Medical Sciences Commons^™

Mitochondria Exert Age-Divergent Effects On Recovery From Spinal Cord Injury, Andrew N. Stewart, Katelyn E. Mcfarlane, Hemendra J. Vekaria, William M. Bailey, Stacey A. Slone, Lauren A. Tranthem, Bei Zhang, Samir P. Patel, Patrick G. Sullivan, John C. Gensel

Physiology Faculty Publications

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue …

Radiation Induces Metabolic Dysregulation In Pulmonary Fibroblasts, Josly Pierre-Louis, Margaret A. T. Freeberg, Jane K. Rebman, Thomas H. Thatcher, Patricia J. Sime

Graduate Research Posters

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we …

Mechanisms And Therapeutic Interventions For Breast Cancer-Induced Fatigue And Mitochondrial Dysfunction, David Andrew Stanton

Graduate Theses, Dissertations, and Problem Reports

According to the latest statistics from the National Cancer Institute (NCI), about 1 in 8 U.S. women (~13%) will develop invasive breast cancer over the course of their lifetime. This translates to an estimated 268,600 new cases of breast cancer for the year 2019, and these diagnoses will collectively make up 15% of all new cancer cases across all cancer types. The majority of these women will experience the often-debilitating symptom of breast cancer-induced fatigue. these patients often have difficulty performing normal activities of daily living, have decreased tolerance to traditional tumor-directed therapies, and have higher rates of cancer recurrence. …

Transcriptional Regulation And Islet Transplantation Advantages Of Brown Adipose Tissue, Jessica D. Kepple

All ETDs from UAB

Metabolic disease encompasses various disorders, including obesity and diabetes, that negatively impact glucose and lipid homeostasis and increase the risk of co-morbidities. Adipose tissue, which regulates whole-body energy balance and acts as a specialized endocrine tissue, is negatively affected by obesity and diabetes. Brown adipose tissue (BAT) functions to dissipate excess energy as heat and therefore is an attractive target against metabolic disease. To develop more effective therapeutic strategies, BAT physiology and genetic regulatory mechanisms need to be better understood. This dissertation highlights studies seeking to illuminate novel transcriptional regulation and islet transplantation applications of BAT. We investigated the requirement …

Beyond The Brain: A Study Of Α-Synuclein's Role In Bone And Adipose Tissue, Carolina A. Figueroa

Electronic Theses and Dissertations

α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but it is also found in bones and adipose tissue. Co-expression analysis showed that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss and weight gain. It is a major component of Lewy bodies (LB) in Parkinson’s disease (PD), leading to progressive immobilization and a range of nonmotor symptoms, including osteopenia, body composition alterations and insulin resistance. This thesis aimed to determine α-Synuclein’s intrinsic role in bone and adipose homeostasis. We discussed the PD pathophysiology emphasizing aspects of bone health and metabolism. By using …

Therapeutic Potential Of A Ketogenic Diet In The Treatment Of Major Depressive Disorder, Jordan A. Murrin

Masters Theses, 2020-current

Major depressive disorder (MDD) is the second most common mental health condition and a leading cause of disability in the world. It is theorized that MDD develops from a combination of biological, psychological, and social stressors. The condition is typically treated using pharmaceuticals and psychotherapy. However, not all individuals with MDD have access to or choose to use these treatments, or may prefer to incorporate therapeutic lifestyle changes such as exercise, sleep, and healthy eating. Even with treatment, MDD can alter brain structure and function, leading to the development of comorbid mental health and chronic metabolic conditions like obesity, cardiovascular …

Tumor-Derived Exosomes Drive Immunosuppressive Macrophages In A Pre-Metastatic Niche Through Nf-Kβ Dependent Glycolytic Metabolic Reprogramming., Samantha M. Morrissey

Electronic Theses and Dissertations

The formation of a pre-metastatic niche is a fundamental requirement for primary tumor metastasis. One of the defining characteristics of a pre-metastatic niche is infiltration of immunosuppressive macrophages. However, how these macrophages acquire their immunosuppressive phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDE) polarize macrophages towards an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent metabolic reprogramming in mice and humans. While NF-κB has previously been shown to act as a direct transcription factor for PD-L1, we report a novel mechanism where TDE-induced NF-κB activation drives PD-L1 expression by augmenting the glycolytic capacity of macrophages through …

Microrna-148a Regulates Low-Density Lipoprotein Metabolism By Repressing The (Pro)Renin Receptor, Na Wang, Lishu He, Hui Lin, Lunbo Tan, Yuan Sun, Xiaoying Zhang, A. H. Jan Danser, Hong S. Lu, Yongcheng He, Xifeng Lu

Saha Cardiovascular Research Center Faculty Publications

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDL receptor (LDLR) regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we have identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silico analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of the (P)RR …

Metabolic Requirements Of Nk Cell Responses To Viral Infection, Annelise Yoo Mah-Som

Arts & Sciences Electronic Theses and Dissertations

In recent years, the field of immunometabolism – the study of how specific changes in cellular metabolism regulate the function of diverse immune cell types—has grown exponentially. Several in vitro studies have examined the metabolic regulation of natural killer (NK) cells, which are first responders for viral infection and malignant transformation; however, much less is known regarding the role of metabolism in directing NK cell responses in vivo, such as during viral infection. In order to examine how NK cell antiviral function is regulated in vivo, we used a wellcharacterized infection with murine cytomegalovirus (MCMV) to assess NK cell cytokine …

Visualizing Metabolic Network Dynamics Through Time-Series Metabolomic Data., Lea F Buchweitz, James T Yurkovich, Christoph Blessing, Veronika Kohler, Fabian Schwarzkopf, Zachary A King, Laurence Yang, Freyr Jóhannsson, Ólafur E Sigurjónsson, Óttar Rolfsson, Julian Heinrich, Andreas Dräger

Articles, Abstracts, and Reports

BACKGROUND: New technologies have given rise to an abundance of -omics data, particularly metabolomic data. The scale of these data introduces new challenges for the interpretation and extraction of knowledge, requiring the development of innovative computational visualization methodologies. Here, we present GEM-Vis, an original method for the visualization of time-course metabolomic data within the context of metabolic network maps. We demonstrate the utility of the GEM-Vis method by examining previously published data for two cellular systems-the human platelet and erythrocyte under cold storage for use in transfusion medicine.

RESULTS: The results comprise two animated videos that allow for new insights …

Acute Blockade Of Pacap-Dependent Activity In The Ventromedial Nucleus Of The Hypothalamus Disrupts Leptin-Induced Behavioral And Molecular Changes In Rats, Matthew M. Hurley, Eden M. Anderson, Christopher Chen, Brian Maunze, Evan Michael Hess, Megan E. Block, Neerali Patel, Zane Cooper, Riley Mccoy, Tanya Dabra, William Conley, Michael J. Reilly, Matthew C. Hearing, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase activating-polypeptide (PACAP) has been shown to reduce …

Apoe As A Metabolic Regulator In Humans, Mice, And Astrocytes, Brandon C. Farmer

Theses and Dissertations--Physiology

Altered metabolic pathways appear to play central roles in the pathophysiology of late-onset Alzheimer’s disease (AD). Carrier status of the E4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD, and increasing evidence suggests that E4 carriers may be at an increased risk for neurodegeneration based on inherent metabolic impairments. A new appreciation is forming for the role of APOE in cerebral metabolism, and how nutritional factors may impact this role. In chapter 1, the literature on nutritional interventions in E4 carriers aimed at mitigating disease risk is reviewed. Studies investigating the mechanism by which …

Investigations Of A Low Carbohydrate Ketogenic Diet As A Possible Treatment For Malignant Brain Tumors, Elizabeth Anaya

Regis University Student Publications (comprehensive collection)

Cancer is now the leading cause of premature death in the U.S. and second worldwide. However, all cancers on average have seen a 20% increase in 5-year survival in the last 30 years. This is not true for brain cancers which have only seen a 1% increase. Brain cancer is extremely hard to treat, costing the most money out of any other cancer. Nevertheless, Otto Warburg’s investigation of cancer as a metabolic disease has led to a variety of new promising treatments. One of these treatments involves starving cancer cells by cutting off their access to glucose, a key component …

Understanding And Targeting Glucose Transporter 3 In Glioblastoma, Catherine Jeanne Libby

All ETDs from UAB

Glioblastoma (GBM) is the most common adult primary malignant brain tumor with a median survival of about 15 months, even after aggressive treatment. Treatment of GBM is difficult for multiple reasons including the location of the tumor, tumor invasiveness, and the high degree of both inter-and intra-tumoral heterogeneity. Contributing to intratumoral heterogeneity are highly tumorigenic, stem-like tumor cells, with the capacity to self-renew and propagate the tumor, termed brain tumor initiating cells (BTICs). BTICs are also commonly therapy resistant, highly invasive, and metabolically plastic with elevated expression of glucose transporter 3 (GLUT3) allowing them to preferentially survive in low nutrient …

Myc-Mediated Transcriptional Regulation Of The Mitochondrial Chaperone Trap1 Controls Primary And Metastatic Tumor Growth., Ekta Agarwal, Brian J. Altman, Jae Ho Seo, Jagadish C. Ghosh, Andrew V Kossenkov, Hsin-Yao Tang, Shiv Ram Krishn, Lucia R. Languino, Dmitry I. Gabrilovich, David W. Speicher, Chi V. Dang, Dario C. Altieri

Department of Cancer Biology Faculty Papers

The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein- 1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II …

Hdl Subclass Proteomic Analysis And Functional Implication Of Protein Dynamic Change During Hdl Maturation, Yuling Zhang, Scott M. Gordon, Hang Xi, Seungbum Choi, Merlin Abner Paz, Runlu Sun, William Yang, Jason Saredy, Mohsin Khan, Alan Thomas Remaley, Jing-Feng Wang, Xiaofeng Yang, Hong Wang

Saha Cardiovascular Research Center Faculty Publications

Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven …

Monocyte Anti-Inflammatory Activity Is Dictated By Metabolic Status During Staphylococcus Aureus Biofilm Infection, Kelsey J. Yamada

Theses & Dissertations

Staphylococcus aureus biofilms represent a significant cause of morbidity and economic burden and are often associated with nosocomial infections, including medically implanted devices. In particular, prosthetic joint infections (PJIs) are a growing concern due to the continued increase in orthopedic procedures. Staphylococcal species cause >50% of all PJIs, while S. aureus represents the most invasive and associated with the most morbidity. S. aureus-associated biofilm infections are recalcitrant to antibiotic therapy, due to both the acquisition of genetic elements and metabolic dormancy. Furthermore, S. aureus biofilm infections remain chronic because they cannot be cleared by the immune system. Recent studies …

Protease-Mediated Growth Of Staphylococcus Aureus On Host Proteins Is Opp3 Dependent, Mckenzie K. Lehman, Austin S. Nuxoll, Kelsey J. Yamada, Tammy Kielian, Steven D. Carson, Paul D. Fey

Journal Articles: Pathology and Microbiology

Staphylococcus aureus has the ability to cause infections in multiple organ systems, suggesting an ability to rapidly adapt to changing carbon and nitrogen sources. Although there is little information about the nutrients available at specific sites of infection, a mature skin abscess has been characterized as glucose depleted, indicating that peptides and free amino acids are an important source of nutrients for the bacteria. Our studies have found that mutations in enzymes necessary for growth on amino acids, including pyruvate carboxykinase (ΔpckA) and glutamate dehydrogenase (ΔgudB), reduced the ability of the bacteria to proliferate within a …

In Vivo Gene Essentiality And Metabolism In Bordetella Pertussis, Laura A. Gonyar, Patrick E. Gelbach, Dennis G. Mcduffe, Alexander F. Koeppel, Qing Chen, Gloria Lee, Louise M. Temple, Scott Stibitz, Erik L. Hewlwtt, Jason A. Papin, F. Heath Damron, Joshua C. Eby

Faculty & Staff Scholarship

Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis …

The Role Of The St6gal-I Sialyltrasferase In Protecting Tumor Cells From Hypoxic Stress, Robert Brent Jones

All ETDs from UAB

An emerging concept in cancer biology is that surface glycosylation can play important roles in the regulation of cancer development and progression. Our group and others have shown that ST6Gal-I, a sialyltransferase that adds α2-6-linked sialic acids to N-glycosylated proteins, is upregulated in many cancers. Furthermore, data has indicated that ST6Gal-I acts as a pro-survival factor in a variety of settings, including resistance to chemotherapeutic drugs, radiotherapy resistance, and serum deprivation. The work presented in this dissertation adds to this understanding of ST6Gal-I’s role as a potent pro-survival factor and explores ST6Gal-I’s function in aiding tumor cells to survive hypoxic …

Highly Efficient 5' Capping Of Mitochondrial Rna With Nad+ And Nadh By Yeast And Human Mitochondrial Rna Polymerase, Jeremy G Bird, Urmimala Basu, David Kuster, Aparna Ramachandran, Ewa Grudzien-Nogalska, Atif Towheed, Douglas C. Wallace, Megerditch Kiledjian, Dmitry Temiakov, Smita S. Patel, Richard H. Ebright, Bryce E. Nickels

Department of Biochemistry and Molecular Biology Faculty Papers

Bacterial and eukaryotic nuclear RNA polymerases (RNAPs) cap RNA with the oxidized and reduced forms of the metabolic effector nicotinamide adenine dinucleotide, NAD+ and NADH, using NAD+ and NADH as non-canonical initiating nucleotides for transcription initiation. Here, we show that mitochondrial RNAPs (mtRNAPs) cap RNA with NAD+ and NADH, and do so more efficiently than nuclear RNAPs. Direct quantitation of NAD+- and NADH-capped RNA demonstrates remarkably high levels of capping in vivo: up to ~60% NAD+ and NADH capping of yeast mitochondrial transcripts, and up to ~15% NAD+ capping of human mitochondrial transcripts. The capping efficiency is determined by promoter …

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 and possibly …

Alpha-Amino-Beta-Carboxy-Muconate-Semialdehyde Decarboxylase Controls Dietary Niacin Requirements For Nad+ Synthesis, Laura Palzer, Jessica J. Bader, Frances Angel, Megan Witzel, Sydney Blaser, Alexis Mcneil, Miles K. Wandersee, N. Adrian Leu, Christopher J. Lengner, Clara E. Cho, Kevin D. Welch, James B. Kirkland, Ralph G. Meyer, Mirella L. Meyer-Ficca

Animal, Dairy, and Veterinary Science Faculty Publications

NAD⁺ is essential for redox reactions in energy metabolism and necessary for DNA repair and epigenetic modification. Humans require sufficient amounts of dietary niacin (nicotinic acid, nicotinamide, and nicotinamide riboside) for adequate NAD⁺ synthesis. In contrast, mice easily generate sufficient NAD⁺ solely from tryptophan through the kynurenine pathway. We show that transgenic mice with inducible expression of human alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase (ACMSD) become niacin dependent similar to humans when ACMSD expression is high. On niacin-free diets, these acquired niacin dependency (ANDY) mice developed reversible, mild-to-severe NAD⁺ deficiency, depending on the nutrient composition of the diet. NAD deficiency …

Ketogenic Diet Modulates Nad+-Dependent Enzymes And Reduces Dna Damage In Hippocampus, Marwa Elamin, David N. Ruskin, Susan A. Masino, Paola Sacchetti

Faculty Scholarship

© 2018 Elamin, Ruskin, Masino and Sacchetti. The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 …

Apoe And Alzheimer’S Disease: Neuroimaging Of Metabolic And Cerebrovascular Dysfunction, Jason A. Brandon, Brandon C. Farmer, Holden C. Williams, Lance A. Johnson

Physiology Faculty Publications

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In …

Pkm2 Influences The Metabolic Fate Of Butyrate In Colorectal Cancer Cells, Megan Louise Pence

Chancellor’s Honors Program Projects

No abstract provided.

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Novel Insights Into Neurofibromin Function And Human Neurofibromatosis Type 1 Mutations Using Genetically Engineered Mouse Models, Ashley Nicole Turner

All ETDs from UAB

Loss of NF1 in different developmental and cellular contexts leads to unique physiological outcomes due to loss of neurofibromin function, including embryonic lethality, sporadic cancers, and the genetic disorder NF1. Neurofibromin acts as a tumor suppressor by modulation of RAS signaling, with other functions of this multi-domain protein being less clear. Even within the monogenic disorder of NF1, the clinical heterogeneity and mutational spectrum are immense, revealing the complexity underlying this disorder. There is a huge urgency and need for NF1 therapeutic treatments, and the same urgency to develop in vivo models to better understand NF1 that can be utilized …

Mechanistic Connections Between Metabolic And Differentiation Programs In T Cells, Danielle Alexandria Chisolm

All ETDs from UAB

Cellular metabolism is closely coupled to differentiation gene programs in many developmental systems. In part, this is due to a similar complement of transcription factors playing dual roles in regulating both the gene expression programs associated with specific metabolic pathways and the differentiation gene program of the cell. In T cells, T cell receptor- (TCR) and IL-2-sensitive transcription factors coordinate the programming of metabolic states with the effector and memory gene programs. Currently, our understanding of the mechanisms by which metabolic states contribute to the regulation of T cell differentiation gene programs is unclear. Metabolites are directly involved in epigenetic …

Mitochondrial Reactive Oxygen Species In Lipotoxic Hearts Induces Post-Translational Modifications Of Akap121, Drp1 And Opa1 That Promote Mitochondrial Fission, Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose Mcglauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel

Department of Biochemistry: Faculty Publications

Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood.

Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.

Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing long-chain acyl-CoA synthetase 1 in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation …