Gerald W Dorn

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (258)2383.55 Total impact

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    ABSTRACT: Background: -MicroRNAs are key players in cardiac stress responses, but the mRNAs whose abundance and/or translational potential are primarily affected by changes in cardiac microRNAs are not well defined. Stimulus-induced, large-scale alterations in the cardiac transcriptome, together with consideration of the law of mass action, further suggest that the mRNAs most substantively targeted by individual microRNAs will vary between unstressed and stressed conditions. To test the hypothesis that microRNA target profiles differ in health and disease, we traced the fate of empirically-determined miR-133a and miR-378 targets in mouse hearts undergoing pressure-overload hypertrophy. Methods and results: -Ago2 immunoprecipitation with RNA-sequencing (RISC-sequencing) was used for unbiased definition of microRNA-dependent and -independent alterations occurring amongst ~13,000 mRNAs in response to transverse aortic constriction (TAC). Of 37 direct targets of miR-133a defined in unstressed hearts (fold-change ≥25%, FDR<0.02), only 4 (11%) continued to be targeted by miR-133a during TAC, while for miR-378 direct targets, 3 of 32 targets (9%) were maintained during TAC. Similarly, only 16% (for miR-133a) and 53% (for miR-378) of hundreds of indirectly affected mRNAs underwent comparable regulation, demonstrating that the effect of TAC on microRNA direct target selection resulted in widespread alterations of signaling function. Numerous microRNA-mediated regulatory events occurring exclusively during pressure overload revealed signaling networks that may be responsive to the endogenous decreases in miR-133a during TAC. Conclusions: -Pressure overload-mediated changes in overall cardiac RNA content alter microRNA targeting profiles, reinforcing the need to define microRNA targets in tissue-, cell- and status-specific contexts.
    Circulation Cardiovascular Genetics 11/2015; DOI:10.1161/CIRCGENETICS.115.001237 · 4.60 Impact Factor
  • Gerald W. Dorn · Rick B. Vega · Daniel P. Kelly ·
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    ABSTRACT: The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts.
    Genes & Development 10/2015; 29(19):1981-1991. DOI:10.1101/gad.269894.115 · 10.80 Impact Factor
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    ABSTRACT: The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiomyocyte-specific interruption of Drp1-mediated mitochondrial fission. To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission-defective adult mouse hearts. Parkin mRNA and protein were present at very low levels in normal mouse hearts, but were upregulated after cardiomyocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiomyocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiomyocyte-specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission-defective hearts, also increasing 6 week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiomyocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/SQSTM1 and processed LC3. Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiomyocytes. Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiomyocytes not only interrupts mitochondrial fission, but markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.
    Circulation Research 06/2015; 117(4). DOI:10.1161/CIRCRESAHA.117.306859 · 11.02 Impact Factor
  • Orian S Shirihai · Moshi Song · Gerald W Dorn ·
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    ABSTRACT: Mitochondria are highly dynamic, except in adult cardiomyocytes. Yet, the fission and fusion-promoting proteins that mediate mitochondrial dynamism are highly expressed in, and essential to the normal functioning of, hearts. Here, we review accumulating evidence supporting important roles for mitochondrial fission and fusion in cardiac mitochondrial quality control, focusing on the PTEN-induced putative kinase 1-Parkin mitophagy pathway. Based in part on recent findings from in vivo mouse models in which mitofusin-mediated mitochondrial fusion or dynamin-related protein 1-mediated mitochondrial fission was conditionally interrupted in cardiac myocytes, we propose several new concepts that may provide insight into the cardiac mitochondrial dynamism-mitophagy interactome. © 2015 American Heart Association, Inc.
    Circulation Research 05/2015; 116(11):1835-1849. DOI:10.1161/CIRCRESAHA.116.306374 · 11.02 Impact Factor
  • Gerald W Dorn ·
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    ABSTRACT: "The broken heart. You think you will die, but you just keep living, day after day after terrible day." - Charles Dickens' Great Expectations(1) There seem to be as many approaches to managing heart failure as there are causal factors. Heart failure management is evolving from a one-size-fits-all approach centered around therapy with neurohormonal antagonists toward strategies tailored to provide the optimal clinical benefit based upon individual patient profile. Thus, a major collective enterprise of the translational research community has been to identify subsets of patients that will derive greater benefit from one or another management scheme. The initial observation that, like cancer and other pathologies, microRNAs are regulated in heart disease(2) was coupled with observations that microRNAs are found circulating in stable form in the blood(3, 4) to raise expectations that microRNAs would prove useful as disease biomarkers, providing insights into aspects of heart disease not revealed through traditional clinical testing(5). In the current issue of Circulation, Melman et al propose miR-30d as a biomarker for heart failure responsiveness to cardiac resynchronization therapy(6). This manuscript aptly illustrates the promise, problems, and pitfalls with the current state of evaluating microRNAs as biomarkers of cardiovascular disease. To quote Pip's sister in Great Expectations: "Answer him one question, and he'll ask you a dozen directly"(1).
    Circulation 05/2015; 131(25). DOI:10.1161/CIRCULATIONAHA.115.017176 · 14.43 Impact Factor
  • Moshi Song · Scot J Matkovich · Yan Zhang · Daniel J Hammer · Gerald W Dorn ·
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    ABSTRACT: Cell growth is orchestrated by changes in gene expression that respond to developmental and environmental cues. Among the signaling pathways that direct growth are enzymes of the protein kinase C (PKC) family, which are ubiquitous proteins belonging to three distinct subclasses: conventional PKCs, novel PKCs, and atypical PKCs. Functional overlap makes determining the physiological actions of different PKC isoforms difficult. We showed that two novel PKC isoforms, PKCδ and PKCε, redundantly govern stress-reactive and developmental heart growth by modulating the expression of cardiac genes central to stress-activated protein kinase and periostin signaling. Mice with combined postnatal cardiomyocyte-specific genetic ablation of PKCδ and germline deletion of PKCε (DCKO) had normally sized hearts, but their hearts had transcriptional changes typical of pathological hypertrophy. Cardiac hypertrophy and dysfunction induced by hemodynamic overloading were greater in DCKO mice than in mice with a single deletion of either PKCδ or PKCε. Furthermore, gene expression analysis of the hearts of DCKO mice revealed transcriptional derepression of the genes encoding the kinase ERK (extracellular signal-regulated kinase) and periostin. Mice with combined embryonic ablation of PKCδ and PKCε showed enhanced growth and cardiomyocyte hyperplasia that induced pathological ventricular stiffening and early lethality, phenotypes absent in mice with a single deletion of PKCδ or PKCε. Our results indicate that novel PKCs provide retrograde feedback inhibition of growth signaling pathways central to cardiac development and stress adaptation. These growth-suppressing effects of novel PKCs have implications for therapeutic inhibition of PKCs in cancer, heart, and other diseases. Copyright © 2015, American Association for the Advancement of Science.
    Science Signaling 04/2015; 8(373):ra39. DOI:10.1126/scisignal.aaa1855 · 6.28 Impact Factor
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    Gerald W Dorn ·
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    ABSTRACT: Mitochondria of adult cardiomyocytes appear hypo-dynamic, lacking interconnected reticular networks and the continual fission and fusion observed in many other cell types. Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts. Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control. This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism-quality control interactome in normal and diseased hearts. Newly discovered functions of mitochondrial dynamics factors in maintaining optimal cardiac mitochondrial fitness suggest that deep interrogation of clinical cardiomyopathy is likely to reveal genetic variants that cause or modify cardiac disease through their effects on mitochondrial fission, fusion, and mitophagy. © 2015 The Author. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 04/2015; 7(7). DOI:10.15252/emmm.201404575 · 8.67 Impact Factor
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    ABSTRACT: A large part of the mammalian genome is transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators of gene expression. Distinct molecular mechanisms allow lncRNAs either to activate or to repress gene expression, thereby participating in the regulation of cellular and tissue function. LncRNAs, therefore, have important roles in healthy and diseased hearts, and might be targets for therapeutic intervention. In this Review, we summarize the current knowledge of the roles of lncRNAs in cardiac development and ageing. After describing the definition and classification of lncRNAs, we present an overview of the mechanisms by which lncRNAs regulate gene expression. We discuss the multiple roles of lncRNAs in the heart, and focus on the regulation of embryonic stem cell differentiation, cardiac cell fate and development, and cardiac ageing. We emphasize the importance of chromatin remodelling in this regulation. Finally, we discuss the therapeutic and biomarker potential of lncRNAs.
    Nature Reviews Cardiology 04/2015; 12(7). DOI:10.1038/nrcardio.2015.55 · 9.18 Impact Factor
  • Scot J Matkovich · Gerald W Dorn ·
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    ABSTRACT: MicroRNAs are a family of short (~21 nucleotide) noncoding RNAs that serve key roles in cellular growth and differentiation and the response of the heart to stress stimuli. As the sequence-specific recognition element of RNA-induced silencing complexes (RISCs), microRNAs bind mRNAs and prevent their translation via mechanisms that may include transcript degradation and/or prevention of ribosome binding. Short microRNA sequences and the ability of microRNAs to bind to mRNA sites having only partial/imperfect sequence complementarity complicate purely computational analyses of microRNA-mRNA interactomes. Furthermore, computational microRNA target prediction programs typically ignore biological context, and therefore the principal determinants of microRNA-mRNA binding: the presence and quantity of each. To address these deficiencies we describe an empirical method, developed via studies of stressed and failing hearts, to determine disease-induced changes in microRNAs, mRNAs, and the mRNAs targeted to the RISC, without cross-linking mRNAs to RISC proteins. Deep sequencing methods are used to determine RNA abundances, delivering unbiased, quantitative RNA data limited only by their annotation in the genome of interest. We describe the laboratory bench steps required to perform these experiments, experimental design strategies to achieve an appropriate number of sequencing reads per biological replicate, and computer-based processing tools and procedures to convert large raw sequencing data files into gene expression measures useful for differential expression analyses.
    Methods in molecular biology (Clifton, N.J.) 04/2015; 1299:27-49. DOI:10.1007/978-1-4939-2572-8_3 · 1.29 Impact Factor
  • Moshi Song · Gerald W Dorn ·
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    ABSTRACT: Mitochondrial fitness is central to heart health. In many cell types, mitochondria are dynamic, interconnected filamentous networks. By comparison, mitochondria of healthy postmitotic adult cardiomyocytes are shortened, round, hypodynamic organelles. Mitochondrial networks are absent in cardiomyocytes; fission, fusion, and organelle mobility are not normally observed. Nevertheless, mitochondrial fission factor Drp1 and fusion factors Mfn1, Mfn2, and Opa1 are abundant and indispensable in adult hearts. Here, we review recent insights into roles for mitochondrial dynamics factors not strictly related to morphometric remodeling, advancing the argument that fission and fusion of cardiomyocyte mitochondria support surveillance, sequestration, and mitophagic removal of damaged organelles. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 02/2015; 21(2):195-205. DOI:10.1016/j.cmet.2014.12.019 · 17.57 Impact Factor
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    ABSTRACT: Rationale: Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation. Objective: To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq. Methods and results: Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion. Conclusions: Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.
    Circulation Research 01/2015; 116(5). DOI:10.1161/CIRCRESAHA.116.304682 · 11.02 Impact Factor
  • Gerald W Dorn ·

    Circulation Research 01/2015; 116(2):225-8. DOI:10.1161/CIRCRESAHA.114.305672 · 11.02 Impact Factor
  • Moshi Song · Katsuyoshi Mihara · Yun Chen · Luca Scorrano · Gerald W Dorn ·
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    ABSTRACT: How mitochondrial dynamism (fission and fusion) affects mitochondrial quality control is unclear. We uncovered distinct effects on mitophagy of inhibiting Drp1-mediated mitochondrial fission versus mitofusin-mediated mitochondrial fusion. Conditional cardiomyocyte-specific Drp1 ablation evoked mitochondrial enlargement, lethal dilated cardiomyopathy, and cardiomyocyte necrosis. Conditionally ablating cardiomyocyte mitofusins (Mfn) caused mitochondrial fragmentation with eccentric remodeling and no cardiomyocyte dropout. Parallel studies in cultured murine embryonic fibroblasts (MEFs) and in vivo mouse hearts revealed that Mfn1/Mfn2 deletion provoked accumulation of defective mitochondria exhibiting an unfolded protein response, without appropriately increasing mitophagy. Conversely, interrupting mitochondrial fission by Drp1 ablation increased mitophagy and caused a generalized loss of mitochondria. Mitochondrial permeability transition pore (MPTP) opening in Drp1 null mitochondria was associated with mitophagy in MEFs and contributed to cardiomyocyte necrosis and dilated cardiomyopathy in mice. Drp1, MPTP, and cardiomyocyte mitophagy are functionally integrated. Mitochondrial fission and fusion have opposing roles during in vivo cardiac mitochondrial quality control. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 01/2015; 21(2). DOI:10.1016/j.cmet.2014.12.011 · 17.57 Impact Factor
  • Poonam Bhandari · Moshi Song · Gerald W Dorn ·
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    ABSTRACT: Mitochondrial dynamism (fusion and fission) is responsible for remodeling interconnected mitochondrial networks in some cell types. Adult cardiac myocytes lack mitochondrial networks, and their mitochondria are inherently "fragmented". Mitochondrial fusion/fission is so infrequent in cardiomyocytes as to not be observable under normal conditions, suggesting that mitochondrial dynamism may be dispensable in this cell type. However, we previously observed that cardiomyocyte-specific genetic suppression of mitochondrial fusion factors optic atrophy 1 (Opa1) and mitofusin/MARF evokes cardiomyopathy in Drosophila hearts. We posited that fusion-mediated remodeling of mitochondria may be critical for cardiac homeostasis, although never directly observed. Alternately, we considered that inner membrane Opa1 and outer membrane mitofusin/MARF might have other as-yet poorly described roles that affect mitochondrial and cardiac function. Here we compared heart tube function in three models of mitochondrial fragmentation in Drosophila cardiomyocytes: Drp1 expression, Opa1 RNAi, and mitofusin MARF RNA1. Mitochondrial fragmentation evoked by enhanced Drp1-mediated fission did not adversely impact heart tube function. In contrast, RNAi-mediated suppression of either Opa1 or mitofusin/MARF induced cardiac dysfunction associated with mitochondrial depolarization and ROS production. Inhibiting ROS by overexpressing superoxide dismutase (SOD) or suppressing ROMO1 prevented mitochondrial and heart tube dysfunction provoked by Opa1 RNAi, but not by mitofusin/MARF RNAi. In contrast, enhancing the ability of endoplasmic/sarcoplasmic reticulum to handle stress by expressing Xbp1 rescued the cardiomyopathy of mitofusin/MARF insufficiency without improving that caused by Opa1 deficiency. We conclude that decreased mitochondrial size is not inherently detrimental to cardiomyocytes. Rather, preservation of mitochondrial function by Opa1 located on the inner mitochondrial membrane, and prevention of ER stress by mitofusin/MARF located on the outer mitochondrial membrane, are central functions of these "mitochondrial fusion proteins". Copyright © 2014. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 12/2014; 80. DOI:10.1016/j.yjmcc.2014.12.018 · 4.66 Impact Factor
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    ABSTRACT: Doxorubicin (DOX) is widely used for treating human cancers, but can induce heart failure through an undefined mechanism. Herein we describe a previously unidentified signaling pathway that couples DOX-induced mitochondrial respiratory chain defects and necrotic cell death to the BH3-only protein Bcl-2-like 19kDa-interacting protein 3 (Bnip3). Cellular defects, including vacuolization and disrupted mitochondria, were observed in DOX-treated mice hearts. This coincided with mitochondrial localization of Bnip3, increased reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and necrosis. Interestingly, a 3.1-fold decrease in maximal mitochondrial respiration was observed in cardiac mitochondria of mice treated with DOX. In vehicle-treated control cells undergoing normal respiration, the respiratory chain complex IV subunit 1 (COX1) was tightly bound to uncoupling protein 3 (UCP3), but this complex was disrupted in cells treated with DOX. Mitochondrial dysfunction induced by DOX was accompanied by contractile failure and necrotic cell death. Conversely, shRNA directed against Bnip3 or a mutant of Bnip3 defective for mitochondrial targeting abrogated DOX-induced loss of COX1-UCP3 complexes and respiratory chain defects. Finally, Bnip3(-/-) mice treated with DOX displayed relatively normal mitochondrial morphology, respiration, and mortality rates comparable to those of saline-treated WT mice, supporting the idea that Bnip3 underlies the cardiotoxic effects of DOX. These findings reveal a new signaling pathway in which DOX-induced mitochondrial respiratory chain defects and necrotic cell death are mutually dependent on and obligatorily linked to Bnip3 gene activation. Interventions that antagonize Bnip3 may prove beneficial in preventing mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.
    Proceedings of the National Academy of Sciences 12/2014; 111(51). DOI:10.1073/pnas.1414665111 · 9.67 Impact Factor
  • Gerald W. Dorn · Scot J. Matkovich ·
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    ABSTRACT: Development, homeostasis and responses to stress in the heart all depend on appropriate control of mRNA expression programs, which may be enacted at the level of DNA sequence, DNA accessibility, and RNA-mediated control of mRNA output. Diverse mechanisms underlie promoter-driven transcription of coding mRNA and their translation into protein, and the ways in which sequence alteration of DNA can make an impact on these processes have been studied for some time. The field of epigenetics explores changes in DNA structure that influence its accessibility by transcriptional machinery, and we are continuing to develop our understanding of how these processes modify cardiac RNA production. In this topical review, we do not focus on how DNA sequence and methylation, and histone interactions, may alter its accessibility, but rather on newly described mechanisms by which some transcribed RNAs may alter initial transcription or downstream processing of other RNAs, involving both short noncoding RNAs (microRNAs) and long noncoding RNAs (lncRNAs). Here we present examples of how these two classes of noncoding RNAs mediate widespread effects on cardiac transcription and protein output, in processes for which we use the broad term ‘epitranscriptional regulation’ (Abstract Diagram), and that are complementary to the DNA methylation and histone modification events studied by classical epigenetics.This article is protected by copyright. All rights reserved
    The Journal of Physiology 11/2014; 593(8). DOI:10.1113/jphysiol.2014.283234 · 5.04 Impact Factor
  • Gerald W Dorn · Richard N Kitsis ·
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    ABSTRACT: Mitochondrial research is experiencing a renaissance in part due to the recognition that these endosymbiotic descendants of primordial protobacteria appear to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us), but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, two components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing non-canonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending upon pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamism and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited.
    Circulation Research 10/2014; 116(1). DOI:10.1161/CIRCRESAHA.116.303554 · 11.02 Impact Factor
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    ABSTRACT: The vast majority of mammalian DNA does not encode for proteins but instead is transcribed into noncoding (nc)RNAs having diverse regulatory functions. The poorly characterized subclass of long ncRNAs (lncRNAs) can epigenetically regulate protein-coding genes by interacting locally in cis or distally in trans. A few reports have implicated specific lncRNAs in cardiac development or failure, but precise details of lncRNAs expressed in hearts and how their expression may be altered during embryonic heart development or by adult heart disease is unknown. Using comprehensive quantitative RNA sequencing data from mouse hearts, livers, and skin cells, we identified 321 lncRNAs present in the heart, 117 of which exhibit a cardiac-enriched pattern of expression. By comparing lncRNA profiles of normal embryonic ( approximately E14), normal adult, and hypertrophied adult hearts, we defined a distinct fetal lncRNA abundance signature that includes 157 lncRNAs differentially expressed compared with adults (fold-change >/= 50%, false discovery rate = 0.02) and that was only poorly recapitulated in hypertrophied hearts (17 differentially expressed lncRNAs; 13 of these observed in embryonic hearts). Analysis of protein-coding mRNAs from the same samples identified 22 concordantly and 11 reciprocally regulated mRNAs within 10 kb of dynamically expressed lncRNAs, and reciprocal relationships of lncRNA and mRNA levels were validated for the Mccc1 and Relb genes using in vitro lncRNA knockdown in C2C12 cells. Network analysis suggested a central role for lncRNAs in modulating NFkappaB- and CREB1-regulated genes during embryonic heart growth and identified multiple mRNAs within these pathways that are also regulated, but independently of lncRNAs.
    Proceedings of the National Academy of Sciences 08/2014; 111(33). DOI:10.1073/pnas.1410622111 · 9.67 Impact Factor
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    ABSTRACT: Super-resolution microscopy techniques-capable of overcoming the diffraction limit of light-have opened new opportunities to explore subcellular structures and dynamics not resolvable in conventional far-field microscopy. However, relying on staining with exogenous fluorescent markers, these techniques can sometimes introduce undesired artifacts to the image, mainly due to large tagging agent sizes and insufficient or variable labeling densities. By contrast, the use of endogenous pigments allows imaging of the intrinsic structures of biological samples with unaltered molecular constituents. Here, we report label-free photoacoustic (PA) nanoscopy, which is exquisitely sensitive to optical absorption, with an 88 nm resolution. At each scanning position, multiple PA signals are successively excited with increasing laser pulse energy. Because of optical saturation or nonlinear thermal expansion, the PA amplitude depends on the nonlinear incident optical fluence. The high-order dependence, quantified by polynomial fitting, provides super-resolution imaging with optical sectioning. PA nanoscopy is capable of super-resolution imaging of either fluorescent or nonfluorescent molecules. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.
    Journal of Biomedical Optics 08/2014; 19(8):86006. DOI:10.1117/1.JBO.19.8.086006 · 2.86 Impact Factor
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    Gerald W Dorn · Elizabeth M McNally ·

    Circulation Research 07/2014; 115(2):208-10. DOI:10.1161/CIRCRESAHA.114.304383 · 11.02 Impact Factor

Publication Stats

16k Citations
2,383.55 Total Impact Points


  • 2008-2015
    • Washington University in St. Louis
      • Center for Pharmacogenomics
      San Luis, Missouri, United States
    • Thomas Jefferson University
      • Division of Hospital Medicine
      Philadelphia, PA, United States
  • 2013
    • Fourth Military Medical University
      Xi’an, Liaoning, China
  • 1998-2011
    • University of California, San Diego
      • Department of Pharmacology
      San Diego, CA, United States
  • 2010
    • Nova Southeastern University
      • Department of Pharmaceutical Sciences
      Florida, NY, United States
  • 1994-2009
    • University of Cincinnati
      • • Department of Internal Medicine
      • • College of Medicine
      Cincinnati, Ohio, United States
  • 2007
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2001-2007
    • Cincinnati Children's Hospital Medical Center
      • • Division of Molecular Cardiovascular Biology
      • • Division of Cardiology
      • • Division of Developmental Biology
      Cincinnati, OH, United States
    • University of Toronto
      • Banting and Best Department of Medical Research
      Toronto, Ontario, Canada
  • 2006
    • University of Helsinki
      • Department of Physical Sciences
      Helsinki, Uusimaa, Finland
  • 2005
    • University of Louisville
      • Institute of Molecular Cardiology
      Louisville, Kentucky, United States
  • 2003
    • Stanford University
      Palo Alto, California, United States
    • Albert Einstein College of Medicine
      • Department of Cell Biology
      New York, New York, United States
  • 2000
    • Stanford Medicine
      Stanford, California, United States