Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development

Mfn2 is a mitochondrial fusion protein with bioenergetic functionsimplicated in the pathophysiology of neuronal and metabolicdisorders. Understanding the bioenergetic mechanism of Mfn2may aid in designing therapeutic approaches for these disorders.Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial meta-bolism requires its localization in the ER, which is independent ofits fusion function. ER-located Mfn2 interacts with mitochondrialMfn1/2 to tether the ER and mitochondria together, allowing Ca2+transfer from the ER to mitochondria to enhance mitochondrialbioenergetics. The physiological relevance of these findings isshown during neurite outgrowth, when there is an increase inMfn2-dependent ER-mitochondria contact that is necessary forcorrect neuronal arbor growth. Reduced neuritic growth in Mfn2KO neurons is recovered by the expression of ER-targeted Mfn2 oran artificial ER-mitochondria tether, indicating that manipulationof ER-mitochondria contacts could be used to treat pathologicconditions involving Mfn2

Synaptic Activity Regulates Mitochondrial Iron Metabolism to Enhance Neuronal Bioenergetics

Synaptic activity is the main energy-consuming process in the central nervous system. We are beginning to understand how energy is supplied and used during synaptic activity by neurons. However, the long-term metabolic adaptations associated with a previous episode of synaptic activity are not well understood. Herein, we show that an episode of synaptic activity increases mitochondrial bioenergetics beyond the duration of the synaptic activity by transcriptionally inducing the expression of iron metabolism genes with the consequent enhancement of cellular and mitochondrial iron uptake. Iron is a necessary component of the electron transport chain complexes, and its chelation or knockdown of mitochondrial iron transporter Mfrn1 blocks the activity-mediated bioenergetics boost. We found that Mfrn1 expression is regulated by the well-known regulator of synaptic plasticity CREB, suggesting the coordinated expression of synaptic plasticity programs with those required to meet the associated increase in energetic demands

Abordagem diagnóstica e terapêutica da toxoplasmose em gestantes e as repercussões no recém-nascido Diagnostic and therapeutic management of toxoplasmosis in pregnancy and the effect in the newborn

OBJETIVO:Avaliar a abordagem diagnóstica e terapêutica da toxoplasmose de gestantes que apresentaram IgM positiva para a doença e o acompanhamento de seus filhos em um hospital público no Rio de Janeiro, RJ. MÉTODOS: Estudo transversal retrospectivo de 2003 a 2006, realizado por meio da análise dos prontuários de 98 gestantes com sorologia IgM positiva para toxoplasmose e seus filhos (99 crianças). O seguimento das crianças com e sem infecção congênita foram analisados, assim como a apresentação clínica daquelas com infecção congênita e os testes diagnósticos utilizados para identificar a infecção pelo Toxoplasma gondii durante a gestação. RESULTADOS: O diagnóstico sorológico foi realizado em 76 pacientes no segundo e terceiro trimestre gestacional. Em 36 gestantes, a determinação dos níveis séricos de IgM foi o único teste diagnóstico realizado para infecção pelo toxoplasma. Em 49 gestantes, os índices de IgM, pela técnica ELFA, foram baixos. O teste de avidez de IgG foi realizado em 62 gestantes e somente 13 o realizaram no primeiro trimestre gestacional. O tratamento específico para toxoplasmose foi empregado em 93 gestantes. A taxa de transmissão vertical foi de 4%. Manifestações clínicas de toxoplasmose congênita foram encontradas em todas as crianças infectadas. Todas as crianças não infectadas apresentaram declínio de IgG específica para toxoplasmose ao longo do acompanhamento ambulatorial; a idade média de IgG comprovadamente negativa nessas crianças foi de 5,4 meses. CONCLUSÕES: Os resultados sugerem que uma sorologia positiva para IgM, como um único marcador sorológico para detectar infecção recente, tem um valor limitado.<br>OBJECTIVE: To analyze the diagnostic and therapeutic approach of pregnant women with positive IgM test for toxoplasmosis and the follow-up of their children in a public hospital of Rio de Janeiro, Brazil. METHODS: This cross-sectional retrospective study from 2003 to 2006 enrolled 98 pregnant women with positive IgM test for toxoplasmosis and 99 children. The follow-up of the children with or without congenital infection was reviewed, as well as the clinical presentation of those with congenital infection and the laboratory tests used to diagnose the infection by Toxoplasma gondii during pregnancy. RESULTS: Toxoplasmosis was diagnosed in the second and third trimesters of pregnancy in 76 patients. In 36 pregnant women, determination of the serum levels of IgM was the only laboratory method used to diagnose the infection. Low IgM levels analyzed by ELFA were detected in 49 pregnant women. IgG avidity test was performed in 62 patients and in 13% of them the exam was carried out during the first trimester of pregnancy. Specific treatment for toxoplasmosis was applied in 93 women. Vertical transmission rate was 4%. Clinical manifestation of congenital toxoplasmosis was found in all infected children. All non-infected children showed a decrease in IgG serum levels for toxoplasmosis during the follow-up. The mean age for negativation of IgG serum levels in these children was 5.4 months. CONCLUSIONS: Our results suggest that the use of a positive IgM test to toxoplasmosis as the only antibody marker to detect recent infection has a limited value