Cellular and Molecular Physiology Commons^™

Effect Of Partial Ablation Of Skeletal Dynamin Related Protein 1 On Mitochondrial Health, Inflammation, And Fibrosis In A Mouse Model Of Duchenne Muscular Dystrophy, Tessa L. Duzz

Graduate Masters Theses

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle weakness, degeneration, fibrosis, and impaired muscle regeneration. Mitochondrial dysfunction is an early pathological feature of DMD and has been linked to excessive mitochondrial fission. Dynamin-related protein 1 (Drp1) is a central regulator of mitochondrial fission, a key process in regulating mitochondrial quality and function. Inhibition of Drp1-mediated mitochondrial fission has shown promise as a potential therapeutic target for alleviating pathology and dysfunction in dystrophic muscle. The objective of this study was to determine whether partial skeletal muscle-specific ablation of Drp1 could improve muscle pathology and mitochondrial health in …

Gcn5l1-Mediated Lysine Acetylation Regulates Mitochondrial Dysfunction In The Aged Heart, Jackson Edmond Stewart

Graduate Theses, Dissertations, and Problem Reports (ETD)

For over a century, cardiovascular disease (CVD) has been and remains the leading cause of death globally. CVD risk and severity increase significantly with advanced age, and mitochondrial dysfunction has been implicated in the pathogenesis of aging. Furthermore, mitochondrial health is crucial for cardiac function, as one-third of total cardiomyocyte volume is occupied by mitochondria in order to meet the high energy demand of contractile and relaxational function. It is thus crucial that we understand the pathological mechanisms driving mitochondrial dysfunction in aging and how this contributes to age-associated cardiovascular disease. The current manuscript aims to fill this knowledge gap …

The Loss Of Opa1 Accelerates Intervertebral Disc Degeneration And Osteoarthritis In Aged Mice, Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige Boneski, Hiromi Sesaki, Ruteja Barve, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and

Mechanisms Of Placental Impairment And The Upregulation Of Fetuin-B During Maternal Undernourishment, Mia Camilliere

NYMC Student Theses and Dissertations

Proper nutrition is crucial during pregnancy to support fetal and placental development. Failure to meet these nutritional needs can result in adverse health outcomes for both mother and baby. Despite its high prevalence in underdeveloped countries, maternal undernourishment is a public health issue worldwide. There are several possible causes of maternal undernourishment, and these can occur alone or in combination, such as poor access to nutrition, hyperemesis gravidarum, and drug use. This condition can adversely affect placental development and function to the extent of placental insufficiency, perturbing the entire pregnancy. The placenta is responsible not only for hormonally and physically …

Assessing The Role Of Daily Thermal Fluctuations In The Performance Of Mitochondrial Energy Transduction Of The Centrarchid, Lepomis Cyanellus, Grayson Hofmann

Masters Theses

Freshwater systems are affected by current climate extremes, forcing species found in these systems to withstand drastic changes in temperature. Temperature changes affect these organisms by altering their metabolic rate and energy balance. Increases in temperature can lead to an increase in oxygen consumption, which ultimately increases the need for more energy production. Mitochondrial energy transduction of green sunfish (Lepomis cyanellus) and many other fish species after a thermal insult, has hardly been explored. This study complements the limited research available on mitochondrial function in similar species, as they ignore the possibility of consecutive thermal events, which are …

The Role Of Cardiac Mitochondria In Arrhythmias And Sudden Unexpected Death In Epilepsy In Models Of Dravet Syndrome, Jessa L. Aldridge

Electronic Theses and Dissertations

Dravet Syndrome (DS) is a pediatric epilepsy disorder. Individuals with DS are at increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). One mechanism implicated in the pathology of SUDEP is cardiac arrhythmias. A central element involved in cardiac regulation is mitochondria. In the heart, mitochondria maintain cardiomyocyte energy (ATP) generation and ion homeostasis but also produce harmful reactive oxygen species (ROS) byproducts. We hypothesized that deficits in cardiac mitochondria could underlie arrhythmias and SUDEP in two independent mouse models of DS. Mitochondria produce ATP through the mitochondrial respiratory chain, also called electron transport chain, comprised of a series of …

Photobiomodulation Of Bovine Oocytes During Maturation Increases Atp Content And Enhances Subsequent Embryonic Development, Kendall Richey

All Theses

Bovine in-vitro production(IVP) of embryos is a growing field for producing offspring with desirable genetics in the cattle industries. While IVP is effective, oocyte cytoplasmic maturation is compromised, and bovine oocytes matured in-vitro have reduced metabolic activity than those matured in-vivo. Mitochondria are the central unit of oocyte metabolism, producing ATP through OXPHOS. Photobiomodulation is a light treatment reported to improve metabolic activity. In five experiments, we measured the effects of photobiomodulation treatment with red LED at 16-(L-16) and 20 h(L-20) of bovine oocyte in-vitro maturation on subsequent embryonic development, mitochondrial activity and nuclear progression. Bovine COCs were aspirated …

Sphingosine Kinase 2 Depletion Dysregulates Hepatic Redox Metabolism And Enhances Inflammation In Early Metabolic Dysfunction-Associated Steatohepatitis (Mash), Kaitlyn Georgene Jackson

Theses and Dissertations

Metabolic dysfunction-associated steatotic liver disease (MASLD) currently affects one in three people worldwide; its prevalence is growing alongside other cardiometabolic disorders. Aberrations to redox and sphingolipid metabolism contribute to MASLD pathologic progression. Sphingosine-1-phosphate (S1P) is an active lipid, meaning that S1P participates in biochemical processes within the cell. S1P is generated by two distinct isoenzymes, sphingosine kinase (SphK)1 and SphK2. The localization of the SphK enzyme dictates S1P function. While cytosolic SphK1-generated S1P is well-characterized, nuclear and mitochondrial SphK2-generated S1P is less known. Moreover, SphK2 depletion effects on cellular redox processes and inflammation are not well-defined.

This study defines the …

Does Vdac2 Have A Bh3 Domain?, Lillian Ferkany

Honors Theses

Mitochondrial outer membrane permeabilization (MOMP) by Bax oligomerization triggers apoptosis. BCl-2 family proteins, classified as BH3 only proteins, pro-survival proteins, or pro-apoptotic proteins, control apoptosis partly through their agonist or antagonistic effects on Bax, which are mediated by their conserved BH3 domains. All BH3 domains form an alpha helix containing 5-7 conserved hydrophobic residues, designated H0-H5, and one conserved aspartic acid that drive interaction with Bax and other ‘multi-domain’ BCl-2 members. BH3 agonists induce Bax oligomerization, while BH3 antagonists sequester Bax to prevent MOMP. We discovered that voltage dependent anion channels (VDACs) in the MOM contain a putative BH3-like domain …

A Dedicated Chaperone Mediates The Safe Transfer Of Mitoribosomal Proteins To Their Site Of Assembly, Gabrielle Ashley Hillman

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondrial ribosomes are functionally specialized for the synthesis of several essential inner membrane proteins of the respiratory chain. While remarkable progress has recently been made towards understanding the structure of mitoribosomes, the unique pathways and factors that facilitate their biogenesis remain largely unknown. This dissertation defines the physiological role of an evolutionarily conserved yeast protein called Mam33 in mitochondrial ribosome assembly. The biomedical relevance of this finding stems from the fact that mutations or changes in its expression of the human ortholog p32 result in mitochondrial dysfunction. In human patients, bi-allelic mutations cause severe multisystemic defects in mitochondrial energy metabolism, …

Identification Of The Alternative Oxidase Gene And Its Expression In The Copepod Tigriopus Californicus, Allison Mcdonald, Carly E. Tward, Willie Cygelfarb, Jaspreet Singh

Biology Faculty Publications

In addition to the typical electron transport system (ETS) in animal mitochondria responsible for oxidative phosphorylation, in some species there exists an alternative oxidase (AOX) pathway capable of catalyzing the oxidation of ubiquinol and the reduction of oxygen to water. The discovery of AOX in animals is recent and further investigations into its expression, regulation, and physiological role have been hampered by the lack of a tractable experimental model organism. Our recent DNA database searches using bioinformatics revealed an AOX sequence in several marine copepods including Tigriopus californicus. This species lives in tidepools along the west coast of North …

Cellular And Subcellular Oxidative Stress Parameters Following Severe Spinal Cord Injury, Nishant P. Visavadiya, Samir P. Patel, Jenna L. Vanrooyen, Patrick G. Sullivan, Alexander G. Rabchevsky

Spinal Cord and Brain Injury Research Center Faculty Publications

The present study undertook a comprehensive assessment of the acute biochemical oxidative stress parameters in both cellular and, notably, mitochondrial isolates following severe upper lumbar contusion spinal cord injury (SCI) in adult female Sprague Dawley rats. At 24 h post-injury, spinal cord tissue homogenate and mitochondrial fractions were isolated concurrently and assessed for glutathione (GSH) content and production of nitric oxide (NO^•), in addition to the presence of oxidative stress markers 3-nitrotyrosine (3-NT), protein carbonyl (PC), 4-hydroxynonenal (4-HNE) and lipid peroxidation (LPO). Moreover, we assessed production of superoxide (O₂^•-) and hydrogen peroxide (H₂O …

A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun

Theses and Dissertations

Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts …

Mitochondrial Therapeutics During Ischemia-Reperfusion; Modulation Of Complex I: Effect Of Metformin., Shawn Y. Sunu

Theses and Dissertations

The modulation of the electron transport during ischemia-reperfusion has been shown to be protective. We hypothesized that metformin, a Complex I inhibitor, may exhibit characteristics of a pharmacological agent that could achieve long-term therapeutic intervention against ischemia-reperfusion injury. Mitochondria were harvested from adult male mice and incubated with or without metformin at 30^oC for 15 minutes, while being shaken at 300 rpm. Metformin decreased Complex I oxidative phosphorylation and Complex I activity. However, metformin also increased injury and decreased the maximum membrane potential. Even though there was a decrease in maximum membrane potential, the proton motive force (PMF) …

Over-Expressed Copper/Zinc Superoxide Dismutase Localizes To Mitochondria In Neurons Inhibiting The Angiotensin Ii-Mediated Increase In Mitochondrial Superoxide, Shumin Li, Adam J. Case, Rui-Fang Yang, Harold D. Schultz, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Angiotensin II (AngII) is the main effector peptide of the renin-angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 (•-)). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 (•-). We have previously reported that over-expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix-localized O2 (•-) scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD), which is believed …

Intrinsic Apoptotic Pathway: Effects Of Calcium On Murine Cytochrome C Release In Brain And Liver Mitochondria, Dane M. Edwards

Senior Honors Theses

A cell may use one of three main apoptotic pathways leading to programmed cell death: the extrinsic pathway, the perforin/granzyme pathway and the intrinsic pathway. The most pertinent to this discussion is the intrinsic pathway, which utilizes the mitochondria as an essential intermediary. Mitochondria’s primary function in relation to this pathway is the subsequent release of pro-apoptotic factors including cytochrome c, which activate a caspase cascade leading to the death of the cell. Cytochrome c is released partly due to an increase in cytosolic calcium levels. Two methods of the release of cytochrome c have been proposed. The first is …