Fueling the heartbeat: Dynamic regulation of intracellular ATP during excitation-contraction coupling in ventricular myocytes.

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was <1 mM, which is eightfold to 10-fold lower than previously estimated. Accordingly, ATP-sensitive K+ (KATP) channels were active at physiological [ATP]i. Cells exhibited two distinct types of ATP fluctuations during an action potential: net increases (Mode 1) or decreases (Mode 2) in [ATP]i. Mode 1 [ATP]i increases necessitated Ca2+ entry and release from the sarcoplasmic reticulum (SR) and were associated with increases in mitochondrial Ca2+. By contrast, decreases in mitochondrial Ca2+ accompanied Mode 2 [ATP]i decreases. Down-regulation of the protein mitofusin 2 reduced the magnitude of [ATP]i fluctuations, indicating that SR-mitochondrial coupling plays a crucial role in the dynamic control of ATP levels. Activation of ß-adrenergic receptors decreased [ATP]i, underscoring the energetic impact of this signaling pathway. Finally, our work suggests that cross-bridge cycling is the largest consumer of ATP in a ventricular myocyte during an action potential. These findings provide insights into the energetic demands of EC coupling and highlight the dynamic nature of ATP concentrations in cardiac muscle.

Câncer de mama: Reprogramação do metabolismo tumoral / Breast Cancer: tumoral metabolism reprogramming

O câncer de mama é a neoplasia de maior incidência em mulheres de todo o mundo, cuja mortalidade se deve principalmente ao desenvolvimento de metástases (condição patológica em que as células tumorais conseguem atravessar a matriz extracelular e se estabelecer em outros tecidos). Devido à importância epidemiológica dessa doença, estudos têm sido realizados em busca de uma melhor compreensão dos processos que atuam na carcinogênese e/ou tumorigênese e que, consequentemente, levam ao desenvolvimento de novas formas de diagnóstico e tratamento que sejam cada vez mais efetivos. Para manter a alta taxa de proliferação e desenvolver um perfil agressivo, características que são observadas em células tumorais, diversas alterações no metabolismo celular se tornam necessárias. O metabolismo tumoral começou a ser descrito por Otto Warburg em 1920, onde afirma que células cancerosas metabolizam glicose de forma diferente das células normais através da glicólise aeróbica. Dados recentes mostram que as alterações também ocorrem no metabolismo lipídico, apontando para uma reprogramação celular. A possibilidade de novos alvos farmacológicos inseriu o metabolismo como alvo das pesquisas recentes. Entretanto, e apesar do avanço, 90 anos depois da descoberta feita por Warburg, os estudos ainda não conseguiram esclarecer por completo como o metabolismo tumoral funciona, demonstrando assim a necessidade de mais pesquisas. Tendo em vista este cenário, essa revisão tem como objetivo documentar e discutir os principais resultados obtidos até o momento, como apontar e sugerir áreas de investigação. (AU)

Breast cancer is the most prevalent neoplasm in women worldwide, whose mortality is mainly due to the development of metastasis (pathological condition in which cancer cells can cross the extracellular matrix and settle in other tissues). Due to the epidemiological importance of this disease, studies have been carried out in order to better understand the processes involved in carcinogenesis and/or tumorigenesis and, consequently, allow the development of new forms of diagnosis and treatment that are increasingly effective. To maintain the high proliferation rate and develop an aggressive profile, features that are observed in tumor cells, several changes in cellular metabolism become necessary. Tumor metabolism began to be described by Otto Warburg in 1920, where he states that cancer cells metabolize glucose differently from normal cells through aerobic glycolysis. Recent data show that changes also occur in lipid metabolism, pointing to cellular reprogramming. The possibility of new pharmacological targets, inserted the metabolism as a target of recent research. However, despite the breakthrough, 90 years after Warburg discovery, studies have not yet been able to fully clarify how tumor metabolism works, demonstrating the need for more research. In view of this scenario, this review aims to document the main results obtained so far and to discuss those aspects that are not yet well understood. (AU)

Breast cancer: Is grief a risk factor?

SUMMARY Cancer is characterized by the disordered growth of cells that have high capacity of invasion to the tissues and organs. One of the types of tumour that has national incidence and high mortality is breast cancer. Studies show that in addition to hereditary factors, lifestyle and environmental factors, there are factors related to emotional distress (mourning), which interfere with the development of breast cancer. Thus, it is necessary to investigate if the experience of mourning can trigger the appearance of the tumour. For this, an integrative review was performed to verify the existence of the relationship between mourning and development of breast cancer, which presented contradictory results. Methodological errors and lack of access to important information, such as alcohol and tobacco use, were pointed out as the main causes of the contradiction found. A possible mechanism involving cortisol release has been proposed, but more research is needed to make it clear whether the association between mourning and breast cancer really exists, and by what path.

RESUMO: O câncer é caracterizado pelo crescimento desordenado das células que possuem alta capacidade de invasão aos tecidos e órgãos. Um dos tipos de tumour que possui incidência nacional e alta mortalidade é o câncer de mama. Estudos mostram que, além dos fatores hereditários, ambientais e dos hábitos de vida, existem fatores relacionados a um trauma emocional (luto) que interferem no desenvolvimento do câncer de mama. Dessa forma, é necessário investigar se a vivência do luto pode desencadear o aparecimento do tumour. Para isso, realizou-se uma revisão integrativa para verificar a existência da relação entre o luto e o desenvolvimento do câncer de mama, que apresentou resultados contraditórios. Os erros metodológicos e a falta de acesso a informações importantes, como uso de álcool e fumo, foram apontadas como as principais causas da contradição encontrada. Um possível mecanismo envolvendo liberação de cortisol tem sido proposto, mas são necessárias mais investigações para que fique claro se a associação entre luto e câncer de mama realmente existe, e por qual mecanismo ocorre.