SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.

Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.

Regulation of cell function and identity by cellular senescence.

During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.

A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.

The ELN gene encodes tropoelastin which is used to generate elastic fibers that insure proper tissue elasticity. Decreased amounts of elastic fibers and/or accumulation of bioactive products of their cleavage, named elastokines, are thought to contribute to aging. Cellular senescence, characterized by a stable proliferation arrest and by the senescence-associated secretory phenotype (SASP), increases with aging, fostering the onset and progression of age-related diseases and overall aging, and has so far never been linked with elastin. Here, we identified that decrease in ELN either by siRNA in normal human fibroblasts or by knockout in mouse embryonic fibroblasts results in premature senescence. Surprisingly this effect is independent of elastic fiber degradation or elastokines production, but it relies on the rapid increase in HMOX1 after ELN downregulation. Moreover, the induction of HMOX1 depends on p53 and NRF2 transcription factors, and leads to an increase in iron, further mediating ELN downregulation-induced senescence. Screening of iron-dependent DNA and histones demethylases revealed a role for histone PHF8 demethylase in mediating ELN downregulation-induced senescence. Collectively, these results unveil a role for ELN in protecting cells from cellular senescence through a non-canonical mechanism involving a ROS/HMOX1/iron accumulation/PHF8 histone demethylase pathway reprogramming gene expression towards a senescence program.

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Plasma membrane damage is a new trigger of cellular senescence.

By blocking proliferation and inducing a secretory phenotype, cellular senescence has beneficial and deleterious effects, the latter being linked to aging. Suda et al. recently reported that plasma membrane (PM) damage (PMD) triggers senescence, suggesting that PMD inducers promote senescence and that the PMD repair machinery can regulate it.

A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.

Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.

Revisiting sensitivity of senescent cells to BH3 mimetics.

B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability.

Cholesterol biosynthetic pathway induces cellular senescence through ERRα.

Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate pathway-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes the transcriptional activity of ERRα that could lead to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis or level in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.

L'avènement de l'espace chez le jeune enfant / The onset of space in young children / O advento do espaço na criança pequena / El advenimiento del espacio en el la primera infancia

Cette étude examine les conditions de l'avènement de l'espace chez les jeunes enfants. Dans ce but, on procède à une relecture attentive de l'analyse du fort-da par Sigmund Freud, montrant comment ce jeu, inventé spontanément par un enfant de 18 mois, témoigne précisément l'articulation entre le langage, l'espace et l'émergence du désir. Nous nous appuierons également sur plusieurs remarques de Jacques Lacan à ce sujet.

Este estudo tem como objetivo questionar as condições do advento do espaço em crianças pequenas. Para isso, faremos uma releitura da análise que Sigmund Freud fez do fort-da, a fim de mostrar como esse jogo espontaneamente inventado por uma criança de um ano e meio atesta precisamente a articulação entre a linguagem, o espaço e o advento do desejo. Nós vamos assentar com diversos comentários de Jacques Lacan sobre o assunto.

This study investigates how the notion of space emerge in young children. To do so, it carries out a careful re-reading of Sigmund Freud's analysis of the "fort-da," showing how this game, spontaneously invented by an 18-month-old child, precisely indicates the articulation between language, space, and the emergence of desire. The discussion also borrows from several remarks made by Jacques Lacan on the topic.

Este estudio se propone interrogar las condiciones del advenimiento del espacio en la primera infancia. Para ello, se presenta el análisis de Sigmund Freud sobre el fort-da, con el fin de mostrar cómo este juego inventado espontáneamente por un niño de un año y medio atestigua precisamente la articulación entre el lenguaje, el espacio y el advenimiento del deseo. También se utilizan varios comentarios de Jacques Lacan sobre este tema.

Désirer, acheter, consommer. Approche lacanienne / Desire, purchasing, consumption: A Lacanian approach / Desejo, compra e consumo: uma abordagem lacaniana / Deseo, compra y consumer. un nfoque lacaniano

Il s'agira ici de questionner la fonction que pour l'être parlant, peuvent occuper les pratiques d'achat et de consommation, encore peu étudiées en tant que telles dans le champ de la psychanalyse et de la psychopathologie. A partir de l'enseignement de Jacques Lacan, nous tâcherons de préciser la logique de ces pratiques, en isolant en quoi elles peuvent constituer pour un sujet une fausse réponse quant à l'embarras de son désir. De là, nous questionnerons aussi comment ces pratiques s'actualisent dans l'espace numérique du monde contemporain, et comment ce faisant elles participent au malaise actuel dans la civilisation.

This paper questions the function that purchasing and consumption practices can have for the speaking being. So far, these practices have been little studied as such in the field of psychoanalysis and psychopathology. Based on Jacques Lacan's teaching, we will try to clarify the logic behind those practices, by identifying in what way they can provide a subject with a false answer to the embarrassment of his desire. Then, we will also question how those practices are updated in the digital space of the contemporary world, and how they contribute to the current discontent in civilization.

O presente estudo tem como objetivo questionar a função que podem ocupar, para o sujeito falante, as práticas de compra e consumo, ainda pouco estudadas como tal no campo da psicanálise e da psicopatologia. A partir do ensino de Jacques Lacan, tentaremos esclarecer a lógica dessas práticas, precisando como elas podem constituir, para um sujeito, uma resposta falsa diante do embaraço de seu desejo. Em seguida, questionaremos igualmente como essas práticas se atualizam no espaço digital do mundo contemporâneo e como, ao fazê-lo, elas participam do atual mal--estar na civilização.

Se tratará de interrogar aquí la función que pueden ocupar, para el ser que habla, las prácticas de compra y de consumo, aún poco estudiadas en el campo del psicoanálisis y de la psicopatología. Desde de la enseñanza de Jacques Lacan, trataremos de aclarar la lógica de dichas prácticas, estableciendo cómo pueden constituir, para un sujeto, una falsa respuesta frente a lo confuso de su deseo. Desde ahí, nos interrogaremos también sobre cómo estas prácticas se actualizan en el espacio numérico del mundo contemporáneo y cómo, al hacerlo, contribuyen con el malestar actual de la civilización.

Ziel dieses Artikels ist es, jene Funktion zu hinterfragen, die Kauf und Konsum für das sprechende Wesen darstellen, Handlungen, die als solche in der Psychoanalyse und Psychopathologie bisher wenig erforscht wurden. Auf der Grundlage der Lehre Jacques Lacans soll versucht werden, die Logik dieser Handlungen zu beschreiben und dabei herauszuarbeiten, inwiefern sie für das Subjekt eine falsche Antwort auf die Verlegenheit angesichts seines Begehrens darstellen könnte. Davon ausgehend wird dann erörtert, wie sich diese Handlungen im digitalen Raum unserer Gegenwart aktualisieren und wie sie eben dadurch zum heutigen Unbehagen in der Kultur beitragen.

La adolescencia con Freud y Flaubert / Adolescence with Freud and Flaubert

resumen El texto aborda dos aspectos fundamentales de la crisis en la adolescencia desde las obras de Sigmund Freud y Gustave Flaubert: su encuentro con su objeto del deseo, el goce, el acto sexual y las causas del desprendimiento de la autoridad paterna y sus efectos. Se estudiaron en la obra de Flaubert las causas del enigma que el autor deja entrever en su texto Memorias de un loco: ¿Soy Otro o yo mismo?, ese sentimiento de extrañeza en el adolescente enfrentado en el despertar de un sueno, con un sentido y un deseo nuevo del objeto de amor. El deseo ardiente de ser como un grande y las mociones hacia los padres, influyen las decisiones para las que el joven no está preparado, dadas la educación acuñada y las respuestas a sus investigaciones sexuales infantiles no satisfechas. Lacan puntúa que la relación sexual no existe y Freud puntúa el amor como siendo narcisista e infantil; las primeras manifestaciones amorosas, dado el fantasma que las recubre, continúan siendo las mismas, lo que se explica a través de Flaubert y del comentario de Lacan a Wedekind, en El despertar de la primavera. En la infancia el cuerpo de goce no está comprometido, por eso es tan simple; el adolescente sería ya una representación de la división del sujeto, del corte hecho por su inconsciente, del cual su cuerpo en ciertos casos portara las marcas, estará sorprendido, desconcertado por ese deseo nuevo que produce su inconsciente hasta el paso al acto sexual.

abstract The text approaches two fundamental aspects of the adolescent crisis from the works of Sigmund Freud and Gustave Flaubert: their encounter with their object in desire, pleasure, sexual act, and the causes the detachment from parental authority and their effects. A study was made on the work of Flaubert on the causes of the enigma, which the author suggests in his Memoirs of a Madman: Am I another or myself? That feeling of strangeness the adolescent experiences on waking up in a dream, with a new feeling and desire of the love object. The ardent desire of being like a grown-up, and the motions toward their parents, influence decisions for which the young are not prepared, given their cradled education and the unsatisfactory answers to their infant sexual investigation. Lacan notes that the sexual relationship does not exist. Freud rates love as being narcissistic and childish. The first amorous manifestations, given the fantasy that cloaks them always remain the same, as explained by Flaubert and Lacan's comment to Wedekind, in The Spring Awakening. In childhood the enjoyment of body is not involved. For this reason, it is so simple, the adolescent would be a representation of the division of the subject, the cut made by their unconscious, which their body, in certain cases, will carry the marks. They will be surprised, puzzled by this new desire that produces their unconscious to step toward the sexual act.

Lacan e a modernidade / Lacan and modernity

Gostaríamos aqui de retornar a alguns diagnósticos de Lacan sobre modernidade, para tentar melhor separar, um por um, dentre seus comentários, os que concernem ao laço social e aqueles concernentes aos sintomas e ao inconsciente dos sujeitos. Porque se Lacan soube marcar lucidamente certos efeitos da modernidade, ele também sublinhou seus limites estruturais, razão pela qual, dizia, ele não era pessimista.(AU)

Here, we would like to review some of Lacan's diagnoses of modernity, in an attempt to achieve a better distinction between his commentaries on social bonding and those on subjects' symptoms and subconscious, one by one. Indeed, while Lacan emphasized and clearly demonstrated certain effects of modernity, he also highlighted its structural limits, and according to him, this was the reason why he was not pessimistic.(AU)

A marca do desejo parental / The impression of parental's desire / La marca del deseo de los padres

Por quais razões e por quais vias alguma coisa do desejo parental pode transmitir-se à criança, marcá-la em seu inconsciente, deixando uma impressão? Inicialmente, é devido à entrada da criança na linguagem, por ela ter consentido uma perda de gozo, que uma primeira possibilidade surge para ela. Intérprete daquilo que se esconde por trás do discurso de seus pais, pouco a pouco se abre para a criança a via da marca do desejo parental. Paralelamente a essa interpretação, é no aguardo e na esperança de uma resposta à questão "O que eu sou para o Outro?" que podemos reconhecer os primeiros traços da transmissão do desejo do Outro parental. Os escritos de R. Gary La promesse de l'aube e de P. Quignard Le nom sur le bout de la langue nos permitem perceber que o sujeito se coloca no lugar daquilo que falta ao Outro. É porque o sujeito consente uma separação da cadeia significante do Outro que o desejo deste Outro poderá se transmitir e se inscrever...

What are the reasons and the path in which something of the parents desire can be transmitted to the child, marking his inconscient and leaving a print? Primarily, it is because the child has entered at the language, due to a consent to a loss of jouissance, that a first possibility comes up. Interpreter of what lies behind the parental speech, gradually, there is an accessible way that opens up to the parental's desire. At the same time, it is in this moment of waiting and hoping for a response to the question "What am I to you?" that we spot the first signs of a transmission of the desire of the Other parental in the child. The writings of R. Gary, La promesse de l'aube and of P. Quignard, Le nom sur le bout de la langue, allow us to recognize that the subject constitutes himself in the lacking-space of the Other. It is because the subject consents to separate himself from the signifying chain of the Other that the desire of this Other can be transmitted and inscribed...

¿Por qué razones y por qué vías algo del deseo de los padres puede transmitirse al niño, marcar su inconsciente y dejar una marca? Al principio es debido a la entrada del niño en el lenguaje, que accedió a una pérdida de goce, que se presenta una primera posibilidad. Intérprete de lo que se esconde detrás del discurso de sus padres, poco a poco, se abre para el pequeño niño la vía de la marca del deseo de los padres. Paralelo a esta interpretación, es en la espera y en la esperanza de una respuesta a la pregunta "¿Qué soy yo para el Otro?" que encontramos las primeras marcas de una transmisión del deseo del Otro parental. Los escritos de R. Gary La promesse de l'aube y de P. Quignard Le nom sur le bout de la langue nos permiten percibir que el sujeto se coloca en el lugar de lo que falta en el Otro. Es porque el sujeto consiente a la separación de la cadena significante del Otro que el deseo de este Otro puede ser transmitido e inscrito...

A marca do desejo parental / The impression of parental's desire / La marca del deseo de los padres

Por quais razões e por quais vias alguma coisa do desejo parental pode transmitir-se à criança, marcá-la em seu inconsciente, deixando uma impressão? Inicialmente, é devido à entrada da criança na linguagem, por ela ter consentido uma perda de gozo, que uma primeira possibilidade surge para ela. Intérprete daquilo que se esconde por trás do discurso de seus pais, pouco a pouco se abre para a criança a via da marca do desejo parental. Paralelamente a essa interpretação, é no aguardo e na esperança de uma resposta à questão "O que eu sou para o Outro?" que podemos reconhecer os primeiros traços da transmissão do desejo do Outro parental. Os escritos de R. Gary La promesse de l'aube e de P. Quignard Le nom sur le bout de la langue nos permitem perceber que o sujeito se coloca no lugar daquilo que falta ao Outro. É porque o sujeito consente uma separação da cadeia significante do Outro que o desejo deste Outro poderá se transmitir e se inscrever(AU)

What are the reasons and the path in which something of the parents desire can be transmitted to the child, marking his inconscient and leaving a print? Primarily, it is because the child has entered at the language, due to a consent to a loss of jouissance, that a first possibility comes up. Interpreter of what lies behind the parental speech, gradually, there is an accessible way that opens up to the parental's desire. At the same time, it is in this moment of waiting and hoping for a response to the question "What am I to you?" that we spot the first signs of a transmission of the desire of the Other parental in the child. The writings of R. Gary, La promesse de l'aube and of P. Quignard, Le nom sur le bout de la langue, allow us to recognize that the subject constitutes himself in the lacking-space of the Other. It is because the subject consents to separate himself from the signifying chain of the Other that the desire of this Other can be transmitted and inscribed(AU)

¿Por qué razones y por qué vías algo del deseo de los padres puede transmitirse al niño, marcar su inconsciente y dejar una marca? Al principio es debido a la entrada del niño en el lenguaje, que accedió a una pérdida de goce, que se presenta una primera posibilidad. Intérprete de lo que se esconde detrás del discurso de sus padres, poco a poco, se abre para el pequeño niño la vía de la marca del deseo de los padres. Paralelo a esta interpretación, es en la espera y en la esperanza de una respuesta a la pregunta "¿Qué soy yo para el Otro?" que encontramos las primeras marcas de una transmisión del deseo del Otro parental. Los escritos de R. Gary La promesse de l'aube y de P. Quignard Le nom sur le bout de la langue nos permiten percibir que el sujeto se coloca en el lugar de lo que falta en el Otro. Es porque el sujeto consiente a la separación de la cadena significante del Otro que el deseo de este Otro puede ser transmitido e inscrito(AU)

A letra e a voz

A partir dos efeitos de linguagem e de escrita desvelados por Joyce em Stephen Hero, e desenvolvidos por Lacan nos seminários dos anos 1970, o presente artigo procura demonstrar como a psicanálise, desde Freud, pode ser dita uma “clínica do fonema”. Com Lacan, o autor enfatiza a interpretação pelo equívoco e o trocadilho, indagando até que ponto se deveria repensar a clínica da psicose. Ao final, ele propõe um entrecruzamento da neurose e da psicose justamente na redução do sentido por meio da letra.(AU)

From the effects of language and writing unveiled by Joyce in Stephen Hero, and developed by Lacan in the seminars of the years 1970, this article seeks to demonstrate how psychoanalysis, since Freud, can be said to be a "clinic of the phoneme". With Lacan, the author emphasizes the interpretation by the mistake and the pun, asking to what extent we should rethink the clinic of psychosis. At the end, he proposes an interweaving of neurosis and psychosis in the reduction of meaning through words.(AU)

Rêve et adolescence / Sonho e adolescência / Dream and adolescence

L’adolescence sera ici étudiée sous l’angle des rêves, nouveaux, qui surprennent les sujets à ce moment de la vie. Nous verrons alors ce que l’adolescence doit au travail de l’inconscient, et au chiffrage de la jouissance qu’il opère. A l’appui de la pièce de Théâtre L’éveil du printemps, de Frank Wedekind, ainsique du commentaire qu’en fit Jacques Lacan, nous démontrerons en quoi c’est un désir nouveau, qui faitl’adolescence, et affecte le sujet(AU)

A adolescência será estudada aqui sob o ângulo dos sonhos, novo, que surpreende os sujeitos nessa época da vida. Veremos, então, a relação da adolescência com o trabalho do inconsciente e o ciframento de gozo que ele opera. A partir da peça de teatro O despertar da primavera, de Frank Wedekind, e do comentário que dela faz Jacques Lacan, demonstraremos que o que faz a adolescência é um desejo que afeta o sujeito(AU)

In this paper, adolescence is studied from the angle of the new dreams which surprise subjects at this time of life. We will consider what the work of the subconscious and the encoding of pleasure it carries out contribute to adolescence. The paper shows the extent to which adolescence consists in a new desire which affects the subject, with reference to Frank Wedekind's play Spring Awakening and Jacques Lacan's commentary on this work(AU)