Amazing structure of respirasome: unveiling the secrets of cell respiration

Respirasome, a huge molecular machine that carries out cellular respiration, has gained growing attention since its discovery, because respiration is the most indispensable biological process in almost all living creatures. The concept of respirasome has renewed our understanding of the respiratory chain organization, and most recently, the structure of respirasome solved by Yang's group from Tsinghua University (Gu et al. Nature 237(7622):639-643, 2016) firstly presented the detailed interactions within this huge molecular machine, and provided important information for drug design and screening. However, the study of cellular respiration went through a long history. Here, we briefly showed the detoured history of respiratory chain investigation, and then described the amazing structure of respirasome.

Fisiopatologia do Transtorno de Humor Bipolar e efeito do tratamento com lítio: enfoque em neuroproteção e função mitocondrial / Bipolar disorder pathophysiology and the effect of lithium treatment: focus on neuroprotection and mitochondrial function

Introdução: Diversas evidências apontam para um papel da disfunção mitocondrial no Transtorno de Humor Bipolar (THB), mas pouco se sabe sobre isso no THB de início recente. Na mitocôndria a atividade da cadeia transportadora de elétrons (CTE) atua juntamente com o ciclo do ácido cítrico na produção de energia, mas não está claro se estão alteradas no THB. O DNA mitocondrial (DNAmt) codifica diversas proteínas da CTE e está associado ao estresse oxidativo, mas nunca foi avaliado em pacientes no THB in vivo. O estresse oxidativo está associado ao THB e à disfunção mitocondrial, mas não se sabe muito das atividades das enzimas antioxidantes no THB de início recente. O óxido nítrico (NO) é uma molécula com efeitos neuromoduladores, mas com um papel no THB ainda não elucidado. O lítio é um tratamento padrão-ouro no THB, tendo mostrado efeitos neuroprotetores. Apesar disso, pouco se conhece do efeito do lítio na CTE, nas enzimas do ciclo do ácido cítrico, no conteúdo de DNAmt e na regulação de NO em humanos. Também não está claro o papel antioxidante do lítio no THB. Metódos: Pacientes com THB em depressão (n=31), não medicados em sua maioria (84%), foram tratados por 6 semanas com lítio. Antes e depois do tratamento, verificaram-se em leucócitos as atividades dos complexos I-IV da CTE, atividades das enzimas citrato sintase, succinato desidrogenase e malato desidrogenase e também o conteúdo de DNAmt; em plasma foram analisados os níveis de NO, substâncias reativas ao ácido tiobarbitúrico (TBARS) e as atividades de catalase (CAT), glutationa peroxidase (GPx), superóxido dismutase (SOD) e razão de SOD/CAT. Os pacientes com depressão bipolar foram comparados com 28 controles saudáveis. Resultados: Em comparação com controles, os pacientes com THB tiveram um aumento de GPx (p < 0,001) e CAT (p=0,005) e uma diminuição de SOD/CAT (p=0,001), sem outras diferenças nos demais biomarcadores. Pacientes com THB I mostraram uma diminuição de citrato sintase (p=0,02) e uma...

Background: Several evidences point to a role for mitochondrial dysfunction in Bipolar Disorder (BD), but few is known about it on short-term BD. In mitochondria the electron transport chain (ETC) acts jointly with citric acid cycle to produce energy, but it is not clear if they are altered in BD. Mitochondrial DNA (mtDNA) encodes several ETC proteins and is associated with oxidative stress, but it was never evaluated in BD in vivo. Oxidative stress is associated with BD and with mitochondrial dysfunction, but few is known about the activities of antioxidant enzymes in short-term BD. Nitric oxide (NO) is a molecule with neuromodulatory effects, but with an unclear role in BD. Lithium is a gold-standard treatment for BD, which has shown neuroprotective effects. However, few is known about lithium effect on ETC, citric acid cycle, mtDNA content, and NO regulation in humans. Also, lithium's antioxidant role in BD is unclear. Methods: Patients with BD depression (n=31) unmedicated in majority (84%) received lithium treatment for 6 weeks. Before and after treatment, in leukocytes the activities of ETC complex I-IV, citrate synthase, succinate dehydrogenase, and malate dehydrogenase, and mtDNA content were evaluated; in plasma, NO levels, thiobarbituric acid reactive substances (TBARS), the activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), and SOD/CAT ratio were evaluated. Bipolar depression patients were compared with 28 healthy controls. Results: When compared with controls, BD patients showed an increase in GPx (p < 0.001) and CAT (p=0.005) and a decrease in SOD/CAT (p=0.001), but showed no difference for other biomarkers. Patients with BD I showed a decrease in citrate synthase (p=0.02) and a slight decrease in mtDNA content (p=0.05) when compared to BD II; mtDNA content was slightly decreased in BD I compared to controls (p=0.05). From baseline to endpoint, there was an increase in ETC complex I activity (p=0.02),...

Clinical, biochemical and genetic analysis of the mitochondrial disorders presenting with cardiac damage / 中华儿科杂志

<p><b>OBJECTIVE</b>Mitochondrial disease is a group of energy metabolic disorders, characterized by involvement of multisystem with high energy requirements. Encephalomyopathies are common clinical findings of the mitochondrial diseases. However, mitochondrial cardiac damage is not rare. In this study, the clinical, biological, and genetic analyses were performed in three patients with mitochondrial cardiac damage, in order to understand the characteristics of mitochondrial diseases.</p><p><b>METHOD</b>Three girls presented with arrhythmia and cardiac enlargement from the age of 3, 4 and 8 years respectively. They were admitted into the Peking University First Hospital. Infection, autoimmune diseases, aminoacidopathies, organic acidurias, mitochondrial-fatty acid oxidation defects, and lysosomal storage disease were excluded by routine laboratory examinations and metabolic analysis for blood amino acids, acylcarnitines, urinary organic acids, and lysosome activity assay. Peripheral leukocytes mitochondrial respiratory chain enzyme I to V activities were measured by spectrophotometry. The entire sequence of the mitochondrial DNA was analyzed.</p><p><b>RESULT</b>In two patients (case 1 and case 3), hypertrophic cardiomyopathy and grade I to grade II of cardiac function were found. One patient (case 2) was diagnosed with arrhythmia and grade I of cardiac function. Increased creatine phosphokinase and creatine kinase isoenzyme MB were observed. Mitochondrial respiratory chain complex deficiencies were indentified in the three patients. Patient 1 had combined deficiencies of complex III and V. The activity of complex I+III was 18.7 nmol/(min·mg mitochondrial protein) (control 84.4 ± 28.5). The activity of complex V was 20.4 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). In her mitochondrial gene, A14693G on tRNA(Glu) and T16519C on D-loop were found. Patient 2 had an isolated complex I deficiency. The activity was 22.0 nmol/(min·mg mitochondrial protein) (control 44.0 ± 5.4). A16183C, T16189C and G15043A mutations on D-loop were found. Patient 3 had a combined deficiency of complex IV and V. The activity of complex IV was 21.0 nmol/(min·mg mitochondrial protein) (control 54.1 ± 12.3). The activity of complex V was 23.2 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). C253T and C16187T mutations on D-loop were detected. Haplotype analysis showed that three patients belong to H2a2a. Improvement was observed after the treatment with L-carnitine, coenzyme Q10, vitamin C and E. At present, the patients are 7, 5 and 8 years old. Although excise intolerance still persists, they had a good general condition with normal school life.</p><p><b>CONCLUSION</b>The mitochondrial diseases with cardiac damage show cardiomyopathy, arrhythmia and exercise intolerance. Many kinds of mitochondrial respiratory chain deficiency were observed. A14693G in mitochondrial tRNA(Glu) gene is probably one of the causes in China.</p>

Effect of concomitant lycopene biosynthesis on CoQ[10] accumulation in transformed Escherichia coli strains

CoQ[10] and lycopene are isoprenoid compounds with nutraceutical and pharmaceutical benefits. In this study, the effect of concomitant lycopene biosynthesis on CoQ[10] accumulation in transformed Escherichia coli DH5 alpha was studied. A lycopene production pathway including geranyl diphosphate synthase [crtE], phytoene synthase [crtB], and phytoene desaturase [crtI] from Erwinia herbicola was constructed in two CoQ[10]-producing E. coli strains. E. coli Ba and E. coli Br containing dds orthologs encoding for decaprenyl diphosphate synthase [Dds], respectively from Agrobacterium tumefaciens and Rhodobacter sphaeroides were transformed by the lycopene pathway resulting in E. coli Ba-lyc and E. coli Br-lyc. The lycopene pathway in E. coli Br-lyc interestingly resulted in a significant increase in CoQ[10] production from 564 +/- 28 to 989 +/- 22 micro g /g DCW. To confirm that the improvement of CoQ[10] production in E. coli Br-lyc was due to lycopene biosynthesis and not just geranylgeranyl diphosphate formation in the lycopene pathway, crtE was only introduced into E. coli Ba and E. coli Br strains. Surprisingly, crtE expression had adverse effects on CoQ[10] production in both strains. The results shed light on the Dds-catalyzed reaction as a bottleneck controlled by precursors; and the efficiency of a parallel lycopene pathway to streamline the flow of metabolites

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

Há evidências que sugerem que as miocardites chagásicas são devidas aos danos induzidos pelo estresse oxidativo, podendo contribuir para a evolução da doença de Chagas. Em doenças infecciosas, a formação de espécies reativas do oxigênio (ROS) é, principalmente, derivada de danos celulares mediados pela invasão e replicação do patógeno e por reações citotóxicas mediadas pelo sistema imune. No entanto, como as ROS são formadas e sua função no estresse oxidativo na cardiomiopatia chagásica (CCM) não estão completamente elucidadas. Nesta revisão, nós discutimos as evidências para o aumento do estresse oxidativo na doença de Chagas, com ênfase nas anormalidades mitocondriais, na disfunção da cadeia de transporte de elétrons e seu papel na manutenção do estresse oxidativo no miocárdio. Discutimos ainda, os resultados da literatura que relatam as conseqüências da manutenção do estresse oxidativo na patogênese da CCM.