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Dissertation
The role of mitochondrial calcium transport in neurological diseases
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007958
Abstract
Mitochondrial Ca2+ uptake and release are crucial for various neuronal processes, including ATP synthesis, synaptic transmission, neurite outgrowth, and gene regulation. However, excessive mitochondrial Ca2+ accumulation can lead to neuronal toxicity via several mechanisms including the opening of the mitochondrial permeability transition pore (mPTP), mitochondrial depolarization, excessive reactive oxygen species (ROS) production, and release of proapoptotic factors from mitochondria. Hence, excessive accumulation of Ca2+ is proposed to be a major trigger of neuronal damage in numerous neurological diseases. Mitochondrial Ca2+ uniporter (MCU) is a pore-forming subunit and the core component of the mitochondrial Ca2+ uptake complex, which functions as a Ca2+-activated Ca2+ channel in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca2+ uptake. The roles of specific components of MCU in regulating Ca2+ dynamics and controlling brain functions are unclear. In this study, we demonstrate that MCUb knockout (KO) led to enhanced mitochondrial Ca2+ uptake in neurons and exacerbates glutamate-induced Ca2+ deregulation and excitotoxicity. Using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male but not female mice, revealing a sex-dependent role of MCUb in controlling resistance to ischemic stroke. Furthermore, neuron-specific deletion of MCU resulted in a robust anticonvulsant effect in both acute (maximal electroshock seizure threshold) and chronic (pilocarpine-induced status epilepticus) epilepsy models. Histopathological analysis revealed reduced neuronal loss in the CA1 hippocampus and diminished reactive microgliosis in neuron-specific MCU KO mice. Finally, we found that neuron-specific MCU deletion enhanced survival, improved behavioral abnormalities, and alleviated epileptic non-convulsive discharges in PS19 mice, a model of tauopathies. We also observed that neuronal MCU deletion led to a significant reduction in neuronal loss and volume loss in the hippocampus, along with a trend toward decreased reactive microglia in PS19 mice. Collectively, these data indicate that MCU components play a critical role in regulating neuronal Ca2+ dynamics and excitotoxicity, suggesting that targeting MCU could lead to development of novel therapeutics for treating neurological diseases, especially stroke, epilepsy, and tauopathies.
Details
- Title: Subtitle
- The role of mitochondrial calcium transport in neurological diseases
- Creators
- Tam Thi Hong Nguyen
- Contributors
- Yuriy Usachev (Advisor)Georgina Aldridge (Committee Member)Gordon Buchanan (Committee Member)Rory Fisher (Committee Member)Stefan Strack (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007958
- Publisher
- University of Iowa
- Number of pages
- xiv, 144 pages
- Copyright
- Copyright 2024 Tam Thi Hong Nguyen
- Language
- English
- Date submitted
- 01/06/2025
- Description illustrations
- Illustrations, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 115-136).
- Public Abstract (ETD)
Neurological diseases, including stroke, epilepsy and Alzheimer’s disease-related dementia (ADRD), encompass a wide range of conditions that can lead to significant morbidity and mortality. Despite ongoing research, most current treatments have significant limitations: stroke treatments are limited by a narrow therapeutic time window, antiepileptic drugs often fail in one-third of epilepsy patients while carrying notable side effects, and ADRD therapies mainly address symptoms without halting disease progression. These challenges highlight the urgent need to uncover the underlying mechanisms driving these diseases. Ca2+ signaling is essential for cell life and death, and its dysregulation can lead to Ca2+ overload, which is implicated in numerous neurological disorders. In this study, we examine the mitochondrial Ca2+ uniporter (MCU) and its role in regulating Ca2+ levels in neurons and disease progression. We found that deleting a component of the MCU complex, MCUb, increased Ca2+ uptake, exacerbating neuronal damage after injury. Using a mouse model of stroke, we observed that MCUb deletion led to greater brain damage in male mice, but not in females, highlighting sex differences. Additionally, deleting MCU in neurons showed promise in reducing seizures and protecting neurons in models of epilepsy and tauopathies, conditions linked to ADRD. Our findings suggest that the MCU complex is crucial for balancing Ca2+ levels in neurons, and targeting this pathway could lead to new treatments for neurological diseases, including stroke, epilepsy, and ADRD. This research offers exciting possibilities for developing therapies aimed at protecting brain health and improving outcomes for those affected by these conditions.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9984831024102771
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