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Mitochondria

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Articles 1 - 30 of 61

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Hormone Signaling, Gene Expression, And Mitochondrial Hormone Receptor Expression In Avian Muscle (Cells), Kentu Rushadd Lassiter May 2019

Hormone Signaling, Gene Expression, And Mitochondrial Hormone Receptor Expression In Avian Muscle (Cells), Kentu Rushadd Lassiter

Theses and Dissertations

Mitochondria are vital to the proper growth and function of muscle cells since they’re responsible for the majority of ATP production used for cellular energy. Previous studies have investigated how differences in mitochondrial function affects feed efficiency (FE) in broilers phenotyped for High and Low FE. Low FE broilers have been shown to have increased levels of reactive oxygen species (ROS), thus contributing to higher levels of oxidative stress and damage seen in these birds. Global gene and protein expression studies conducted on breast muscle of the High FE and Low FE phenotypes have suggested that differences in mitochondrial ...


Mitochondrial Metabolism In Major Neurological Diseases, Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson, Ramon Sun Nov 2018

Mitochondrial Metabolism In Major Neurological Diseases, Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson, Ramon Sun

Molecular and Cellular Biochemistry Faculty Publications

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation ...


Understanding Nuage-Mitochondrial Coupling In Drosophila Pirna Biogenesis, Tianfang Ge Aug 2018

Understanding Nuage-Mitochondrial Coupling In Drosophila Pirna Biogenesis, Tianfang Ge

GSBS Dissertations and Theses

In the Drosophilaovary, PIWI-interacting RNAs (piRNAs) suppress transposon expression, ensuring female fertility. PIWI proteins Aub and Ago3, loaded with ping-pong piRNAs and reside in perinuclear nuage granules, engage in reciprocal transposon transcript cleavage termed the ping-pong cycle. The other PIWI protein Piwi, loaded with phased piRNAs and resides in the nucleus, silences transposon transcriptionally. Ping-pong piRNAs are made through the ping-pong amplification loop by Aub and Ago3, whereas phased piRNAs are made through consecutive endonucleolytic cleavages that spread in 5′-to-3′ direction, presumably by Zucchini (Zuc), an endonuclease resides on the surface of mitochondria. The ping-pong and phasing biogenesis ...


Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu Jul 2018

Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu

Open Access Articles

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved ...


Mitochondrial Mrna Translation Is Required For Maintenance Of Oxidative Capacity, David Lee May 2018

Mitochondrial Mrna Translation Is Required For Maintenance Of Oxidative Capacity, David Lee

Theses and Dissertations

Oxidative metabolism is required to produce adequate energy to sustain human life. A primary example of deteriorating oxidative capacity is seen in the cardiac musculature during chronic heart failure. This suggests that by improving oxidative potential, chronic heart disease could be mitigated and one approach to accomplish this may be through targeting the mt-mRNA translation system. Purpose: This investigation’s purpose was to characterize disruptions in mt-mRNA translation machinery in multiple forms of cardiomyopathy and to determine if mitochondrial mRNA translation initiation factor (mtIF2) is necessary to maintain oxidative capacity in cardiomyocytes. Methods Using a combination of animal and cell ...


Chromatin Remodeling Dynamics During Brown Adipogenesis, Suzanne Natalie Shapira Jan 2018

Chromatin Remodeling Dynamics During Brown Adipogenesis, Suzanne Natalie Shapira

Publicly Accessible Penn Dissertations

Brown adipose tissue (BAT) is specialized to expend energy through the action of the mitochondrial uncoupling protein UCP1. Increasing brown fat mass or activity through genetic or chemical manipulation in mice suppresses obesity and its comorbidities; as such, there is great interest in developing approaches to increase the amount and/or function of brown fat to combat metabolic disorders. My thesis work aimed to dissect the molecular mechanisms by which the helix- loop-helix transcription factor Early B-Cell Factor 2 (EBF2) regulates brown adipocyte commitment and terminal differentiation. Through analysis of tissue-specific knockout mouse models, we found that EBF2 is required ...


Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto Nov 2017

Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto

UMass Metabolic Network Publications

In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target ...


Ydj1 Governs Fungal Morphogenesis And Stress Response, And Facilitates Mitochondrial Protein Import Via Mas1 And Mas2, Jinglin L. Xie, Iryna Bohovych, Erin O.Y. Wong, Jean-Philippe Lambert, Anne-Claude Gingras, Oleh Khalimonchuk, Leah E. Cowen, Michelle D. Leach Oct 2017

Ydj1 Governs Fungal Morphogenesis And Stress Response, And Facilitates Mitochondrial Protein Import Via Mas1 And Mas2, Jinglin L. Xie, Iryna Bohovych, Erin O.Y. Wong, Jean-Philippe Lambert, Anne-Claude Gingras, Oleh Khalimonchuk, Leah E. Cowen, Michelle D. Leach

Biochemistry -- Faculty Publications

Mitochondria underpin metabolism, bioenergetics, signalling, development and cell death in eukaryotes. Most of the ~1,000 yeast mitochondrial proteins are encoded in the nucleus and synthesised as precursors in the cytosol, with mitochondrial import facilitated by molecular chaperones. Here, we focus on the Hsp40 chaperone Ydj1 in the fungal pathogen Candida albicans, finding that it is localised to both the cytosol and outer mitochondrial membrane, and is required for cellular stress responses and for filamentation, a key virulence trait. Mapping the Ydj1 protein interaction network highlighted connections with co-chaperones and regulators of filamentation. Furthermore, the mitochondrial processing peptidases Mas1 and ...


The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino Aug 2017

The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino

UMass Metabolic Network Publications

Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.


Metalloproteases Of The Inner Mitochondrial Membrane, Roman M. Levytskyy, Iryna Bohovych, Oleh Khalimonchuk Aug 2017

Metalloproteases Of The Inner Mitochondrial Membrane, Roman M. Levytskyy, Iryna Bohovych, Oleh Khalimonchuk

Biochemistry -- Faculty Publications

The inner mitochondrial membrane (IM) is among most protein-rich cellular compartments. The metastable IM sub-proteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with high probability for protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial sub-compartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP-independent Oma1 ...


Age-Associated Metabolic Reprogramming, Oxidative Stress Response, And Cancer Progression, Jyung Mean Son Aug 2017

Age-Associated Metabolic Reprogramming, Oxidative Stress Response, And Cancer Progression, Jyung Mean Son

Theses and Dissertations

Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigates whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were performed in quiescent NHFs from younger (newborn, 3-d, 5-m, and 1-y) and older (58-y, 61-y, 63-y, 68-y, and 70-y) donors as well as NHFs from the same individual at different ages (29-y, 36-y, and 46-y). Results show significant changes in cellular metabolism during ...


The Effect Of Target-Specific Biomolecules In Breast Cancer, Mohannad Garoub Jun 2017

The Effect Of Target-Specific Biomolecules In Breast Cancer, Mohannad Garoub

FIU Electronic Theses and Dissertations

Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as ...


Mutant Tdp-43 Does Not Impair Mitochondrial Bioenergetics In Vitro And In Viv, Hibiki Kawamata, Pablo Peixoto, Csaba Konrad, Gloria Palomo, Kirsten Bredvik, Meri Gerges, Federica Valsecchi, Leonard Petrucelli, John M. Ravits, Anatoly Starkov, Giovanni Manfredi May 2017

Mutant Tdp-43 Does Not Impair Mitochondrial Bioenergetics In Vitro And In Viv, Hibiki Kawamata, Pablo Peixoto, Csaba Konrad, Gloria Palomo, Kirsten Bredvik, Meri Gerges, Federica Valsecchi, Leonard Petrucelli, John M. Ravits, Anatoly Starkov, Giovanni Manfredi

Publications and Research

Background: Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics. Furthermore, it was proposed that TDP-43 mutations cause oxidative phosphorylation impairment associated with respiratory chain defects and that these effects were caused by mitochondrial localization of the mutant ...


Enhancement Of Reactive Oxygen Species Production And Chlamydial Infection By The Mitochondrial Nod-Like Family Member Nlrx1, Ali A. Abdul-Sater, Najwene Saïd-Sadier, Verissa M. Lam, Bhavni Singh, Matthew A. Pettengill, Fraser Soares, Ivan Tattoli, Simone Lipinski, Stephen E. Girardin, Philip Rosenstiel, David M. Ojcius Apr 2017

Enhancement Of Reactive Oxygen Species Production And Chlamydial Infection By The Mitochondrial Nod-Like Family Member Nlrx1, Ali A. Abdul-Sater, Najwene Saïd-Sadier, Verissa M. Lam, Bhavni Singh, Matthew A. Pettengill, Fraser Soares, Ivan Tattoli, Simone Lipinski, Stephen E. Girardin, Philip Rosenstiel, David M. Ojcius

David M. Ojcius

Chlamydia trachomatis infections cause severe and irreversible damage that can lead to infertility and blindness in both males and females. Following infection of epithelial cells, Chlamydia induces production of reactive oxygen species (ROS). Unconventionally, Chlamydiae use ROS to their advantage by activating caspase-1, which contributes to chlamydial growth. NLRX1, a member of the Nod-like receptor family that translocates to the mitochondria, can augment ROS production from the mitochondria following Shigella flexneri infections. However, in general, ROS can also be produced by membrane-bound NADPH oxidases. Given the importance of ROS-induced caspase-1 activation in growth of the chlamydial vacuole, we investigated the ...


Role Of Energy Metabolism In The Thermogenic Gene Program, Minwoo Nam Jan 2017

Role Of Energy Metabolism In The Thermogenic Gene Program, Minwoo Nam

GSBS Dissertations and Theses

In murine and human brown adipose tissue (BAT), mitochondria are powerful generators of heat. Emerging evidence has suggested that the actions of mitochondria extend beyond this conventional biochemical role. In mouse BAT and cultured brown adipocytes, impaired mitochondrial respiratory capacity is accompanied by attenuated expression of Ucp1, a key thermogenic gene, implying a mitochondrial retrograde signaling. However, few have investigated this association in the context of mitochondria-nucleus communication.

Using mice with adipose-specific ablation of LRPPRC, a regulator of respiratory capacity, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to transcriptional and metabolic reprogramming of BAT. Impaired respiratory ...


Uncoupling The Dynamics Of Inner And Outer Mitochondrial Membrane Fission, Samantha Gumbin Jan 2017

Uncoupling The Dynamics Of Inner And Outer Mitochondrial Membrane Fission, Samantha Gumbin

Undergraduate Honors Theses

Mitochondria are dynamic organelles undergoing constant changes in their morphology through two opposing processes; mitochondrial fission and fusion. The current model of mitochondria fission begins with the endoplasmic reticulum (ER) localizing to the mitochondrial outer membrane and initiating membrane constriction. Additional key molecular players, specifically a mitochondrial transmembrane protein, MFF and a cytosolic GTPase, Drp1, localize to the outer mitochondrial membrane to drive constriction and subsequent fission of the mitochondria. While several proteins have been identified to be involved in mitochondrial fission, almost all of them function at the outer mitochondrial membrane (OMM). We therefore have very little knowledge about ...


Exploring The Role Of Lipin1 In Mitophagy Process Using Lipin1 Deficient-Egfp Tagged Lc3 Transgenic Mice, Abdullah Ali Alshudukhi Jan 2017

Exploring The Role Of Lipin1 In Mitophagy Process Using Lipin1 Deficient-Egfp Tagged Lc3 Transgenic Mice, Abdullah Ali Alshudukhi

Browse all Theses and Dissertations

Lipin1 (phosphatidic acid phosphatase) is a key molecule in the cells with two functions: first, it converts phosphatidic acid into diacylglycerol in the cytosol which in turn makes triglycerides. Second, in nucleus lipin1 acts as a transcriptional factor which regulates the expression of genes involved in the fatty acid oxidation and lipid metabolism. Clinically, Lpin1 gene mutations have been detected in patients with severe rhabdomyolysis accompanied with aggregated and dysfunctional mitochondria in their type II muscle fiber. Previously, we have observed that mice with lipin1 deficiency had aggregated mitochondria and abnormal autophagosomes formations by electron microscopy. The mechanism underlying the ...


Characterization Of The Rcf1 Q-X3-R-X-R-X3-Q Motif And Its Role In Supporting Oxidative Phosphorylation Enzyme Complexes, Joshua Garlich Oct 2016

Characterization Of The Rcf1 Q-X3-R-X-R-X3-Q Motif And Its Role In Supporting Oxidative Phosphorylation Enzyme Complexes, Joshua Garlich

Dissertations (2009 -)

Mitochondrial respiratory complexes are critical components of cellular energy production that require tight regulation to ensure optimal function. Rcf1 and Rcf2 are mitochondrial proteins that can physically associate with the yeast respiratory complexes III and IV, and the higher-ordered III-IV respiratory supercomplex that also contains the ADP/ATP translocase, AAC. Rcf1 can physically associate with both complex III and IV independently, and can be chemically crosslinked to AAC, indicating a close physical proximity to a predominant regulator of energy flux within the cell. It was therefore hypothesized that Rcf1, through its physical association with complexes III and IV, and its ...


Sending Out An Sos: Mitochondria As A Signaling Hub, Iryna Bohovych, Oleh Khalimonchuk Sep 2016

Sending Out An Sos: Mitochondria As A Signaling Hub, Iryna Bohovych, Oleh Khalimonchuk

Biochemistry -- Faculty Publications

Normal cellular physiology is critically dependent on numerous mitochondrial activities including energy conversion, cofactor and precursor metabolite synthesis, and regulation of ion and redox homeostasis. Advances in mitochondrial research during the last two decades provide solid evidence that these organelles are deeply integrated with the rest of the cell and multiple mechanisms are in place to monitor and communicate functional states of mitochondria. In many cases, however, the exact molecular nature of various mitochondria-to-cell communication pathways is only beginning to emerge. Here, we review various signals emitted by distressed or dysfunctional mitochondria and the stress-responsive pathways activated in response to ...


Mechanism Of Rapid Electron Transfer Reactions Involving Cytochrome Bc1, Cytochrome C And Cytochrome Oxidase, Jeremy Erik Durchman Aug 2016

Mechanism Of Rapid Electron Transfer Reactions Involving Cytochrome Bc1, Cytochrome C And Cytochrome Oxidase, Jeremy Erik Durchman

Theses and Dissertations

Electron transfer between mitochondrial proteins complexes represents the primary means by which living things acquire the requisite energy for survival. The coupling of electron transfer to proton translocation creates an electrochemical gradient that drives the synthesis of highly energetic compounds such as ATP. The purpose of these studies is to measure rates of electron transfer and elucidate the important governing factors in the redox events involving cytochrome bc1, cytochrome c and cytochrome oxidase. Using rapid initiation of redox events triggered by laser flash excitation of ruthenium compounds, and strategically monitoring unique spectral properties of these proteins in the visible region ...


Mitochondrial Calcium Uniporter Is A Nodal Regulator Of Physiological And Pathological Stress Responses In Myocardium, Tyler Paul Rasmussen May 2016

Mitochondrial Calcium Uniporter Is A Nodal Regulator Of Physiological And Pathological Stress Responses In Myocardium, Tyler Paul Rasmussen

Theses and Dissertations

A long held hypothesis in mitochondrial biology holds that increases in mitochondrial Ca2+ levels stimulate the activity of matrix dehydrogenases that catalyze production of NADH and eventually donate electrons to electron transport in order to increase ATP formation. At the same time, mitochondrial Ca2+ overload is a deleterious event leading to opening of the mitochondrial permeability transition pore, increasing reactive oxygen species and initiating pathways that contribute to cell death. These fundamental hypotheses are best studied in the heart because of the critical energy supply-demand relationship in myocardium, but were untestable in vivo until the discovery of the ...


Axonal Transport And Life Cycle Of Mitochondria In Parkinson's Disease Model, Hyun Sung Apr 2016

Axonal Transport And Life Cycle Of Mitochondria In Parkinson's Disease Model, Hyun Sung

Open Access Dissertations

In neurons, normal distribution and selective removal of mitochondria are essential for preserving compartmentalized cellular function. Parkin, an E3 ubiquitin ligase associated with familial Parkinson’s disease, has been implicated in mitochondrial dynamics and removal. However, it is not clear how Parkin plays a role in mitochondrial turnover in vivo, and whether the mature neurons possess a compartmentalized Parkin-dependent mitochondrial life cycle. Using the live Drosophila nervous system, here, I investigate the involvement of Parkin in mitochondrial dynamics; organelle distribution, morphology and removal. Parkin deficient animals displayed less number of axonal mitochondria without disturbing organelle motility behaviors, morphology and metabolic ...


Mir494 Reduces Renal Cancer Cell Survival Coinciding With Increased Lipid Droplets And Mitochondrial Changes, Punashi Dutta, Edward Haller, Arielle Sharp, Meera Nanjundan Jan 2016

Mir494 Reduces Renal Cancer Cell Survival Coinciding With Increased Lipid Droplets And Mitochondrial Changes, Punashi Dutta, Edward Haller, Arielle Sharp, Meera Nanjundan

Cell Biology, Microbiology, and Molecular Biology Faculty Publications

Background: miRNAs can regulate cellular survival in various cancer cell types. Recent evidence implicates the formation of lipid droplets as a hallmark event during apoptotic cell death response. It is presently unknown whether MIR494, located at 14q32 which is deleted in renal cancers, reduces cell survival in renal cancer cells and if this process is accompanied by changes in the number of lipid droplets.

Methods: 769-P renal carcinoma cells were utilized for this study. Control or MIR494 mimic was expressed in these cells following which cell viability (via crystal violet) and apoptotic cell numbers (via Annexin V/PI staining) were ...


C. Elegans As A Genetics Model To Study Paternal Mitochondria Elimination And Apoptosis Kinetics Regulation, Hanzeng Li Jan 2016

C. Elegans As A Genetics Model To Study Paternal Mitochondria Elimination And Apoptosis Kinetics Regulation, Hanzeng Li

Chemistry & Biochemistry Graduate Theses & Dissertations (1986-2018)

The round worm, Caenorhabditis elegans, provides a simple system to study complex questions. The philosophy behind it is that a single cell contains almost all of the components that make up life, even as complex as a human. I studied two conserved and fundamental biological topics over the span of the past 6 years: programmed cell death, and paternal mitochondrial elimination (PME). Programmed cell death (apoptosis) is the process by which individual cells sacrifice themselves for the good of the organism. Cells undergo apoptosis in a finely regulated fashion. Using C. elegans, I investigated the regulatory mechanism of CED-8, an ...


Role Of Non-Catalytic Ligands In Macromolecule Function, Muneaki Watanabe Jan 2016

Role Of Non-Catalytic Ligands In Macromolecule Function, Muneaki Watanabe

Graduate Theses and Dissertations

Human hexokinase Type-I (HKI) binds to the outer mitochondrial membrane, and in so doing protects the mitochondrion, controls adenine nucleotide flux through the membrane and blocks mitochondrion-linked apoptosis. Adenosine 5’-triphosphate (ATP) releases HKI from the outer mitochondrial membrane, but the mechanism of ATP release is unclear. ATP-release is not due to the generation of glucose 6-phosphate (G6P) from ATP and glucose or by the binding of ATP to HKI at its catalytic or regulatory domains. Instead, the voltage dependent anion channel (VDAC) has a high affinity binding site for ATP as revealed by titrations using ATP and fluorescent analogs ...


Pyridinium Derivatives For Metastatic Melanoma Therapy, Jessica Leigh Reedy Jan 2016

Pyridinium Derivatives For Metastatic Melanoma Therapy, Jessica Leigh Reedy

Theses and Dissertations

Melanoma incidence is increasing faster than any other cancer worldwide.1 Early detection is often curative, but metastatic melanoma is lethal (5-year survival <20%) due to the development of resistance to all approved drugs.1 However, emerging evidence suggests that differences in melanoma metabolism relative to non-malignant cells may provide a target to improve treatment.2-14 Specifically, melanoma cells have increased mitochondrial electron transport chain (ETC) activity, elevated levels of reactive oxygen species, and a simultaneous hyperpolarized mitochondrial membrane potential relative to non-malignant cells.4, 8, 11, 15-17 Furthermore, melanoma cells have upregulated glucose consumption and concurrent increased levels of glucose transporters (GLUTs) relative to non-malignant cells; the products of glycolysis (pyruvate and NADPH) aid in the detoxification reactive oxygen species (ROS), while the intermediates are utilized in energy production via increased oxidative metabolism.15, 18 Collectively, melanoma cells exhibit alterations in metabolic, mitochondrial, and cell-surface targets that can be potentially exploited for therapeutic strategies for selective cancer cell killing relative to non-malignant cells.

The research presented here demonstrates the therapeutic potential for a new class of mitochondrial-targeted fluorescent lipophilic-cations: pyridinium derivatives (UIRF 17023.186PV1 U.S. Provisional Patent Application No. 62/268,980 Patent Pending). Importantly, the pyridinium derivatives presented in this study have not been previously investigated as a mitochondrial-targeted therapy.19-21 Furthermore, the research presented outlines the feasibility of improving melanoma cellular accumulation of these pyridinium derivatives by including a GLUT targeting moiety in the form of a ...


Evidence For Pipecolate Oxidase In Mediating Protection Against Hydrogen Peroxide Stress, Sathish Kumar Natarajan, Ezhumalai Muthukrishnan, Oleh Khalimonchuk, Justin L. Mott, Donald F. Becker Jan 2016

Evidence For Pipecolate Oxidase In Mediating Protection Against Hydrogen Peroxide Stress, Sathish Kumar Natarajan, Ezhumalai Muthukrishnan, Oleh Khalimonchuk, Justin L. Mott, Donald F. Becker

Biochemistry -- Faculty Publications

Pipecolate, an intermediate of the lysine catabolic pathway, is oxidized to Δ1-piperideine-6-carboxylate (P6C) by the flavoenzyme lpipecolate oxidase (PIPOX). P6C spontaneously hydrolyzes to generate α-aminoadipate semialdehyde, which is then converted into α-aminoadipate acid by α-aminoadipatesemialdehyde dehydrogenase. l-pipecolate was previously reported to protect mammalian cells against oxidative stress. Here, we examined whether PIPOX is involved in the mechanism of pipecolate stress protection. Knockdown of PIPOX by small interference RNA abolished pipecolate protection against hydrogen peroxide-induced cell death in HEK293 cells suggesting a critical role for PIPOX. Subcellular fractionation analysis showed that PIPOX is localized in the mitochondria of HEK293 ...


Co-Treatment With Conjugated Linoleic Acid And Nitrite Modulates Mitochondrial Respiration And Electron Transport Chain Activity In Vivo And Attenuates Mitochondrial Dysfunction During Cardiac Injury., Patrick Van Hoose Dec 2015

Co-Treatment With Conjugated Linoleic Acid And Nitrite Modulates Mitochondrial Respiration And Electron Transport Chain Activity In Vivo And Attenuates Mitochondrial Dysfunction During Cardiac Injury., Patrick Van Hoose

Electronic Theses and Dissertations

Cardiovascular disease and subsequent complications, such as myocardial infarction (MI), is the leading cause of death within the United States. Clinical intervention to reduce cardiac damage following myocardial ischemia is limited. Polyunsaturated fatty acids have been linked to an overall beneficial effect on cardiovascular health and function. Conjugated linoleic acid (cLA) is an 18:2 unsaturated fatty acid found within the diet in ruminant meat and dairy products. The cis-9 trans-11 isomer of cLA is the most prominent isomer within the diet and cLA has been linked to favorable outcomes in numerous disease states. The mechanism mediating the effects of ...


Impacts Of Micrornas On Skeletal Muscle Protein Synthesis And Mitochondrial Quality, David Lee May 2015

Impacts Of Micrornas On Skeletal Muscle Protein Synthesis And Mitochondrial Quality, David Lee

Theses and Dissertations

microRNA (miRNA) post-transcriptional modification is becoming a well-established mechanism for controlling mRNA translation. microRNAs -1, -133, and -206 are under the control of skeletal muscle promoters and affect muscle plasticity and metabolic health. A detailed review on the generation and processing of miRNAs with a view to skeletal muscle brings up intriguing connections in the transcriptional connections between multiple miRNAs. Additionally, exciting new research has defined a role of miRNAs in skeletal muscle mitochondria showing an additional, direct link to metabolic function. Multiple investigations in models of exercise, aging, hypertrophy, and injury have shown how these interventions can affect miRNA ...


Liquid Chromatography-Mass Spectrometry Analysis Of Dysfunctional Mitochondrial Metabolism: Insights Into Rotenone Toxicity And Friedreichâ'S Ataxia, Andrew J. Worth Jan 2015

Liquid Chromatography-Mass Spectrometry Analysis Of Dysfunctional Mitochondrial Metabolism: Insights Into Rotenone Toxicity And Friedreichâ'S Ataxia, Andrew J. Worth

Publicly Accessible Penn Dissertations

Mitochondrial dysfunction plays a role in a wide range of diseases resulting in an enormous public health burden. The goal of this thesis is to identify metabolic pathways that are disrupted in response to mitochondrial insults. A large proportion of this work is based on the generation of stable isotope labelled metabolites to allow for the rigorous quantification of intracellular metabolites by liquid chromatography-mass spectrometry. Once developed, this methodology was employed in cell culture models initially to characterize an unidentified acyl-CoA thioester induced by propionate metabolism. This novel pathway was identified as the direct formation of 2-methyl-2-pentenoyl-CoA, and using isotopic ...