Mitochondria and Powering the Mind: Secrets of Synaptic Energy with VAP
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.
Photo Credits: Bapat, O., Purimetla, T., Kruessel, S. et al. Nat Commun15, 205 (2024).
Mitochondrial Dynamics Crucial in Determining Muscle Fiber Type, Study Finds
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.
Revolutionizing Cancer Treatment: Enhancing Immune Response through Mitochondrial Manipulation
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.
© News Copyright: World Mitochondria Society (WMS)
The Secrets of Aging: Mitochondrial DNA Release and Cellular Senescence
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.
Image Credits: NIH, National Institute on Aging.
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Non-Invasive Photobiomodulation Therapies for Diabetes Management and Complication Reduction
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).
© News Copyright: World Mitochondria Society (WMS)
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