scholarly journals Identification of Fis1 interactors in Toxoplasma gondii reveals a novel protein required for peripheral distribution of the mitochondrion

2019 ◽  
Author(s):  
Kylie Jacobs ◽  
Robert Charvat ◽  
Gustavo Arrizabalaga
Keyword(s):  
Life Cycle ◽  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Membrane Contact Sites ◽  
Intracellular Parasites

ABSTRACTToxoplasma gondii’s singular mitochondrion is very dynamic and undergoes morphological changes throughout the parasite’s life cycle. During parasite division, the mitochondrion elongates, enters the daughter cells just prior to cytokinesis and undergoes fission. Extensive morphological changes also occur as the parasite transitions from the intracellular to the extracellular environment. We show that treatment with the ionophore monensin causes reversible constriction of the mitochondrial outer membrane, and that this effect depends on the function of the fission related protein Fis1. We also observed that mislocalization of the endogenous Fis1 causes a dominant negative effect that affects the morphology of the mitochondrion. As this suggests Fis1 interacts with proteins critical for maintenance of mitochondrial structure, we performed various protein interaction trap screens. In this manner we identified a novel outer mitochondrial membrane protein, LMF1, which is essential for positioning of the mitochondrion in intracellular parasites. Normally, while inside a host cell, the parasite mitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regions of coupling with the parasite pellicle, suggesting the presence of membrane contact sites. In intracellular parasites lacking LMF1 the mitochondrion is retracted away from the pellicle and instead is collapsed, as only normally seen in extracellular parasites. We show that this phenotype is associated with defects in parasite fitness and mitochondrial segregation. Thus, LMF1 is necessary for mitochondrial association with the parasite pellicle during intracellular growth and proper mitochondrial morphology is a prerequisite for mitochondrial division.IMPORTANCEToxoplasma gondii is an opportunistic pathogen that can cause devastating tissue damage in the immunocompromised and the congenitally infected. Current therapies are not effective against all life stages of the parasite and many cause toxic effects. The single mitochondrion of this parasite is a validated drug target and it changes its shape throughout its life cycle. When the parasite is inside of a cell, the mitochondrion adopts a lasso shape that lies in close proximity to the pellicle. The functional significance of this morphology is not understood nor are the proteins involved currently known. We have identified a protein that is required for proper mitochondrial positioning at the periphery and that likely plays a role in tethering this organelle. Loss of this protein results in dramatic changes to the mitochondrial morphology and significant parasite division and propagation defects. Our results give important insight into the molecular mechanisms regulating mitochondrial morphology.

scholarly journals Identification of Fis1 Interactors in Toxoplasma gondii Reveals a Novel Protein Required for Peripheral Distribution of the Mitochondrion

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kylie Jacobs ◽  
Robert Charvat ◽  
Gustavo Arrizabalaga
Keyword(s):  
Life Cycle ◽  
Toxoplasma Gondii ◽  
Morphological Changes ◽  
Dominant Negative Effect ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Content Type ◽  
Membrane Contact Sites ◽  
Intracellular Parasites ◽  
Single Mitochondrion

ABSTRACT Toxoplasma gondii’s single mitochondrion is very dynamic and undergoes morphological changes throughout the parasite’s life cycle. During parasite division, the mitochondrion elongates, enters the daughter cells just prior to cytokinesis, and undergoes fission. Extensive morphological changes also occur as the parasite transitions from the intracellular environment to the extracellular environment. We show that treatment with the ionophore monensin causes reversible constriction of the mitochondrial outer membrane and that this effect depends on the function of the fission-related protein Fis1. We also observed that mislocalization of the endogenous Fis1 causes a dominant-negative effect that affects the morphology of the mitochondrion. As this suggests that Fis1 interacts with proteins critical for maintenance of mitochondrial structure, we performed various protein interaction trap screens. In this manner, we identified a novel outer mitochondrial membrane protein, LMF1, which is essential for positioning of the mitochondrion in intracellular parasites. Normally, while inside a host cell, the parasite mitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regions of coupling with the parasite pellicle, suggesting the presence of membrane contact sites. In intracellular parasites lacking LMF1, the mitochondrion is retracted away from the pellicle and instead is collapsed, as normally seen only in extracellular parasites. We show that this phenotype is associated with defects in parasite fitness and mitochondrial segregation. Thus, LMF1 is necessary for mitochondrial association with the parasite pellicle during intracellular growth, and proper mitochondrial morphology is a prerequisite for mitochondrial division. IMPORTANCE Toxoplasma gondii is an opportunistic pathogen that can cause devastating tissue damage in the immunocompromised and congenitally infected. Current therapies are not effective against all life stages of the parasite, and many cause toxic effects. The single mitochondrion of this parasite is a validated drug target, and it changes its shape throughout its life cycle. When the parasite is inside a cell, the mitochondrion adopts a lasso shape that lies in close proximity to the pellicle. The functional significance of this morphology is not understood and the proteins involved are currently not known. We have identified a protein that is required for proper mitochondrial positioning at the periphery and that likely plays a role in tethering this organelle. Loss of this protein results in dramatic changes to the mitochondrial morphology and significant parasite division and propagation defects. Our results give important insight into the molecular mechanisms regulating mitochondrial morphology.

Abstract 080: Eya4 Induces Hypertrophy Via Regulation Of p27kip1

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Tatjana Williams ◽  
Moritz Hundertmark ◽  
Peter Nordbeck ◽  
Sabine Voll ◽  
Melanie Muehlfelder ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Effect ◽  
Mutant Form ◽  
Cardiac Phenotype ◽  
Truncating Mutation

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

scholarly journals Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

2019 ◽  
Author(s):  
Yanjun Kou ◽  
Yunlong He ◽  
Jiehua Qiu ◽  
Shu Yazhou ◽  
Fan Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Blast Disease ◽  
Cereal Crops ◽  
Mitochondrial Morphology ◽  
Invasive Growth ◽  
In Planta ◽  
Antioxidant Treatment

SUMMARYMagnaporthe oryzaecauses Blast disease, which is one of the most devastating infections in rice and several important cereal crops.M. oryzaeneeds to coordinate gene regulation, morphological changes, nutrient acquisition, and host evasion, in order to invade and proliferate within the plant tissues. Thus far, the molecular mechanisms underlying the regulation of invasive growthin plantahave remained largely unknown. We identified a precise filamentous-punctate-filamentous cycle in mitochondrial morphology duringMagnaporthe-Rice interaction. Interestingly, loss of either the mitochondrial fusion (MoFzo1) or fission (MoDnm1) machinery, or inhibition of mitochondrial fission using Mdivi-1 caused significant reduction inM. oryzaepathogenicity. Furthermore, exogenous carbon source(s) but not antioxidant treatment delayed such mitochondrial dynamics/transition during invasive growth. Such nutrient-based regulation of organellar dynamics preceded MoAtg24-mediated mitophagy, which was found to be essential for proper biotrophic development and invasive growthin planta. We propose that precise mitochondrial dynamics and mitophagy occur during the transition from biotrophy to necrotrophy, and are required for proper induction and establishment of the blast disease in rice.

scholarly journals Dehydroepiandrosterone Effect on Toxoplasma gondii: Molecular Mechanisms Associated to Parasite Death

2021 ◽  
Author(s):  
Jorge Morales-Montor
Keyword(s):  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Cytochrome B5 ◽  
Protozoan Parasite ◽  
Intracellular Parasites ◽  
Sds Page ◽  
Parasitic Load ◽  
Dhea Treatment

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date it has not been explored the role of DHEA on T. gondii. In here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization, as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and passive invasion process. 2D SDS-PAGE analysis revealed that in the presence of the hormone a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.

Abstract 14: Pim-1 Preserves Mitochondrial Morphology by Inhibiting Drp1 Translocation

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shabana Din ◽  
Matt Mason ◽  
Mirko Volkers ◽  
Bevan Johnson ◽  
Mathias Konstandin ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fragmentation ◽  
Simulated Ischemia

Rationale: Mitochondrial morphological dynamics affect the outcome of ischemic heart damage. Mitochondrial fission protein Dynamin Related Protein 1 (Drp1) is a mediator of mitochondrial morphological changes and cell death during ischemic injury. Mitochondrial integrity is maintained by cardioprotective kinase Pim1, which enhances resistance to apoptotic challenge and ischemia reperfusion injury. In this study we examine the relationship between Pim1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemia. Objective: To demonstrate that Pim1 inhibits Drp1 translocation to the mitochondria in response to ischemic injury. Methods and Results: Simulated ischemia and simulated ischemia reperfusion (sI & sI/R) induced mitochondrial fragmentation and cell death in neonatal rat cardiac myocytes (NRCM), respectively. Mitochondrial fragmentation accompanied Drp1 translocation to the mitochondria in NRCM. Inhibition of Drp1 by mdivi1 preserved mitochondrial reticular morphology and inhibited apoptotic cell death. Mice subjected to sI/R injury displayed Drp1 mitochondrial localization, while exposure to mdivi1 led to reduced infarct size. Interestingly, transgenic hearts overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after sI. In contrast, Pim1 dominant negative (PDN) transgenic hearts and NRCM exhibit increased Drp1 translocation to mitochondria and fragmented mitochondria. PDN hearts exhibit decreased phosphorylation of serine 637 and upregulation of BH3 protein PUMA, inducing Drp1 accumulation at mitochondria and increased sensitivity to apoptotic stimuli. In PDN NRCMs, overexpression of Puma dominant negative (PumaDN) attenuated localization of Drp1 to mitochondria and inhibited cell death during sI. Conclusion: Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to simulated ischemia. Therefore, selective manipulation of Pim1 should be pursued as a therapeutic target to maintain mitochondrial morphology for cardioprotection.

RUNX1/EVI1 That Blocks Myeloid Differentiation Inhibits C/EBPα Function.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4161-4161
Author(s):  
Katsuya Tokita ◽  
Kazuhiro Maki ◽  
Kinuko Mitani
Keyword(s):  
Dna Binding ◽  
Molecular Mechanisms ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Dominant Negative Effect ◽  
Granulocytic Differentiation ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Differentiation Block ◽  
Myeloid Progenitors

Abstract RUNX1/EVI1 chimeric transcription factor produced by t(3;21) causes leukemic transformation in hematopoietic stem cell tumors such as chronic myelogenous leukemia (CML) in blastic crisis and myelodysplastic syndrome (MDS) in leukemic transformation, possibly through differentiation block of malignant myeloid progenitors. We have recently reported that Runx1/EVI1 knock-in heterozygous mice show defective hematopoiesis in the fetal liver similar to Runx1 knock-out mice, but possess dysplastic hematopoietic progenitors with high self-renewal capacity. Notably, Runx1/EVI1 knock-in chimeric mice developed acute megakaryoblastic leukemia. The molecular characterization of RUNX1/EVI1 points two major functions; one is dominant-suppressive function over wild-type RUNX1 and the other is EVI1’s own function; blockade of TGFb-mediated signal, inhibition of JNK and stimulation of AP-1 activity. C/EBPa is a key transcriptional regulator that induces the granulocytic differentiation of myeloid progenitors and several lines of evidence suggest that disturbance in C/EBPa signaling is one of the major molecular events in myeloid malignancies. In this study, we investigated whether RUNX1/EVI1 affects the expression and function of C/EBPa. We introduced RUNX1/EVI1 cDNA into LG-3 cells that differentiate along the myeloid lineage upon granulocyte colony-stimulating factor exposure, and confirmed that RUNX1/EVI1 suppressed the differentiation. To further investigate the molecular mechanisms of RUNX1/EVI1-mediated differentiation block, we analyzed RUNX1/EVI1’s effect on the functions of C/EBPa. RUNX1/EVI1 was found to associate with C/EBPa. By using the reporter assay with the CEBPA promoter, we observed a dominant-negative effect of RUNX1/EVI1 over C/EBPa-mediated transcriptional activation via the CtBP-binding site in the EVI1 portion. In the gel-shift assay, RUNX1/EVI1 down-regulated DNA-binding activity of C/EBPa. Therefore, recruitment of histone deacetylase via CtBP and disruption of DNA binding could be likely scenarios for the RUNX1/EVI1-induced dominant repression on C/EBPa. Importantly, co-expression of C/EBPa restored differentiation ability of the RUNX1/EVI1-expressing LG-3 cells. All these data argue that inhibition of C/EBPa function may be causatively related to the RUNX1/EVI1’s leukemogenic potential.

scholarly journals Fine control of aerenchyma and lateral root development through AUX/IAA- and ARF-dependent auxin signaling

2019 ◽  
Vol 116 (41) ◽  
pp. 20770-20775 ◽  
Author(s):  
Takaki Yamauchi ◽  
Akihiro Tanaka ◽  
Hiroki Inahashi ◽  
Naoko K. Nishizawa ◽  
Nobuhiro Tsutsumi ◽  
...  
Keyword(s):  
Root Development ◽  
Molecular Mechanisms ◽  
Auxin Transport ◽  
Lateral Roots ◽  
Cortical Cell ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Auxin Signaling ◽  
Transport Inhibitor ◽  
Auxin Transport Inhibitor

Lateral roots (LRs) are derived from a parental root and contribute to water and nutrient uptake from the soil. Auxin/indole-3-acetic acid protein (AUX/IAA; IAA) and auxin response factor (ARF)-mediated signaling are essential for LR formation. Lysigenous aerenchyma, a gas space created by cortical cell death, aids internal oxygen transport within plants. Rice (Oryza sativa) forms lysigenous aerenchyma constitutively under aerobic conditions and increases its formation under oxygen-deficient conditions; however, the molecular mechanisms regulating constitutive aerenchyma (CA) formation remain unclear. LR number is reduced by the dominant-negative effect of a mutated AUX/IAA protein in the iaa13 mutant. We found that CA formation is also reduced in iaa13. We have identified ARF19 as an interactor of IAA13 and identified a lateral organ boundary domain (LBD)-containing protein (LBD1-8) as a target of ARF19. IAA13, ARF19, and LBD1-8 were highly expressed in the cortex and LR primordia, suggesting that these genes function in the initiation of CA and LR formation. Restoration of LBD1-8 expression recovered aerenchyma formation and partly recovered LR formation in the iaa13 background, in which LBD1-8 expression was reduced. An auxin transport inhibitor suppressed CA and LR formation, and a natural auxin stimulated CA formation in the presence of the auxin transport inhibitor. Our findings suggest that CA and LR formation are both regulated through AUX/IAA- and ARF-dependent auxin signaling. The initiation of CA formation lagged that of LR formation, which indicates that the formation of CA and LR are regulated differently by auxin signaling during root development in rice.

scholarly journals Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2673-2691
Author(s):  
Daisuke Ariyasu ◽  
Emika Kubo ◽  
Daisuke Higa ◽  
Shinsuke Shibata ◽  
Yutaka Takaoka ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Gh Deficiency ◽  
Gene Promoter ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Dominant Negative Effect ◽  
Wild Type ◽  
New Paradigm ◽  
Gh Secretion

Abstract Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.

scholarly journals The Heterozygous Disproportionate Micromelia (Dmm) Mouse: Morphological Changes in Fetal Cartilage Precede Postnatal Dwarfism and Compared With Lethal Homozygotes Can Explain the Mild Phenotype

2008 ◽  
Vol 56 (11) ◽  
pp. 1003-1011 ◽  
Author(s):  
Robert E. Seegmiller ◽  
Brandon D. Bomsta ◽  
Laura C. Bridgewater ◽  
Cindy M. Niederhauser ◽  
Carolina Montaño ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Coding Region ◽  
Transmission Microscopy ◽  
Mild Phenotype ◽  
Morphological Alterations ◽  
Rib Cartilage ◽  
Negative Effect ◽  
Reduced Rate

The disproportionate micromelia ( Dmm) mouse has a mutation in the C-propeptide coding region of the Co/2a1 gene that causes lethal dwarfism when homozygous ( Dmm/Dmm) but causes only mild dwarfism observable ∼1-week postpartum when heterozygous ( Dmm/+). The purpose of this study was 2-fold: first, to analyze and quantify morphological changes that precede the expression of mild dwarfism in Dmm/+ animals, and second, to compare morphological alterations between Dmm/+ and Dmm/Dmm fetal cartilage that may correlate with the marked skeletal differences between mild and lethal dwarfism. Light and electron transmission microscopy were used to visualize structure of chondrocytes and extracellular matrix (ECM) of fetal rib cartilage. Both Dmm/+ and Dmm/Dmm fetal rib cartilage had significantly larger chondrocytes, greater cell density, and less ECM per unit area than +/+ littermates. Quantitative RT-PCR showed a decrease in aggrecan mRNA in Dmm/+ vs +/+ cartilage. Furthermore, the cytoplasm of chondrocytes in Dmm/+ and Dmm/Dmm cartilage was occupied by significantly more distended rough endoplasmic reticulum (RER) compared with wild-type chondrocytes. Fibril diameters and packing densities of +/+ and Dmm/+ cartilage were similar, but Dmm/Dmm cartilage showed thinner, sparsely distributed fibrils. These findings support the prevailing hypothesis that a C-propeptide mutation could interrupt the normal assembly and secretion of Type II procollagen trimers, resulting in a buildup of proα1(II) chains in the RER and a reduced rate of matrix synthesis. Thus, intracellular entrapment of proα1(II) seems to be primarily responsible for the dominant-negative effect of the Dmm mutation in the expression of dwarfism.

scholarly journals Mdm12p, a Component Required for Mitochondrial Inheritance That Is Conserved between Budding and Fission Yeast

1997 ◽  
Vol 136 (3) ◽  
pp. 545-553 ◽  
Author(s):  
Karen H. Berger ◽  
L. Farah Sogo ◽  
Michael P. Yaffe
Keyword(s):  
Membrane Protein ◽  
Fission Yeast ◽  
Outer Membrane ◽  
Subcellular Fractionation ◽  
Biochemical Properties ◽  
Dominant Negative ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Temperature Sensitive ◽  
Giant Mitochondria

Saccharomyces cerevisiae cells lacking the MDM12 gene product display temperature-sensitive growth and possess abnormally large, round mitochondria that are defective for inheritance by daughter buds. Analysis of the wild-type MDM12 gene revealed its product to be a 31-kD polypeptide that is homologous to a protein of the fission yeast Schizosaccharomyces pombe. When expressed in S. cerevisiae, the S. pombe Mdm12p homolog conferred a dominant-negative phenotype of giant mitochondria and aberrant mitochondrial distribution, suggesting partial functional conservation of Mdm12p activity between budding and fission yeast. The S. cerevisiae Mdm12p was localized by indirect immunofluorescence microscopy and by subcellular fractionation and immunodetection to the mitochondrial outer membrane and displayed biochemical properties of an integral membrane protein. Mdm12p is the third mitochondrial outer membrane protein required for normal mitochondrial morphology and distribution to be identified in S. cerevisiae and the first such mitochondrial component that is conserved between two different species.

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