Han-A Park

Han-A Park
Yale University | YU · Department of Internal Medicine

Ph.D.

About

60
Publications
3,657
Reads
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1,075
Citations
Additional affiliations
August 2017 - March 2021
University of Alabama
Position
  • Professor (Assistant)
May 2011 - January 2017
Yale University
Position
  • PostDoc Position
Education
September 2004 - December 2010
The Ohio State University
Field of study
  • Human Nutrition

Publications

Publications (60)
Article
Full-text available
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rod...
Article
Full-text available
Aims: B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth and synapse formation are indispensable for neuronal survival in development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes in...
Article
Full-text available
α-Tocotrienol (TCT) represents the most potent neuroprotective form of natural vitamin E that is Generally Recognized As Safe certified by the U.S. Food and Drug Administration. This work addresses a novel molecular mechanism by which α-TCT may be protective against stroke in vivo. Elevation of intracellular oxidized glutathione (GSSG) triggers neu...
Article
Full-text available
Oxidized glutathione (GSSG) is commonly viewed as a byproduct of GSH metabolism. The pathophysiological significance of GSSG per se remains poorly understood. Adopting a microinjection approach to isolate GSSG elevation within the cell, this work identifies that GSSG can trigger neural HT4 cell death via a 12-lipoxygenase (12-Lox)-dependent mechani...
Preprint
Whole exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the TNK2 gene. Although TNK2 encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specifi...
Article
Objectives Oxidative stress plays an important role in neuronal loss associated with mitochondrial dysfunction. Excess reactive oxygen species (ROS) production damages mitochondria, impairing neuronal energy metabolism. The damaged mitochondria promote aberrant ROS production leading to neuronal death. Fucoxanthin, a carotenoid with antioxidant pro...
Article
Objectives Alpha-tocotrienol (α-TCT), a form of vitamin E, is a lipophilic antioxidant with neuroprotective properties. We recently reported that α-TCT treatment prevents oxidative stress-induced proteolytic cleavage of B-cell lymphoma-extra large (Bcl-xL), a pro-survival mitochondrial protein necessary during neuronal growth. However, it is still...
Article
Objectives During the initial wave of the COVID-19 pandemic, older adults were identified as a vulnerable population at high risk for severe illness and mortality. However, symptoms of infection varied widely among adults younger than 50 years old. While some younger adults experienced severe illness, as many as 40% of infected persons remained asy...
Article
Objectives Neurite branching is necessary to achieve neurite complexity and synaptic plasticity. Therefore, understanding how neurons utilize intracellular energy to support neurite branching is key to elucidating cellular mechanisms of neuronal development. B-cell lymphoma extra large (Bcl-xL) is a pro-survival protein found in the mitochondria. T...
Article
Full-text available
Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochond...
Article
Alpha-tocotrienol (α-TCT) is a member of the vitamin E family. It has been reported to protect the brain against various pathologies including cerebral ischemia and neurodegeneration. However, it is still unclear if α-TCT exhibits beneficial effects during brain development. We hypothesized that treatment with α-TCT improves intracellular redox hom...
Article
Full-text available
Mitochondrial ATP synthase is vital not only for cellular energy production but also for energy dissipation and cell death. ATP synthase c-ring was suggested to house the leak channel of mitochondrial permeability transition (mPT), which activates during excitotoxic ischemic insult. In this present study, we purified human c-ring from both eukaryot...
Article
Full-text available
B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial protein known to inhibit mitochondria-dependent intrinsic apoptotic pathways. An increasing number of studies have demonstrated that Bcl-xL is critical in regulating neuronal energy metabolism and has a protective role in pathologies associated with an energy deficit. However, it is less known...
Article
Objectives B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria and is also reported to support brain function by enhancing neuronal energy metabolism and synapse formation. We have previously shown that Bcl-xL is required for neurite outgrowth, and neurons lacking Bcl-xL were susceptible against neurotoxic chall...
Article
Objectives Neurite outgrowth and branching is critical during neuronal development. Failure to achieve proper neurite complexity is highly associated with developmental disorders. We have previously shown that oxidative stress contributes to alteration of neurite morphology. Therefore, nutrients capable of regulating neuronal redox balance may help...
Article
Objectives The F1Fo ATP synthase is a multienzyme complex that produces mitochondrial ATP. Aberrant expression or assembly of F1Fo ATP synthase subunits leads to alterations in energy metabolism. We recently found that breast cancer cells exposed to fluid shear stress (FSS) have significantly enhanced metastatic behavior including chemoresistance a...
Article
Objectives Neurite outgrowth is a foundational process in brain development and recovery from brain injury. Assembly of the cytoskeleton and formation of new synapses during neurite outgrowth requires an abundance of energy. We have reported that the mitochondrial protein Bcl-xL is necessary for neurite outgrowth and arborization. However, Bcl-xL u...
Article
Reactive oxygen species (ROS) are a major contributor to intracellular organelle damage in neurons. ROS-induced mitochondrial dysfunction is highly associated with impaired energy metabolism that occurs during neurodegeneration. Therefore, the use of antioxidants may be beneficial in protecting the brain from injury caused by ROS. Lycopene is a car...
Article
Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane. Bcl-xL supports growth, development, and maturation of neurons, and it also prevents neuronal death during neurotoxic stimulation. This article reviews the mechanisms and upstream signaling that regulate the activity and abundance of Bcl-xL. Our team and others...
Article
Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1−/y mouse have a mitochondrial inner membrane leak contributing to a “leak metabolism.” In human Fragile X syndrome (FXS) fibroblasts and in Fmr1−/y mouse neurons, closure of th...
Article
Full-text available
Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approa...
Article
Full-text available
Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die i...
Article
Full-text available
Parkinson’s disease (PD) is a neurodegenerative disorder caused by the depletion of dopaminergic neurons in the basal ganglia, the movement center of the brain. Approximately 60,000 people are diagnosed with PD in the United States each year. Although the direct cause of PD can vary, accumulation of oxidative stress-induced neuronal damage due to i...
Article
Objectives Fluid sheer stress (FSS) is a physical stimuli of circulating tumor cells responsible for development of and progression to cancer. FSS is reported to enhance chemoresistance and proliferation in breast cancer cells. However, cellular mechanisms explaining how FSS contributes to the metastatic phenotype of breast cancer cell are less kno...
Article
Objectives Neurite outgrowth is a pivotal process of brain development and recovery after brain injury. This metabolically demanding process requires assembly of the cytoskeleton and formation and maintenance of synapses. We have recently found that treatment with alpha-tocotrienol, an antioxidant and a member of the vitamin E family, prevents loss...
Article
Full-text available
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunctio...
Chapter
Full-text available
The brain requires vast amounts of energy to carry out neurotransmission; indeed, it is responsible for approximately one-fifth of the body’s energy consumption. Therefore, in order to understand functions of brain cells under both normal and pathological conditions, it is critical to elucidate dynamics of intracellular energy. The mitochondrion is...
Article
Full-text available
Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F1FO ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial...
Article
Objectives: B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria. Bcl-xL is reported to support brain function by enhancing neuronal energy metabolism, synapse formation, and neurite outgrowth. However, under exposure to excitotoxic stimulation and subsequent oxidative stress, Bcl-xL undergoes caspase dependent...
Article
Objectives: B-cell lymphoma-extra large (Bcl-xL) is a protein found in the mitochondrial membrane with anti-apoptotic properties. Bcl-xL has demonstrated neuroprotective effects by enhancing mitochondrial function. However, during oxidative stress, Bcl-xL undergoes cleavage to form pro-cell death ∆N-Bcl-xL. Accumulation of ∆N-Bcl-xL causes abnorma...
Article
Full-text available
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic Bcl-2 protein found in the mitochondrial membrane. Bcl-xL is reported to support normal brain development and protects neurons against toxic stimulation during pathological process via its roles in regulation of mitochondrial functions. Despite promising evidence showing neuroprotective prop...
Article
Full-text available
The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore,...
Chapter
Full-text available
Synaptic plasticity is a process by which neurons adapt or alter the strength of information transfer, and it is known to play a role in memory formation, learning, and recovery after injury. In this chapter, we describe how ischemic insults alter neuronal intracellular mechanisms and signaling pathways, and we discuss how, after neuronal injury, s...
Chapter
Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for ATP production by mitochondria, recent findings have confirmed that the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the m...
Article
The mitochondrial permeabilty transition (mPT) is believed to be a major cell death pathway during neurodegenerative diseases, traumatic brain injury and stroke. Excessive release of the excitatory neurotransmitter glutamate in the brain triggers intracellular Ca+2 overload and leads to the opening of the mitochondrial permability transition pore (...
Article
Full-text available
Mitochondria play a central role in ageing, cardiac disease, cell death and cancer. Different pro-death signals lead to the permeabilization of the outer and inner mitochondrial membranes. Permeabilization of the inner mitochondrial membrane is facilitated by the mitochondrial permeability transition pore (mPTP), which is a key player in activation...
Conference Paper
ABT-737 is a pharmacological inhibitor of the anti-apoptotic Bcl-2 family protein, Bcl-xL. ABT-737 occupies the BH3-binding domain, supporting apoptosis of cancer cells. We have shown that ABT-737 lowers neuronal metabolic efficiency by inhibiting ATP synthase activity. However, we unexpectedly found that ABT-737 protects brains from ischemic injur...
Article
This protocol comprises the entire process of fluorescent measurement of vesicle recycling using the probe SynaptopHluorin, a pH-dependent GFP variant whose fluorescence increases at the synapse upon vesicle release due to fluorescence quenching in acidic vesicles. This technique provides a genetic tool to monitor synaptic vesicle recycling in real...
Article
Full-text available
Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca2+) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity...
Article
Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cell Ca2+ dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction and cell death. The molecular identity of the mitochon...
Chapter
Delivery of substances of endogenous or foreign origin into a cell represents a powerful approach to query molecular cell biology. For the delivery of genes and proteins there are a wide variety of physical and chemical approaches that are commonly used. These approaches are frequently harsh to the cell and perturb biological responses. Furthermore...
Article
Full-text available
Hemangioendotheliomas are classified as endothelial cell tumors, which are the most common soft tissue tumors in infants. In a murine model of hemangioendothelioma, we previously showed that MCP-1 is required for its development and that the expression of MCP-1 in EOMA cells is redox sensitive. Here, we sought to identify the source of oxidants tha...
Data
Figure S1 Left panel: HT4 cell lysates (20μg) were incubated with GSSG (10 mM) for 1h and subjected to SDS-PAGE under either reducing or non-reducing condition for the detection of formation of protein-glutathione mixed disulfides (glutathionylation). Cells incubated with GSSG under non-reducing condition were rich in glutathionylated proteins. Sam...
Article
Full-text available
A demethylated derivative of curcumin (DC; 67.8% bisdemethylcurcumin, 20.7% demethylmonodemethoxycurcumin, 5.86% bisdemethoxycurcumin, 2.58% demethylcurcumin) was prepared by using a 95% extract of curcumin (C(95); 72.2% curcumin, 18.8% monodemethoxycurcumin, 4.5% bisdemethoxycurcumin). DC increased glutathione and reduced reactive oxygen species (...
Article
Full-text available
c-Src is heavily expressed in the brain and in human neural tissues. Our pursuit for characterization of the neuroprotective mechanisms of tocotrienols led to the first evidence demonstrating that rapid c-Src activation plays a central role in executing glutamate-induced neurodegeneration. It is now known that Src deficiency or blockade of Src acti...