RESUMEN
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent and destructive skin alterations in intertriginous areas. OBJECTIVES: We investigated the expression and role in HS of granulocyte colony-stimulating factor (G-CSF), the regulator of neutrophil biology, as clinical signs of a neutrophilic granulocyte-driven inflammation are distinctive in the disease. METHODS: Skin and blood samples obtained from different cohorts of patients with HS and control individuals were assessed by RNA sequencing, quantitative polymerase chain reaction on reverse transcribed mRNA, and/or enzyme-linked immunosorbent assay. Mechanistic studies using keratinocytes, dermal fibroblasts, immune cell populations and skin biopsies were performed. RESULTS: G-CSF was abundant in HS skin, particularly in inflamed nodules and abscesses. Its levels even exceeded those found in other inflammatory skin diseases. Interleukin (IL)-1 and IL-17, respectively, induced G-CSF production by fibroblasts and keratinocytes. These effects were enhanced by tumour necrosis factor (TNF)-α and IL-36. Accordingly, fibroblasts separated from HS lesions expressed G-CSF, and IL-1 receptor antagonist reduced G-CSF levels in explanted HS skin. G-CSF blood levels positively correlated with severity of HS. Elevated lesional G-CSF receptor levels were linked to upregulation of molecules that contribute to prolonged activation of neutrophils by components of bacteria and damaged host cells [formyl peptide receptor 1 (FPR1), FPR2 and free fatty acid receptor 2 (FFAR2)], neutrophil survival [TNF receptor superfamily member 10C (TNFRSF10C/TRAIL-R3) and TNF receptor superfamily member 6B], kinases (tyrosine-protein kinase HCK and hexokinase 3), and skin destruction [MMP25 (matrix metalloproteinase 25) and ADAM8 (disintegrin and metalloproteinase domain-containing protein 8)]. G-CSF elevated the expression of FPR1, FFAR2, and TNFRSF10C/TRAIL-R3 in neutrophils and synergized with bacterial components to induce skin-destructive enzymes. CONCLUSIONS: The G-CSF pathway engages both tissue and immune cells, is strongly activated in HS lesions, and offers the opportunity to target the neutrophil-driven inflammation.
Asunto(s)
Hidradenitis Supurativa , Proteínas ADAM , Factor Estimulante de Colonias de Granulocitos , Humanos , Queratinocitos , Proteínas de la Membrana , Neutrófilos , Piel , Factor de Necrosis Tumoral alfaRESUMEN
Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.
Asunto(s)
Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Mutación/genética , Fenotipo , Adulto , Estudios de Seguimiento , Regulación de la Expresión Génica , Humanos , Masculino , NADH Deshidrogenasa/genéticaRESUMEN
New tetraester derivatives of 1,4,5,8-tetraazaanthracene have been prepared and characterized by spectroscopic and electrochemical techniques. The LUMO level of the compounds is close to -4 eV (the so-called air operating stability border in n-channel field effect transistors). Tetraesters were obtained with reasonable yields without the necessity of using high-quality reactants or solvents, resulting in their low cost.
RESUMEN
There are many theories of aging and a number of them encompass the role of mitochondria in this process. Mitochondrial DNA mutations and deletions have been shown to accumulate in many tissues in mammals during aging. However, there is little evidence that these mutations could affect the functioning of aging tissues.
Asunto(s)
Envejecimiento , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Envejecimiento de la Piel , Animales , Apoptosis , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Eliminación de Gen , Humanos , Ratones , Mutación , Estrés Oxidativo/genética , Piel/patologíaRESUMEN
Anabolic and catabolic cytokines and growth factors such as BMP-7 and IL-1beta play a central role in controlling the balance between degradation and repair of normal and (osteo)arthritic articular cartilage matrix. In this report, we investigated the response of articular chondrocytes to these factors IL-1beta and BMP-7 in terms of changes in gene expression levels. Large scale analysis was performed on primary human adult articular chondrocytes isolated from two human, independent donors cultured in alginate beads (non-stimulated and stimulated with IL-1beta and BMP-7 for 48 h) using Affymetrix gene chips (oligo-arrays). Biostatistical and bioinformatic evaluation of gene expression pattern was performed using the Resolver software (Rosetta). Part of the results were confirmed using real-time PCR. IL-1beta modulated significantly 909 out of 3459 genes detectable, whereas BMP-7 influenced only 36 out of 3440. BMP-7 induced mainly anabolic activation of chondrocytes including classical target genes such as collagen type II and aggrecan, while IL-1beta, both, significantly modulated the gene expression levels of numerous genes; namely, IL-1beta down-regulated the expression of anabolic genes and induced catabolic genes and mediators. Our data indicate that BMP-7 has only a limited effect on differentiated cells, whereas IL-1beta causes a dramatic change in gene expression pattern, i.e. induced or repressed much more genes. This presumably reflects the fact that BMP-7 signaling is effected via one pathway only (i.e. Smad-pathway) whereas IL-1beta is able to signal via a broad variety of intracellular signaling cascades involving the JNK, p38, NFkB and Erk pathways and even influencing BMP signaling.
Asunto(s)
Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1beta/farmacología , Anciano , Autopsia , Proteína Morfogenética Ósea 7 , Proteínas Morfogenéticas Óseas/farmacología , Células Cultivadas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
OBJECTIVE: In this study, the human chondrosarcoma cell line SW1353 was investigated by gene expression analysis in order to validate it as an in vitro model for primary human (adult articular) chondrocytes (PHCs). METHODS: PHCs and SW1353 cells were cultured as high density monolayer cultures with and without 1ng/ml interleukin-1beta (IL-1beta). RNA was isolated and assayed using a custom-made oligonucleotide microarray representing 312 chondrocyte-relevant genes. The expression levels of selected genes were confirmed by real-time polymerase chain reaction and the gene expression profiles of the two cell types, both with and without IL-1beta treatment, were compared. RESULTS: Overall, gene expression profiling showed only very limited similarities between SW1353 cells and PHCs at the transcriptional level. Similarities were predominantly seen with respect to catabolic effects after IL-1beta treatment. In both cell systems matrix metalloproteinase-1 (MMP-1), MMP-3 and MMP-13 were strongly induced by IL-1beta, without significant induction of MMP-2. IL-6 was also found to be up-regulated by IL-1beta in both cellular models. On the other hand, intercellular mediators such as leukemia inhibitory factor (LIF) and bone morphogenetic protein-2 (BMP-2) were not induced by IL-1beta in SW1353 cells, but significantly up-regulated in PHCs. Bioinformatical analysis identified nuclear factor kappa-B (NFkappaB) as a common transcriptional regulator of IL-1beta induced genes in both SW1353 cells and PHCs, whereas other transcription factors were only found to be relevant for individual cell systems. CONCLUSION: Our data characterize SW1353 cells as a cell line with only a very limited potential to mimic PHCs, though SW1353 cells can be of value to study the induction of protease expression within cells, a phenomenon also seen in chondrocytes.
Asunto(s)
Cartílago Articular/citología , Condrocitos/fisiología , Regulación de la Expresión Génica/genética , Interleucina-1/genética , Anciano , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/genética , Línea Celular Tumoral , Regulación hacia Abajo/genética , Matriz Extracelular/genética , Femenino , Humanos , Interleucina-6/genética , Factor Inhibidor de Leucemia , Masculino , Metaloproteinasas de la Matriz/análisis , Persona de Mediana Edad , Modelos Biológicos , FN-kappa B/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa/métodos , Factores de Transcripción/análisis , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba/genéticaRESUMEN
Functional genomics represents a new challenging approach in order to analyze complex diseases such as osteoarthritis on a molecular level. The characterization of the molecular changes of the cartilage cells, the chondrocytes, enables a better understanding of the pathomechanisms of the disease. In particular, the identification and characterization of new target molecules for therapeutic intervention is of interest. Also, potential molecular markers for diagnosis and monitoring of osteoarthritis contribute to a more appropriate patient management. The DNA-microarray technology complements (but does not replace) biochemical and biological research in new disease-relevant genes. Large-scale functional genomics will identify molecular networks such as yet identified players in the anabolic-catabolic balance of articular cartilage as well as disease-relevant intracellular signaling cascades so far rather unknown in articular chondrocytes. However, at the moment it is also important to recognize the limitations of the microarray technology in order to avoid over-interpretation of the results. This might lead to misleading results and prevent to a significant extent a proper use of the potential of this technology in the field of osteoarthritis.
Asunto(s)
Cartílago/metabolismo , Perfilación de la Expresión Génica/métodos , Pruebas Genéticas/métodos , Genómica/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Osteoartritis/genética , Osteoartritis/metabolismo , Perfilación de la Expresión Génica/tendencias , Marcadores Genéticos/genética , Humanos , Ciencia del Laboratorio Clínico/métodos , Ciencia del Laboratorio Clínico/tendencias , Análisis de Secuencia por Matrices de Oligonucleótidos/tendencias , Osteoartritis/diagnósticoRESUMEN
OBJECTIVE: To investigate quantitatively the mRNA expression levels of YKL-40, an established marker of rheumatoid and osteoarthritic cartilage degeneration in synovial fluid and serum, and a closely related molecule YKL-39, in articular chondrocytes. METHODS: cDNA array and online quantitative polymerase chain reaction (PCR) were used to measure mRNA expression levels of YKL-39 and YKL-40 in chondrocytes in normal, early degenerative, and late stage osteoarthritic cartilage samples. RESULTS: Expression analysis showed high levels of both proteins in normal articular chondrocytes, with lower levels of YKL-39 than YKL-40. Whereas YKL-40 was significantly down regulated in late stage osteoarthritic chondrocytes, YKL-39 was significantly up regulated. In vitro both YKLs were down regulated by interleukin 1beta. CONCLUSIONS: The up regulation of YKL-39 in osteoarthritic cartilage suggests that YKL-39 may be a more accurate marker of chondrocyte activation than YKL-40, although it has yet to be established as a suitable marker in synovial fluid and serum. The decreased expression of YKL-40 by osteoarthritic chondrocytes is surprising as increased levels have been reported in rheumatoid and osteoarthritic synovial fluid, where it may derive from activated synovial cells or osteophytic tissue or by increased matrix destruction in the osteoarthritic joint. YKL-39 and YKL-40 are potentially interesting marker molecules for arthritic joint disease because they are abundantly expressed by both normal and osteoarthritic chondrocytes.
Asunto(s)
Cartílago Articular/metabolismo , Condrocitos/metabolismo , Glicoproteínas/genética , Osteoartritis/metabolismo , ARN Mensajero/análisis , Adipoquinas , Adulto , Anciano , Anciano de 80 o más Años , Cartílago Articular/efectos de los fármacos , Estudios de Casos y Controles , Proteína 1 Similar a Quitinasa-3 , Condrocitos/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Humanos , Interleucina-1/farmacología , Lectinas , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Regulación hacia ArribaRESUMEN
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a disease mainly due to a mutation at position 3243 (A --> G) in the leucine tRNA gene in mitochondrial DNA. Symptoms of the disorder are complex and the exact pathogenesis is not understood. A review of the literature on the subject is presented.
RESUMEN
In every human cell there are hundreds of mitochondria, which are required for oxidative phosphorylation as well as many other metabolic processes. Each mitochondrion contains approximately 5 mitochondrial DNA molecules. These circular DNAs of 16.5 kb in size contain only 39 genes. Mutations in mitochondrial DNA are responsible for many diseases. Alterations in these molecules may also play a role in ageing and in tumour formation.
RESUMEN
Aggrecanase cleavage at the Glu(373)-Ala(374) site in the interglobular domain of the cartilage proteoglycan aggrecan is a key event in arthritic diseases. The observation that substrates representing only the aggrecanase cleavage site are not catabolized efficiently by aggrecanase prompted us to investigate the requirement of aggrecanase for additional structural elements of its substrate other than the actual cleavage site. Based on the recombinant substrate rAgg1mut we constructed deletion mutants with successively truncated N- or C-termini of the interglobular domain. Catabolism by aggrecanase activities induced in rat chondrosarcoma cells, porcine chondrocytes, and by human recombinant ADAMTS4 showed a gradually decreasing catabolism of progressively shortened, N-terminal deletion mutants of the substrate rAgg1mut. A reduction to 32 amino acids N-terminal to the aggrecanase site resulted in a decrease of at least 42% of aggrecanase cleavage products as compared with the wild-type substrate. When only 16 amino acids preceded the Glu(373)-Ala(374) site, aggrecanase cleavage was completely inhibited. In contrast, C-terminal deletions did not negatively affect aggrecanase cleavage up to the reduction to 13 amino acids C-terminal to the cleavage site. Unlike aggrecanase(s), membrane type 1-matrix metalloprotease (MT1-MMP), able to cleave rAgg1mut both at the aggrecanase and the MMP site, was insensitive to N-terminal deletions regarding aggrecanase cleavage, indicating that the importance of the N-terminus is characteristic for aggrecanase(s). Taken together, the results demonstrate that the amino-terminus of rAgg1mut, containing the MMP site, plays an important role for efficient cleavage by aggrecanase(s), possibly by serving as a further site of interaction between the enzyme and its substrate.
Asunto(s)
Endopeptidasas/metabolismo , Proteínas de la Matriz Extracelular , Proteoglicanos/genética , Proteoglicanos/metabolismo , Proteínas ADAM , Proteína ADAMTS4 , Agrecanos , Secuencia de Aminoácidos , Animales , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/aislamiento & purificación , Lectinas Tipo C , Metaloproteinasas de la Matriz Asociadas a la Membrana , Metaloendopeptidasas/metabolismo , Datos de Secuencia Molecular , Oligopéptidos , Péptidos/genética , Péptidos/aislamiento & purificación , Procolágeno N-Endopeptidasa , Proteoglicanos/aislamiento & purificación , Ratas , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Eliminación de Secuencia , Especificidad por Sustrato , Células Tumorales CultivadasRESUMEN
A soluble, C-terminal truncated form of human membrane type 1 matrix metalloproteinase (MT1-MMP) containing the hemopexin-like domain was expressed in Pichia pastoris strain KM71. High levels of secreted protein were detected. Although the c-DNA for the proenzyme (Ala(21)-Glu(523) called DeltaTM-MT1-MMP) was cloned, almost only active MT1-MMP (Tyr(112)-Glu(523)) with identical N-terminus as described for the wild-type enzyme was isolated. This active enzyme was highly purified and characterized with respect to its biochemical properties. The recombinant protein showed high stability against autolysis and proteolysis by yeast proteases, although the calculated in vivo half-life is rather low. The biochemical properties of this new MT1-MMP species were compared with the well-characterized catalytic domain (Ile(114)-Ile(318)) of MT1-MMP. The novel form of MT1-MMP exhibited a higher stability against autolysis than the isolated catalytic domain (Ile(114)-Ile(318)).
Asunto(s)
Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Pichia/genética , Western Blotting , Clonación Molecular , Electroforesis en Gel de Poliacrilamida , Activación Enzimática , Estabilidad de Enzimas , Expresión Génica , Vectores Genéticos , Humanos , Metaloproteinasa 1 de la Matriz/química , Metaloproteinasa 1 de la Matriz/aislamiento & purificación , Plásmidos/genética , Pliegue de Proteína , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Transformación GenéticaAsunto(s)
Colagenasas/fisiología , Factor XII/metabolismo , Fibrinólisis/fisiología , Metaloproteinasa 8 de la Matriz/fisiología , Metaloendopeptidasas/fisiología , Dominio Catalítico , Activación Enzimática , Humanos , Hidrólisis , Calicreínas , Metaloproteinasa 13 de la Matriz , Metaloproteinasas de la Matriz Asociadas a la Membrana , Metaloendopeptidasas/química , Modelos Moleculares , Fragmentos de Péptidos/metabolismo , Conformación Proteica , Especificidad por Sustrato , Trombina/farmacologíaRESUMEN
We have cloned and sequenced a cDNA of the human homologue of the Saccharomyces cerevisiae Suv3 putative RNA helicase which is indispensable for mitochondrial function in yeast. The human Suv-3-like protein has a typical mitochondrial leader sequence. Northern blot data and analysis of ESTs in the data banks indicate that this human gene (SUPV3L1) is expressed in practically all tissues, though at different levels. Sequence homology analysis has shown a strong conservation of the protein in a number of eukaryotic organisms -- plants, mammals and fungi, but no close homologues exist in bacteria with the exception of the purple bacterium Rhodobacter sphaeroides. This gene is thus ubiquitously present in all eukaryotic organisms.
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Secuencia Conservada , ARN Helicasas/genética , Rhodobacter sphaeroides/enzimología , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/enzimología , Secuencia de Aminoácidos , Animales , Clonación Molecular , ARN Helicasas DEAD-box , ADN Complementario , Etiquetas de Secuencia Expresada , Humanos , Datos de Secuencia Molecular , Rhodobacter sphaeroides/genética , Saccharomyces cerevisiae/genética , Homología de Secuencia de AminoácidoRESUMEN
Increasing numbers of diseases due to disturbances in mitochondrial DNA (mtDNA) are being discovered. Mutations in mtDNA mainly cause malfunctioning of muscle and nerve cells. The most common diseases and their molecular diagnosis are briefly described.
Asunto(s)
Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Mutación Puntual , ADN Mitocondrial/genética , HumanosRESUMEN
The release of aggrecan catabolites from cartilage is an early event in the pathogenesis of degenerative joint diseases. The enzymes involved in this process are unknown, controversial, and the subject of intense investigation. In this paper we have utilized a recombinant substrate containing the interglobular domain (IGD) of aggrecan to study specifically aggrecanase versus matrix metalloproteinase (MMP) catabolism in this domain of aggrecan. Our studies have shown that (i) there are species differences in the expression of latent versus active MMP activity on the aggrecan IGD; (ii) interleukin-1alpha exposure induces both aggrecanase and MMP activities, whereas retinoic acid induces only aggrecanase activity and inhibits the MMP activity on the aggrecan IGD; (iii) activators of latent MMP activity (p-aminophenylmercuric acetate and trypsin) significantly reduce aggrecanase activity; (iv) the time course of the appearance of aggrecanase versus the MMP catabolism of aggrecan IGD differs; (v) aggrecanase is a protease with metalloprotease characteristics; however (vi) the physiological (tissue) inhibitors of MMPs show weak inhibition (TIMP-1) or no inhibition (TIMP-2) of aggrecanase activity. Collectively, these studies show that aggrecanase and MMP catabolism of the aggrecan IGD are independent and uncoupled.
Asunto(s)
Cartílago Articular/enzimología , Condrocitos/enzimología , Endopeptidasas/biosíntesis , Metaloendopeptidasas/biosíntesis , Animales , Cartílago Articular/citología , Bovinos , Medios de Cultivo Condicionados , Interleucina-1/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Porcinos , Inhibidor Tisular de Metaloproteinasa-1/farmacología , Inhibidor Tisular de Metaloproteinasa-2/farmacología , Tretinoina/farmacologíaRESUMEN
The recent detection of membrane type 1 matrix metalloproteinase (MT1-MMP) expression in human articular cartilage [Büttner, Chubinskaya, Margerie, Huch, Flechtenmacher, Cole, Kuettner, and Bartnik (1997) Arthritis Rheum. 40, 704-709] prompted our investigation of MT1-MMP's catabolic activity within the interglobular domain of aggrecan. For these studies we used rAgg1mut, a mutated form of the recombinant fusion protein (rAgg1) that has been used as a substrate to monitor 'aggrecanase' catabolism in vitro [Hughes, Büttner, Eidenmüller, Caterson and Bartnik (1997) J. Biol. Chem. 272, 20269-20274]. The rAgg1 was mutated (G332 to A) to avoid the generation of a splice variant seen with the original genetic construct, which gave rise to heterogeneous glycoprotein products. This mutation yielded a homogeneous recombinant product. Studies in vitro with retinoic acid-stimulated rat chondrosarcoma cells indicated that the rAgg1mut substrate was cleaved at the 'aggrecanase' site equivalent to Glu373-Ala374 (human aggrecan sequence enumeration) in its interglobular domain sequence segment. The differential catabolic activities of the recombinant catalytic domain (cd) of MT1-MMP and matrix metalloproteinases (MMPs) 3 and 8 were then compared by using this rAgg1mut as a substrate. Coomassie staining of rAgg1mut catabolites separated by SDS/PAGE showed similar patterns of degradation with all three recombinant enzymes. However, comparative immunodetection analysis, with neoepitope antibodies BC-3 (anti-ARGS...) and BC-14 (anti-FFGV...) to distinguish between 'aggrecanase' and MMP-generated catabolites, indicated that the catalytic domain of MT1-MMP exhibited strong 'aggrecanase' activity, cdMMP-8 weak activity and cdMMP-3 no activity. In contrast, cdMMP-3 and cdMMP-8 led to strongly BC-14-reactive catabolic fragments, whereas cdMT1-MMP resulted in weak BC-14 reactivity. N-terminal sequence analyses of the catabolites confirmed these results and also identified other potential minor cleavage sites within the interglobular domain of aggrecan. These results indicate that MT1-MMP is yet another candidate for 'aggrecanase' activity in vivo.
Asunto(s)
Endopeptidasas/metabolismo , Proteínas de la Matriz Extracelular , Metaloendopeptidasas/metabolismo , Proteoglicanos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Agrecanos , Secuencia de Aminoácidos , Animales , Neoplasias Óseas/patología , Catálisis , Condrosarcoma/patología , Colagenasas/metabolismo , Humanos , Lectinas Tipo C , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz , Metaloproteinasas de la Matriz Asociadas a la Membrana , Metaloendopeptidasas/genética , Datos de Secuencia Molecular , Mutación Puntual , Proteoglicanos/genética , Ratas , Proteínas Recombinantes de Fusión/genética , Células Tumorales CultivadasRESUMEN
Saccharomyces cerevisiae nuclear genes SUV3 and DSS1 encode putative RNA helicase and RNase II, respectively, which are subunits of the mitochondrial degradosome (mtEXO): a three-protein complex which has a 3' to 5' exoribonuclease activity and plays a major role in regulating stability of mitochondrial RNA. Lack of either of the two gene products results in a respiratory negative phenotype, while on the molecular level it causes a total block of mitochondrial translation, loss of the in vitro exoribonuclease activity and changes in stability and processing of many mtRNAs. We have found that the yeast nuclear gene PET127 present on a low or high copy number vector can effectively suppress the effects of the SUV3 or DSS1 gene disruptions. Since the product of the PET127 gene is involved in processing of the 5' ends of mitochondrial mRNAs, we suggest that there is a functional coupling between the 5' and 3' ends of mitochondrial mRNAs.