Cell Biology Commons^™

Crosstalk Between Upr And Mitochondria: The Triad Of Er-Mitochondria Contacts, Ca²⁺, And Ros, Ester Zito, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease …

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 …

Mitochondria Dynamics In Microglia During Health, Inflammation, And Aging, Alicia Nicole Pietramale

Dartmouth College Ph.D Dissertations

Microglia continually surveil the brain, allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain has remained unclear. In this dissertation, I combine intravital imaging, ultrastructural analyses, and metabolic and cytoskeletal markers to investigate how mitochondrial organization relates to microglial function across health, inflammation, and aging.

I first show that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. This heterogeneous partitioning is conserved …

Glycative Stress Disrupts The Mitochondrial-Lysosome Axis And Promotes Geroconversion In Aging Cardiomyocytes, Diana Bou-Teen, Simonas Valiuska, Elisabet Miro-Casas, Chiara Rubeo, Elena Bonzon-Kulichenko, Zuzana Nichtova, Celia Fernandez-Sanz, Javier Inserte, Antonio Rodriguez-Sinovas, Begoña Benito, Eduard Ródenas-Alesina, Jesús Vázquez, Ignacio Ferreira-González, Marisol Ruiz-Meana

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more …

Long Acting Beta2-Adrenergic Receptor Agonists Reverse Diabetic Nephropathy And Liver Steatosis In Murine Models Of Diabetes And Are Associated With Protection In Retrospective Human Studies, Brennan Winkler

MUSC Theses and Dissertations

Diabetes Mellitus (DM) affects 13.9% of men and 14.3% of women worldwide, a total of approximately 828 million people. Patients with diabetes are at risk of several complications including diabetic nephropathy (DN) and metabolic-associated steatohepatitis (MASH). These diseases eventually lead to end stage kidney disease (ESKD) and liver failure requiring dialysis and organ transplantation. In addition, diabetes exacerbates disease severity of autosomal dominant polycystic kidney disease (ADPKD), the most common potentially lethal genetic disease to affect humans with a prevalence of 1 in 500-1000. Therefore, a therapeutic approach that can attenuate organ damage and restore function in patients with DM, …

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 …

Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage In Cpvt, Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Zuzana Nichtova, Mark Bannister, Jinxi Wang, Sage Quiggle, Rachel Battershell, Matthew Gorr, Sandor Györke, Bum-Rak Choi, Christopher George, Andriy Belevych, György Csordás, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca 2+ ] in the mitochondrial intermembrane space (IMS) and activates the Ca 2+ -sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).

METHODS: We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(Ser2336Leu)(+/-) . We created a new biosensor to measure IMS-[Ca2+ ] …

Modulation Of Redox-Sensitive Cardiac Ion Channels, Rawan S. Orfali, Al Hassan Gamal El-Din, Varnika Karthik, Elisanjer Lamis, Vanna Xiao, Alena Ramanishka, Abdullah Alwatban, Osama Alkhamees, Ali Alaseem, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate …

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 …

Mitochondrial Network Expansion And Loss During Oligodendrocyte Life And Death, Xhoela Bame

Dartmouth College Ph.D Dissertations

Oligodendrocytes are the myelinating cells of the central nervous system, known for modulating signal transmission, refining neural circuits, and providing metabolic support to axons. Oligodendrocytes are generated throughout life from oligodendrocyte precursor cells (OPCs) and are damaged or lost in demyelinating and neurodegenerative diseases and age-related pathologies. Thus, understanding the cellular checkpoints that occur during the generation and degeneration of oligodendrocytes is crucial for maintaining their population in health and recovering it in disease and aging.

Using high-resolution optical imaging, I have discovered a dynamic redistribution and subcellular partitioning of mitochondria during oligodendrogenesis. Mitochondria transiently expanded towards the differentiating OPC …

Genetic Analysis Of Methionine Restriction-Associated Mitochondrial Unfolded Protein Response Signaling., Josh D. Dodge

Biology Dissertations - Archive

The lifespan of an organism is dictated by various genetic and environmental factors. One such determinant is the health of mitochondria which are organelles that mediate various critical cell functions including a significant role in generating the vast supply of cellular energy. Indeed, the gradual decline of mitochondrial function is believed to be a hallmark and possible cause of aging. Paradoxically, mild mitochondrial dysfunction early in life extends lifespan in various model organisms. Cells use diverse approaches to promote mitochondrial homeostasis, including the transcriptional reprogramming of cells by mitochondrial unfolded protein response (UPRmt) to mitigate mitochondrial stress. Consistently, UPRmt activation …

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 …

Characterizing A Rad23 Dependent Ultraviolet Radiation Resistance In Tetrahymena Thermophila, Emma June Liimatta

Graduate Theses/Dissertations

In 2020, 10 million deaths were attributed to cancer, with multidrug resistance being responsible for over 90% of deaths in cancer patients receiving treatment. This study utilized the model organism Tetrahymena thermophila to study how cells become resistant to Ultraviolet Radiation (UV) radiation, a process similar to multidrug resistance, specifically focusing on the nucleotide excision repair and ubiquitin shuttle protein Rad23. The National Cancer Institute documented 30-60% of cancers tested had a mutation in RAD23. Knockdown of RAD23 in Tetrahymena thermophila demonstrated a UV resistance phenotype with decreased nucleotide excision repair and differential expression of proteins active within caspase-independent …

Opa1 And Disease-Causing Mutants Perturb Mitochondrial Nucleoid Distribution, J. Macuada, I. Molina-Riquelme, G. Vidal, N. Pérez-Bravo, C. Vásquez-Trincado, G. Aedo, D. Lagos, P. Yu-Wai-Man, R. Horvath, T. J. Rudge, B. Cartes-Saavedra, V. Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on …

Diesel Exhaust Particles Alter Mitochondrial Bioenergetics And Camp Producing Capacity In Human Bronchial Epithelial Cells, Isabella Cattani-Cavalieri, Marina Trombetta-Lima, Hong Yan, Ana L. Manzano-Covarrubias, Hoeke A. Baarsma, Asmaa Oun, Melissa Mol Van Der Veen, Emily Oosterhout, Amalia M. Dolga, Rennolds S. Ostrom, Samuel Santos Valenca, Martina Schmidt

Pharmacy Faculty Articles and Research

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown.

Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24–72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of …

Ceramide-Mediated Orchestration Of Oxidative Stress Response Through Filopodia-Derived Small Extracellular Vesicles, Zainuddin Quadri, Ahmed Elsherbini, Simone M. Crivelli, Salim S. El-Amouri, Priyanka Tripathi, Zhihui Zhu, Xiaojia Ren, Liping Zhang, Stefka D. Spassieva, Mariana N. Nikolova‑Karakashian, Erhard Bieberich

Markey Cancer Center Faculty Publications

Extracellular vesicles (EVs) are shed from the plasma membrane, but the regulation and function of these EVs remain unclear. We found that oxidative stress induced by H 2 O 2 in Hela cells stimulated filopodia formation and the secretion of EVs. EVs were small (150 nm) and labeled for CD44, indicating that they were derived from filopodia. Filopodia-derived small EVs (sEVs) were enriched with the sphingolipid ceramide, consistent with increased ceramide in the plasma membrane of filopo- dia. Ceramide was colocalized with neutral sphingomyelinase 2 (nSMase2) and acid sphingomyelinase (ASM), two sphingomyelinases generating ceramide at the plasma membrane. Inhibition of …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Characterization Of Mitochondrial Morphology In Drosophila: Early Embryogenesis Description Via Confocal Microscopy, Kendall Miller

Biological Sciences Undergraduate Honors Theses

Mitochondria are not static organelles, but instead are dynamic networks that undergo rapid changes in subcellular distribution, organization, and activity in response to external stimuli. Notably, mitochondria can undergo fission and fusion, collectively known as mitochondrial dynamics. Mitochondrial fusion creates assembled networks of mitochondria that are maximally efficient at generating ATP through oxidative phosphorylation. Conversely, mitochondrial fission leads to network fragmentation and a shift towards glycolysis, which is the dominant mode of ATP generation in oxygen-limiting and stressed conditions. While mitochondrial dynamics have been intensively studied in isolated cells under stressful conditions, much less is known about how mitochondria behave …

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 …

Loss Of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids And Drives Sexually Dimorphic Liver Disease In Mice, Mikala M. Zelows, Corissa Cady, Nikitha Dharanipragada, Anna E. Mead, Zachary A. Kipp, Evelyn A. Bates, Venkateshwari Varadharajan, Rakhee Banerjee, Se-Hyung Park, Nathan R. Shelman, Harrison A. Clarke, Tara R. Hawkinson, Terrymar Medina, Ramon C. Sun, Todd A. Lydic, Terry D. Hinds, Jr., J. Mark Brown, Samir Softic, Gregory A. Graf, Robert N. Helsley

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.

Approach and results: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine …

Stat3 Modulates Cd4+ T Mitochondrial Dynamics And Function In Aging, Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella Kalantar, Jingting Yu, Sara Santacruz-Calvo, Madison K. Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J. Drummond, Elizabeth A. Proctor, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Markey Cancer Center Faculty Publications

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and …

Effects Of Osmotic Stress On Oxygen Consumption Of Drosophila Cells (Kc167), Ali A. Ahmed, Rajib Hassan, Michael A. Menze

The Cardinal Edge

This article investigates the effect of osmotic stress on a drosophila cell line called Kc167.

The embryonic-derived fly (Drosophila melanogaster) cell line, Kc-167, was employed as a model for water-stress sensitivity in Arthropods. Like mammalian cells, cells derived from the fruit fly contain the same basic set of membranous components found in all eukaryotic cells. A series of experiments were conducted to characterize the mitochondrial repones of Kc167 cells to water stress. Precisely, the oxygen flux in a sealed respirometer chamber containing Kc167 cells was measured under hyperosmotic and control conditions. Mitochondrial uncouplers were used in some experiments for intact …

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 …

Mitochondrial Roles In Developmentally Programmed Heart Disease, Eli John Louwagie

Dissertations and Theses

Offspring of diabetic and obese mothers (ODOM) have greater risks of heart disease at birth and later in life. However, prevention is hindered because underlying mechanisms are poorly understood. Mounting studies in the Developmental Origins of Health and Disease field suggest that mitochondria play key roles in developmentally programmed heart disease similar to the roles they play in cardiomyopathy in adults with diabetes and obesity. However, whether mitochondria are responsible for the short[1]and long-term cardiac disease seen in ODOM remains unknown. Here, we sought to delineate the roles of mitochondria in the hearts of ODOM, determine whether mitochondria are playing …

Therapies For Mitochondrial Disorders, Kayli Sousa Smyth, Anne Mulvihill

SURE Journal: Science Undergraduate Research Experience Journal

Mitochondria are cytoplasmic, double-membrane organelles that synthesise adenosine triphosphate (ATP). Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is maternally inherited from the oocyte. Mitochondrial proteins are encoded by either nuclear DNA (nDNA) or mtDNA, and both code for proteins forming the mitochondrial oxidative phosphorylation (OXPHOS) complexes of the respiratory chain. These complexes form a chain that allows the passage of electrons down the electron transport chain (ETC) through a proton motive force, creating ATP from adenosine diphosphate (ADP). This study aims to explore current and prospective therapies for mitochondrial disorders (MTDS). MTDS are clinical syndromes coupled with abnormalities …

Dpc29 Promotes Mitochondrial Translation Post-Initation In Saccharomyces Cerevisiae, Kyle Andrew Hubble

Graduate School of Biomedical Sciences Theses and Dissertations

Although the cytosolic and bacterial translation systems are well studied, much less is known about translation in mitochondria. In the yeast Saccharomyces cerevisiae, mitochondrial gene expression is predominately regulated by translational activators. These regulators are thought to promote translation by binding the elongated 5’-UTRs on their target mRNAs. Since mammalian mitochondrial mRNAs generally lack 5’-UTRs, they must regulate translation by other mechanisms. As expected, most yeast translational activators lack orthologues in mammals. Recently, a mitochondrial gene-specific translational activator, TACO1, was reported in mice and humans. To better define its role in mitochondrial translation I examined the yeast TACO1 orthologue, DPC29. …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations and Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

Mechanisms And Roles Of Dynamic Actin Assembly Around Dysfunctional Mitochondria, Tak Shun Fung

Dartmouth College Ph.D Dissertations

Possessing the ability to efficiently generate ATP required to sustain cellular functions, mitochondria are often considered the ‘powerhouses of the cell’. However, our understanding of mitochondria in cell biology was further expanded when we recognized that communication between this unique organelle and the rest of the cell regulates cellular bioenergetics, metabolism and signaling processes such as mitophagy and apoptosis. Here, I investigate signaling between mitochondria and the actin cytoskeleton, and how this signaling regulates mitochondrial dynamics and cellular function. Specifically, I find that, upon mitochondrial dysfunction, actin polymerizes rapidly around the dysfunctional organelle, which we term ‘acute damage-induced actin’ (ADA). …

Role Of Galactose, Thiazolidinediones, And Neet Proteins In Mitochondrial Physiology And Therapeutic Development., Robert Anthony Skolik

Electronic Theses and Dissertations

This dissertation explores the relationship between mitochondrial physiology and development of therapeutics. Mitochondrial dysfunction is associated with both acute and chronic forms of pathophysiology. This work aims to address development efforts at the cell culture and drug-target levels with respect to mitochondria. At the cell culture level, I characterize an approach that has been shown to improve the physiological dependency on mitochondria in tumor-derived cells. I demonstrate that prolonged replacement of glucose with galactose in culture medium induces a global metabolic shift in hepatocellular carcinoma (HepG2) cells to closer reflect a primary hepatocyte phenotype (Chapter 2). I characterize this shift …

Determining The Effects Of Chemical Exposure On Hepatocyte Mitochondrial Networks And Cell Viability, Bethany Eaton

All Master's Theses

Mitochondria are cellular organelles that are becoming more recently studied. One of their main functions is the production of energy through cellular respiration, which is crucial to cell life. However, they are also associated with numerous disease states. It is hypothesized that reactive oxygen species (ROS), largely produced in mitochondria, induce oxidative stress and affect mitochondrial morphology along with cell viability. This study compares chemical exposure of menadione, an ROS producer, and phthalates (plasticizers) on two mouse hepatocyte cell lines to determine the effects they have on mitochondrial morphology and cell viability. Three experiments were performed to analyze the effects …