentiation of fast-twitch fibers, unraveling a previously unknown regulatory mechanism in muscle development.

Overall, these findings elucidate the critical role of mitochondrial dynamics in activating mTORC2 on mitochondria, ultimately dictating the differentiation of muscle fibers. The study not only enhances our understanding of muscle biology but also unveils potential avenues for therapeutic interventions in muscle-related pathologies.

Article DOI.

The Secrets of Aging: Mitochondrial DNA Release and Cellular Senescence

2024-03-01T15:39:15+01:00

A recent National Institute of Aging funded study, published in Nature on February 29, 2024, reveals that mitochondrial DNA (mtDNA) release is a key factor in cellular senescence and inflammation in mice. This process contributes to the aging-related dysfunction and disorders by activating changes in senescent cells. When this leakage of mtDNA is inhibited in aged mice, there's a noticeable reduction in inflammation, an improvement in bone health, and a decrease in overall frailty. The study highlights apoptosis and the process of widespread mitochondrial outer membrane permeabilization (MOMP) as essential in this context. It demonstrates how mtDNA released during MOMP triggers changes leading to cell death and immune clearance.

The research, led by the Mayo Clinic, identifies the escape of aging cells from apoptosis, which leads to their accumulation and harmful effects on neighboring cells and tissues through the senescence-associated secretory phenotype (SASP). By examining the role of mitochondria in senescence and SASP, it was discovered that inhibiting mtDNA release could suppress these aging effects. Treating old mice with compounds that prevent mitochondrial pore formation resulted in reduced brain inflammation and improved musculoskeletal health.

These findings offer new insights into mitochondrial function in cellular aging and suggest potential therapeutic strategies for mitigating age-related conditions. Further investigation is required to understand these mechanisms in humans and explore the therapeutic potential of inhibiting mtDNA release in senescent cells.

This hot topic will be a subject of discussion at the upcoming World Mitochondrial Society (WMS) meeting in Berlin, where experts will discuss the implications of mitochondrial DNA release on aging and potential interventions.

Article DOI.

Image Credits: NIH, National Institute on Aging.

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Revolutionizing Cancer Treatment: Enhancing Immune Response through Mitochondrial Manipulation

2024-02-28T16:43:31+01:00

In a study published in Science, researchers led by Kailash Chandra Mangalhara and Gerald S. Shadel explored a groundbreaking approach to boosting the body's immune response against cancer by tweaking how mitochondria in cancer cells handle energy. They focused on a part of the cell's power plant called the mitochondrial electron transport chain (ETC), which is crucial for powering immune cells to fight off invaders. By adjusting the flow of electrons within the mitochondria of cancer cells, specifically through a segment known as complex I, the team found a way to increase the levels of a molecule called succinate. This, in turn, activated important immune system genes in the cancer cells, making them more visible and vulnerable to attack by the body's T cells.

This discovery is significant because it sidesteps the need for interferon-gamma, a common but sometimes problematic component in cancer immunotherapy. Instead, the method relies on a more direct modulation of cancer cell properties to stimulate an immune attack. Specifically, by altering a regulatory protein within the mitochondria, the researchers could enhance the immune system's ability to detect and destroy melanoma cells without adversely affecting noncancerous cells. This strategy opens new avenues for treating cancers that have become adept at evading the immune system, potentially offering a more targeted and less side-effect-prone therapy option.

Article DOI.

Non-Invasive Photobiomodulation Therapies for Diabetes Management and Complication Reduction

2024-02-22T11:40:30+01:00

The WMS wish to highlight 2 excellent studies just published by 2 different teams.

Recent studies have highlighted the potential of photobiomodulation (PBM) and transcranial photobiomodulation (tPBM) as non-invasive therapeutic interventions for diabetes management and the mitigation of its complications. These innovative approaches focus on improving mitochondrial function, insulin therapy outcomes, and systemic metabolic health through light-based stimulation.

Key Findings

1. Blood Glucose Management via PBM
Research by Michael B. Powner and Glen Jeffery demonstrates that PBM with 670 nm light significantly reduces blood glucose levels following glucose intake, by enhancing mitochondrial functions and potentially increasing glucose demand. This method showed a notable decrease in blood glucose spikes, offering a new avenue for managing post-meal blood glucose fluctuations.

2. tPBM's Role in Microglial Function and Diabetic Complications
A study by Shaojun Liu, Dongyu Li, et al., explored tPBM's effectiveness in improving microglial morphology and reactivity in diabetic mice. The treatment was found to stimulate the brain's drainage system, enhance energy expenditure, and improve locomotor activity, suggesting tPBM as an effective method for treating microglial dysfunction and potentially preventing diabetic physiological disorders.

3. Broad Therapeutic Effects of tPBM
Additional research supports tPBM's beneficial effects on various diabetic complications, including diabetic foot, periodontitis, and retinopathy. tPBM has also been shown to improve insulin sensitivity and metabolic disorders in adipocytes and high-fat diet-induced mice. The underlying mechanisms involve the activation of cytochrome c oxidase-mediated protein kinase B, leading to increased mitochondrial ATP and ROS generation, lipid consumption, glucose absorption, and glycogen accumulation.

Conclusion

The integration of PBM and tPBM into diabetes management strategies offers a promising outlook for both controlling blood glucose levels and addressing a spectrum of diabetic complications. These non-invasive therapies not only provide a novel approach to enhancing metabolic health but also contribute to the broader effort of improving quality of life for individuals with diabetes. The evidence suggests that further exploration and clinical trials could solidify the role of photobiomodulation therapies in diabetes care protocols, potentially revolutionizing treatment methodologies with their systemic benefits and minimal side effects.

The mitochondria continue to astonish us.

References

1. Powner, M.B., & Jeffery, G. (2024). Light stimulation of mitochondria reduces blood glucose levels. Journal of Biophotonics, 10.1002/jbio.202300521.

2. Liu, S., Li, D., ... Zhu, D. (2023). Transcranial photobiomodulation improves insulin therapy in diabetic microglial reactivity and the brain drainage system. Communications Biology, 6, Article number: 1239.

Photo Credits:

Powner, M.B., & Jeffery, G. (2024).

Intranasal Delivery of Mitochondria-Targeted Neuroprotective Drugs: A New Approach for Treating Traumatic Brain Injury

2024-02-20T11:17:33+01:00

Researchers led by Jignesh D. Pandya, have identified a promising method for delivering neuroprotective drugs directly to the brain for treating traumatic brain injury (TBI) through intranasal administration, bypassing the blood-brain barrier (BBB).

This non-invasive approach enhances drug bioavailability, reduces the need for high doses, and minimizes adverse side effects.

Focusing on compounds targeted at mitochondria—key regulators of cell death and damage following TBI—the study reviews the advantages of intranasal delivery over traditional methods.

It highlights successful applications in animal models, such as reducing stroke damage and reversing Alzheimer’s symptoms, and outlines the screening of compounds based on pharmacological properties for intranasal use.

This innovative strategy could significantly impact the treatment of TBI, especially in military settings, by offering a rapid, effective, and field-applicable method to counteract the progression of TBI pathogenesis.

Image Description:

Schematic representation of key aspects of intranasal delivery of neuroprotection compounds to the brain. TBI is difficult to treat as most therapeutic agents (98%) cannot reach in the brain, mainly due to the selective permeability of the blood–brain barrier (BBB). The olfactory and trigeminal nerves can serve as direct nose-to-brain routes that bypass the BBB that can impede absorption of most CNS targeted compounds, resulting in higher bioavailability. In addition, compared to traditional routes, the nasal administration of drugs can direct the rapid CNS absorption to brain tissues, thereby circumventing the hepatic first-pass metabolism and gastric degradation and allowing fast onset of pharmacological action.

Article DOI.

Image Credits: Pandya, J.D., Musyaju, S., Modi, H.R. et al. J Transl Med22, 167 (2024).

The Role of Mitochondria in Zika Virus Propagation & Immune Evasion

2024-02-07T17:14:32+01:00

The World Mitochondria Society is beginning to outline the agenda for their annual meeting, with a spotlight on groundbreaking research. One notable study to be discussed is the discovery of how the Zika Virus NS1 protein promotes the formation of tunneling nanotubes, which facilitate mitochondrial transfer. This insight not only enhances our understanding of viral behavior but also underscores the complex role of mitochondria in cellular communication and pathogenesis. Such findings could pave the way for innovative treatments and preventive strategies for viral infections, emphasizing the mitochondria's pivotal role in health and disease.

The Zika virus (ZIKV) remains a significant public health challenge, withits unique capability for vertical transmission and association withcongenital abnormalities. Despite various studies, the strategies employedby ZIKV to spread and evade the immune system have only been partiallyunderstood. Recent investigations have unveiled a novel role of ZIKVnon-structural protein 1 (NS1) in enhancing viral propagation and survival,specifically through the induction of tunneling nanotubes (TNTs) formitochondrial transfer among host cells, including placental trophoblasts.

This study identifies that ZIKV uniquely prompts the formation of TNTs inhost cells, a capability not shared with other flaviviruses. This process,driven by the viral NS1 protein and its N-terminal region, facilitates theintercellular transfer of not just viral components but also mitochondria.The transfer of mitochondria via TNTs plays a crucial role in not onlyproviding the energy needed for viral replication but also in evading thehost's immune response. Infected cells receiving mitochondria through TNTsshow a reduced interferon response, indicating a sophisticated mechanism ofimmune evasion by ZIKV.

The uncovering of this previously unrecognized mechanism underscores the sophisticated strategies employed by ZIKV to manipulate host cell structures and evade immune responses. The pivotal role of NS1 in ZIKV's lifecycle opens up new avenues for therapeutic interventions targeting the virus's reliance on host mitochondria for propagation and immune evasion. This study highlights the complexity of ZIKV-host interactions and the central role of mitochondria in viral pathogenesis.

To mitigate ZIKV infection, strategies could focus on inhibiting TNTformation or disrupting the interaction between NS1 and mitochondria.Further research is needed to develop inhibitors targeting these specificmechanisms without adversely affecting host cell functions. Enhancing themitochondrial antiviral signaling pathway represents another potentialstrategy against ZIKV infection. The ongoing development of vaccines andspecific antiviral treatments will be crucial in preventing the spread ofZIKV and its associated health impacts.

Article DOI: 10.21203/rs.3.rs-3674059/v1
Image copyrirght: © Felix Hol/Blaise Daures.