RESUMO
Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In some instances, survival times for relapsed ALL at these sites are longer than those for relapsed disease involving only the bone marrow. Isolated relapse of ALL in the myocardium is rare, especially in children, making diagnosis and treatment of it difficult. More recent treatment options such as chimeric antigen receptor T-cell therapy carry a high risk of cytokine release syndrome and associated risk of worsening cardiac function. Herein we present the case of an 11-year-old boy who presented with relapsed symptomatic B-cell ALL in the myocardium following allogeneic hematopoietic stem cell transplantation. This is an unusual presentation of relapsed ALL and this case demonstrates the associated challenges in its diagnosis and treatment. The case report is followed by a literature review of the advances in treatment of pediatric leukemia and their application to extramedullary relapse of this disease in particular.
RESUMO
There are multiple conditions that can make children prone to having a sudden cardiac arrest (SCA) or sudden cardiac death (SCD). Efforts have been made by multiple organizations to screen children for cardiac conditions, but the emphasis has been on screening before athletic competition. This article is an update of the previous American Academy of Pediatrics policy statement of 2012 that addresses prevention of SCA and SCD. This update includes a comprehensive review of conditions that should prompt more attention and cardiology evaluation. The role of the primary care provider is of paramount importance in the evaluation of children, particularly as they enter middle school or junior high. There is discussion about whether screening should find any cardiac condition or just those that are associated with SCA and SCD. This update reviews the 4 main screening questions that are recommended, not just for athletes, but for all children. There is also discussion about how to handle post-SCA and SCD situations as well as discussion about genetic testing. It is the goal of this policy statement update to provide the primary care provider more assistance in how to screen for life-threatening conditions, regardless of athletic status.
Assuntos
Morte Súbita Cardíaca/prevenção & controle , Política de Saúde , Atenção Primária à Saúde , Adolescente , Luto , Reanimação Cardiopulmonar , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Criança , Família/psicologia , Testes Genéticos , Humanos , Programas de Rastreamento , Papel do Médico , Médicos de Atenção Primária , Prevenção Primária , Fatores de Risco , Prevenção SecundáriaRESUMO
OBJECTIVE: To evaluate whether initiation of dexmedetomidine (DEX) infusion before surgical incision and cardiopulmonary bypass (CPB) versus initiation after CPB had an impact on the incidence of junctional ectopic tachycardia (JET). DESIGN: Retrospective cohort study. SETTING: Single tertiary-care cardiac center. PARTICIPANTS: Children undergoing cardiopulmonary bypass for repair of congenital heart disease involving ventricular septal defects between January 2010 and February 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-four patients undergoing ventricular septal defect closure were included in the final analysis. Of the 99 patients (74%) exposed to DEX, intraoperative initiation was performed in 73 (pre-CPB, n = 39 patients [29%]; intraoperative post-CPB initiation, n = 34 patients [25%]), and postoperative initiation was performed on arrival to the intensive care unit (ICU) in 26 patients (19%). In 71 of the 73 patients, infusions that were initiated intraoperatively were continued in the postoperative period for up to the first 12 hours. Postoperative JET was observed in 22 of the 134 patients (15%). Of the 99 patients exposed to DEX in the perioperative period, JET was observed in 8 patients (11%). Of the 35 patients not exposed to any DEX, JET was observed in 12 patients (34%). Analysis was performed using DEX exposure and timing as predictor variables. Multivariable analysis modeled with DEX exposure as a predictor variable showed that when initiated preincision and continued through the postoperative period, DEX was associated with significant reduction in postoperative JET (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02-0.37, p = 0.002). Exposure to DEX in the postoperative period alone did not result in suppression of JET (OR 0.5, 95% CI 0.11-2.17, p = 0.366). When modeled by using timing of DEX initiation as the predictive variable, preincision initiation of DEX infusion resulted in significantly greater suppression of JET (OR 0.04, 95% CI 0.002-0.28, p = 0.006) compared with initiation intraoperatively after CPB (OR 0.16, 95% CI 0.03-0.71, p = 0.024) or on arrival to the ICU (OR 0.504, CI 0.105-2.171, p = 0.365). Use of DEX exclusively in the postoperative period did not demonstrate any significant benefit in reducing JET (OR 0.506, 95% CI 0.106-2.17, p = 0.366). CONCLUSIONS: Preincision initiation of DEX and its continued use during the immediate postoperative period are significantly associated with reduced risk of JET after congenital heart surgeries involving repair of ventricular septal defect.
Assuntos
Ponte Cardiopulmonar/efeitos adversos , Dexmedetomidina/administração & dosagem , Comunicação Interventricular/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios/métodos , Taquicardia Ectópica de Junção/prevenção & controle , Adolescente , Analgésicos não Narcóticos/administração & dosagem , Ponte Cardiopulmonar/métodos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Comunicação Interventricular/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taquicardia Ectópica de Junção/epidemiologiaRESUMO
Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long-term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in mice led to enhanced activation of TrkB and its downstream targets ERK and AKT, both important factors in neuronal development. DHF treatment significantly restored spatial, contextual, and working memory, and the positive effects persisted for at least 3months after completion of the treatment. Consistent with preservation of cognitive functions, chronic DHF treatment mitigated radiation-induced suppression of hippocampal neurogenesis. Spine density and major components of the excitatory synapses, including glutamate receptors and postsynaptic density protein 95 (PSD-95), were also maintained at normal levels by DHF treatment after irradiation. Taken together, our results show that chronic treatment with DHF after irradiation significantly mitigates radiation-induced cognitive defects. This is achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity.
Assuntos
Encéfalo/efeitos da radiação , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Lesões por Radiação/tratamento farmacológico , Receptor trkB/agonistas , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Regulação para Baixo/efeitos da radiação , Flavonas/farmacologia , Hipocampo/patologia , Hipocampo/efeitos da radiação , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Neurogênese/efeitos da radiação , Plasticidade Neuronal/efeitos dos fármacos , Proteína Oncogênica v-akt/efeitos dos fármacos , Lesões por Radiação/patologia , Receptores de Glutamato/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/efeitos da radiaçãoRESUMO
Coq9 is a polypeptide subunit in a mitochondrial multi-subunit complex, termed the CoQ-synthome, required for biosynthesis of coenzyme Q (ubiquinone or Q). Deletion of COQ9 results in dissociation of the CoQ-synthome, but over-expression of Coq8 putative kinase stabilizes the CoQ-synthome in the coq9 null mutant and leads to the accumulation of two nitrogen-containing Q intermediates, imino-demethoxy-Q6 (IDMQ6) and 3-hexaprenyl-4-aminophenol (4-AP) when para-aminobenzoic acid (pABA) is provided as a ring precursor. To investigate whether Coq9 is responsible for deamination steps in Q biosynthesis, we utilized the yeast coq5-5 point mutant. The yeast coq5-5 point mutant is defective in the C-methyltransferase step of Q biosynthesis but retains normal steady-state levels of the Coq5 polypeptide. Here, we show that when high amounts of 13C6-pABA are provided, the coq5-5 mutant accumulates both 13C6-imino-demethyl-demethoxy-Q6 (13C6-IDDMQ6) and 13C6-demethyl-demethoxy-Q6 (13C6-DDMQ6). Deletion of COQ9 in the yeast coq5-5 mutant along with Coq8 over-expression and 13C6- pABA labeling leads to the absence of 13C6-DDMQ6, and the nitrogen-containing intermediates 13C6-4-AP and 13C6-IDDMQ6 persist. We describe a coq9 temperature-sensitive mutant and show that at the non-permissive temperature, steady-state polypeptide levels of Coq9-ts19 increased, while Coq4, Coq5, Coq6, and Coq7 decreased. The coq9-ts19 mutant had decreased Q6 content and increased levels of nitrogen-containing intermediates. These findings identify Coq9 as a multi-functional protein that is required for the function of Coq6 and Coq7 hydroxylases, for removal of the nitrogen substituent from pABA-derived Q intermediates, and is an essential component of the CoQ synthome.
Assuntos
Ácido 4-Aminobenzoico/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas Mitocondriais/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquinona/metabolismo , Desaminação , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Modelos Moleculares , Mutação Puntual , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Temperatura , Ubiquinona/genéticaRESUMO
Exposure to high concentration of oxygen (hyperoxia) leads to lung injury in experimental animal models and plays a role in the pathogenesis of diseases such as Acute Respiratory Distress Syndrome (ARDS) and Bronchopulmonary dysplasia (BPD) in humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. The major goal of this study was to characterize the changes in the pulmonary transcriptome following hyperoxia exposure and further elucidate the sex-specific changes. Male and female (8-10 wk) wild type (WT) (C57BL/6J) mice were exposed to hyperoxia (FiO2>0.95) and gene expression in lung tissues was studied at 48 h. A combination of fold change ≥1.4 and false discovery rate (FDR)<5% was used to define differentially expressed genes (DEGs). Overrepresentation of gene ontology terms representing biological processes and signaling pathway impact analysis (SPIA) was performed. Comparison of DEG profiles identified 327 genes unique to females, 585 unique to males and 1882 common genes. The major new findings of this study are the identification of new candidate genes of interest and the sex-specific transcriptomic changes in hyperoxic lung injury. We also identified DEGs involved in signaling pathways like MAP kinase and NF-kappa B which may explain the differences in sex-specific susceptibility to hyperoxic lung injury. These findings highlight changes in the pulmonary transcriptome and sex-specific differences in hyperoxic lung injury, and suggest new pathways, whose components could serve as sex-specific biomarkers and possible therapeutic targets for acute lung injury (ALI)/acute respiratory distress (ARDS) in humans.
Assuntos
Lesão Pulmonar Aguda/etiologia , Regulação da Expressão Gênica , Hiperóxia/complicações , Transcriptoma , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Reprodutibilidade dos Testes , Fatores Sexuais , Transdução de SinaisRESUMO
Coenzyme Q (ubiquinone or Q) is an essential lipid component of the mitochondrial electron transport chain. In Caenorhabditis elegans Q biosynthesis involves at least nine steps, including the hydroxylation of the hydroquinone ring by CLK-1 and two O-methylation steps mediated by COQ-3. We characterize two C. elegans coq-3 deletion mutants, and show that while each has defects in Q synthesis, their phenotypes are distinct. First generation homozygous coq-3(ok506) mutants are fertile when fed the standard lab diet of Q-replete OP50 Escherichia coli, but their second generation homozygous progeny does not reproduce. In contrast, the coq-3(qm188) deletion mutant remains sterile when fed Q-replete OP50. Quantitative PCR analyses suggest that the longer qm188 deletion may alter expression of the flanking nuo-3 and gdi-1 genes, located 5' and 3', respectively of coq-3 within an operon. We surmise that variable expression of nuo-3, a subunit of complex I, or of gdi-1, a guanine nucleotide dissociation inhibitor, may act in combination with defects in Q biosynthesis to produce a more severe phenotype. The phenotypes of both coq-3 mutants are more drastic as compared to the C. elegans clk-1 mutants. When fed OP50, clk-1 mutants reproduce for many generations, but show reduced fertility, slow behaviors, and enhanced life span. The coq-3 and clk-1 mutants all show arrested development and are sterile when fed the Q-deficient E. coli strain GD1 (harboring a mutation in the ubiG gene). However, unlike clk-1 mutant worms, neither coq-3 mutant strain responded to dietary supplementation with purified exogenous Q(10). Here we show that the Q(9) content can be determined in lipid extracts from just 200 individual worms, enabling the determination of Q content in the coq-3 mutants unable to reproduce. An extra-chromosomal array expressing wild-type C. elegans coq-3 rescued fertility of both coq-3 mutants and partially restored steady-state levels of COQ-3 polypeptide and Q(9) content, indicating that primary defect in both is limited to coq-3. The limited response of the coq-3 mutants to dietary supplementation with Q provides a powerful model to probe the effectiveness of exogenous Q supplementation as compared to restoration of de novo Q biosynthesis.
Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Genes de Helmintos , Metiltransferases/genética , Metiltransferases/metabolismo , Mutação , Ubiquinona/biossíntese , Sequência de Aminoácidos , Animais , Sequência de Bases , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , DNA de Helmintos/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Teste de Complementação Genética , Homozigoto , Masculino , Modelos Biológicos , Dados de Sequência Molecular , Fenótipo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Ubiquinona/administração & dosagem , Ubiquinona/deficiência , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
Free radicals or reactive oxygen species (ROS) are relatively short-lived and are difficult to measure directly; so indirect methods have been explored for measuring these transient species. One technique that has been developed using Escherichia coli and Saccharomyces cerevisiae systems, relies on a connection between elevated superoxide levels and the build-up of a high-spin form of iron (Fe(III)) that is detectable by electron paramagnetic resonance (EPR) spectroscopy at g = 4.3. This form of iron is referred to as "free" iron. EPR signals at g = 4.3 are commonly encountered in biological samples owing to mononuclear high-spin (S = 5/2) Fe(III) ions in sites of low symmetry. Unincorporated iron in this study refers to this high-spin Fe(III) that is captured by desferrioxamine which is detected by EPR at g value of 4.3. Previously, we published an adaptation of Fe(III) EPR methodology that was developed for Caenorhabditis elegans, a multi-cellular organism. In the current study, we have systematically characterized various factors that modulate this unincorporated iron pool. Our results demonstrate that the unincorporated iron as monitored by Fe(III) EPR at g = 4.3 increased under conditions that were known to elevate steady-state ROS levels in vivo, including: paraquat treatment, hydrogen peroxide exposure, heat shock treatment, or exposure to higher growth temperature. Besides the exogenous inducers of oxidative stress, physiological aging, which is associated with elevated ROS and ROS-mediated macromolecular damage, also caused a build-up of this iron. In addition, increased iron availability increased the unincorporated iron pool as well as generalized oxidative stress. Overall, unincorporated iron increased under conditions of oxidative stress with no change in total iron levels. However, when total iron levels increased in vivo, an increase in both the pool of unincorporated iron and oxidative stress was observed suggesting that the status of the unincorporated iron pool is linked to oxidative stress and iron levels.
Assuntos
Caenorhabditis elegans/metabolismo , Ferro/metabolismo , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/efeitos dos fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Resposta ao Choque Térmico , Peróxido de Hidrogênio/toxicidade , Ferro/administração & dosagem , Ferro/química , Oxidantes/toxicidade , Estresse Oxidativo , Paraquat/toxicidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Somatic growth pattern in infants undergoing staged palliation for hypoplastic left heart syndrome (Norwood procedure [NP], stage 2 palliation [S2P], and Fontan procedure [FP]) during transition toward a more energy efficient series circulation is not well understood. OBJECTIVES: We sought to determine growth pattern in these infants and factors influencing it. METHODS: Patients who underwent NP since 2001 and survived at least 1 year after S2P were followed until FP or death/heart transplantation (n = 46). Weight for age z-scores (WAZ) were measured prior to NP; at initial discharge; prior to S2P; at four time periods after S2P; and prior to FP. Impact of gender, race, era of NP, anatomic subtype, NP shunt type, gastrostomy, home-surveillance program (daily weights and pulse oximetry), and interstage oxygen saturation on WAZ was evaluated. RESULTS: Repeated measures anova showed a significant change in WAZ across time periods (P < 0.0005), with a significant decline from Pre-NP to Pre-S2P (P < 0.0005) and steady increase from Pre-S2P to Pre-FP (P= 0.016). None of the factors evaluated had a significant effect on this growth pattern. Length of hospital stay after NP was negatively correlated with WAZ at discharge (P= 0.001), but not for other time periods. Intervals from discharge to S2P and NP to S2P interval did not correlate with WAZ. CONCLUSION: Somatic growth is significantly impaired after NP but recovers steadily following S2P, as the patient transitions toward separated series circulation. Earlier S2P may lead to earlier resumption of normal growth in this critical period of early infancy.
Assuntos
Peso Corporal , Técnica de Fontan , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Procedimentos de Norwood , Fatores Etários , Análise de Variância , Arkansas , Criança , Pré-Escolar , Ingestão de Energia , Feminino , Técnica de Fontan/efeitos adversos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Procedimentos de Norwood/efeitos adversos , Cuidados Paliativos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: In the past decade, many advances in the care of patients undergoing the Norwood procedure (NP) have been reported, but management remains nonstandardized at many institutions. We studied the impact of a standardized management protocol for neonates undergoing NP. METHODS: Care of NP patients has been protocol-driven at our institution since 2005, with routine use of regional low flow perfusion; near infrared spectroscopy; phenoxybenzamine with cardiopulmonary bypass; delayed sternal closure; peritoneal drainage; gastrostomy tubes; postoperative vocal cord assessment; and a home surveillance program of daily weight and oxygen saturation measurement. Patients undergoing NP from 2001 to 2004 (n = 40, group 1), in whom these interventions were only selectively employed, were retrospectively compared with those receiving standardized management from 2005 to 2007 (n = 40, group 2), with endpoints of survival in-hospital and to stage 2 palliation (S2P). Effect of protocol elements on outcome was evaluated by univariate and multivariate analyses. RESULTS: Hospital survival (95% vs. 70%, P= .003) and survival to S2P (85% vs. 58%, P= .006) was better in group 2. By univariate analysis, regional low flow perfusion, gastrostomy usage, and near infrared spectroscopy were associated with improved hospital and survival to S2P. In multivariable analysis, gastrostomy usage was associated with improved hospital survival (P= .027) and survival to S2P (P= .049), while our home surveillance program was a predictor of survival to S2P (P= .016). CONCLUSION: Protocol-driven management of NP patients was associated with better hospital survival and survival to S2P. Among protocol elements, gastrostomy usage was linked to both improved hospital survival and survival to S2P. Home surveillance was associated with increased survival to S2P.
Assuntos
Procedimentos Cirúrgicos Cardíacos/normas , Protocolos Clínicos/normas , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Avaliação de Processos e Resultados em Cuidados de Saúde/normas , Equipe de Assistência ao Paciente/normas , Qualidade da Assistência à Saúde/normas , Antagonistas Adrenérgicos alfa/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Ponte Cardiopulmonar/normas , Pré-Escolar , Drenagem/normas , Feminino , Gastrostomia/normas , Serviços de Assistência Domiciliar/normas , Mortalidade Hospitalar , Humanos , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Cuidados Paliativos/normas , Perfusão/normas , Fenoxibenzamina/uso terapêutico , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Espectroscopia de Luz Próxima ao Infravermelho/normas , Esterno/cirurgia , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Oxidative stress, caused by free radicals within the body, has been associated with the process of aging and many human diseases. Because free radicals, in particular superoxide, are difficult to measure, an alternative indirect method for measuring oxidative stress levels has been used successfully in Escherichia coli and yeast. This method is based on a proposed connection between elevated superoxide levels and release of iron from solvent-exposed [4Fe-4S] enzyme clusters that eventually leads to an increase in hydroxyl radical production. In past studies using bacteria and yeast, a positive correlation was found between superoxide production or oxidative stress due to superoxide within the organism and electron paramagnetic resonance (EPR) detectable "free" iron levels. In the current study, we have developed a reliable and efficient method for measuring "free" iron levels in Caenorhabditis elegans using low-temperature Fe(III) EPR at g=4.3. This method uses synchronized worm cultures grown on plates that are homogenized and treated with desferrioxamine, an Fe(III) chelator, prior to packing the EPR tube. Homogenization was found not to alter "free" iron levels, whereas desferrioxamine treatment significantly raised these levels, indicating the presence of both Fe(II) and Fe(III) in the "free" iron pool. The correlation between free radical levels and the observed "free" iron levels was examined by using heat stress and paraquat treatment. The intensity of the Fe(III) EPR signal, and thus the concentration of the "free" iron pool, varied with the treatments that altered radical levels without changing the total iron levels. This study provides the groundwork needed to uncover the correlation among oxidative stress, "free" iron levels, and longevity in C. elegans.
Assuntos
Caenorhabditis elegans/metabolismo , Ferro/metabolismo , Animais , Caenorhabditis elegans/efeitos dos fármacos , Temperatura Baixa , Espectroscopia de Ressonância de Spin Eletrônica , Espectrometria de Massas , Paraquat/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Saccharomyces cerevisiae lacking Cu,Zn superoxide dismutase (SOD1) show several metabolic defects including aerobic blockages in methionine and lysine biosynthesis. We have previously shown that mutations in genes implicated in the formation of iron-sulfur clusters, designated seo (suppressors of endogenous oxidation), reverse the oxygen-dependent methionine and lysine auxotrophies of a sod1Delta strain. We now report the surprising finding that seo mutants do not reduce oxidative damage as shown by the lack of reduction of EPR-detectable "free" iron, which is characteristic of sod1Delta mutants. In fact, they exhibit increased oxidative damage as evidenced by increased accumulation of protein carbonyls. The seo class of mutants overaccumulates mitochondrial iron, and this iron accumulation is critical for suppression of the sod1Delta biosynthetic defects. Blocking overaccumulation of mitochondrial iron abolished the ability of the seo mutants to suppress the sod1Delta auxotrophies. By contrast, increasing the mitochondrial iron content of sod1Delta yeast using high copy MMT1, which encodes a mitochondrial iron transporter, was sufficient to mimic the seo mutants. Our studies indicated that suppression of the sod1Delta methionine auxotrophy was dependent on the pentose phosphate pathway, which is a major source of NADPH production. By comparison, the sod1Delta lysine auxotrophy appears to be reversed in the seo mutants by increased expression of genes in the lysine biosynthetic pathway, perhaps through sensing of mitochondrial damage by the retrograde response.