Periodic Reporting for period 1 - MAMllingIR (Endoplasmic Reticulum-Mitochondria contact sites structural and functional adaptation during Insulin Resistance)
Berichtszeitraum: 2022-07-01 bis 2024-06-30
The rise in obesity and related metabolic disorders is a significant global health crisis, largely driven by lifestyle factors associated with the so-called Western diet. This diet, characterised by high levels of sugar, salt, fat and calories, combined with an increasingly sedentary lifestyle, exposes a large proportion of the world's population to environmental stressors that severely impact metabolic health. One of the most worrying consequences of this lifestyle is the disruption of glucose homeostasis - a critical process that ensures stable blood glucose levels through the coordinated action of various tissues, hormones and neural circuits.
Maintaining glucose levels within a narrow, healthy range is essential to provide energy for cells while avoiding harmful spikes or drops in blood glucose. However, in people who are obese, an important complication occurs: the loss of insulin sensitivity in metabolically active tissues such as skeletal muscle and the liver. This condition, known as insulin resistance, leads to elevated blood glucose levels, a hallmark of type 2 diabetes and a major risk factor for other serious health complications.
At the heart of this metabolic dysfunction are two intracellular organelles, the endoplasmic reticulum (ER) and mitochondria. These organelles play critical roles in cellular function, but their activities are significantly disrupted by the high-fat, high-calorie Western diet. This disruption affects intracellular signalling processes that are crucial for maintaining cellular function and metabolic balance. Historically, the roles of the ER and mitochondria in the development of metabolic diseases have been studied independently.
However, recent research has shown that these organelles are deeply interconnected, both physically and metabolically, through structures known as mitochondria-associated ER membranes (MAMs). These MAMs facilitate direct communication between the ER and mitochondria, supporting inter-organelle signalling that is essential for dynamic metabolic regulation.
The primary aim of the project is to investigate and elucidate the role of MAMs in the context of metabolic diseases such as obesity and diabetes. By understanding how miscommunication between the ER and mitochondria contributes to insulin resistance and metabolic dysfunction, the project aims to identify new molecular targets for therapeutic intervention. This research is not only crucial to advancing the scientific understanding of metabolic diseases, but also has significant potential to inform public health strategies and reduce the burden of these diseases on healthcare systems.
Maintaining glucose levels within a narrow, healthy range is essential to provide energy for cells while avoiding harmful spikes or drops in blood glucose. However, in people who are obese, an important complication occurs: the loss of insulin sensitivity in metabolically active tissues such as skeletal muscle and the liver. This condition, known as insulin resistance, leads to elevated blood glucose levels, a hallmark of type 2 diabetes and a major risk factor for other serious health complications.
At the heart of this metabolic dysfunction are two intracellular organelles, the endoplasmic reticulum (ER) and mitochondria. These organelles play critical roles in cellular function, but their activities are significantly disrupted by the high-fat, high-calorie Western diet. This disruption affects intracellular signalling processes that are crucial for maintaining cellular function and metabolic balance. Historically, the roles of the ER and mitochondria in the development of metabolic diseases have been studied independently.
However, recent research has shown that these organelles are deeply interconnected, both physically and metabolically, through structures known as mitochondria-associated ER membranes (MAMs). These MAMs facilitate direct communication between the ER and mitochondria, supporting inter-organelle signalling that is essential for dynamic metabolic regulation.
The primary aim of the project is to investigate and elucidate the role of MAMs in the context of metabolic diseases such as obesity and diabetes. By understanding how miscommunication between the ER and mitochondria contributes to insulin resistance and metabolic dysfunction, the project aims to identify new molecular targets for therapeutic intervention. This research is not only crucial to advancing the scientific understanding of metabolic diseases, but also has significant potential to inform public health strategies and reduce the burden of these diseases on healthcare systems.
The project has made significant progress in elucidating the mechanisms that regulate MAMs during metabolic stress, providing insights into the molecular pathways that contribute to diabetes.
To identify the molecular signatures underlying metabolic disease, we used different models representing different stages of disease progression. This approach allowed us to capture both early and late molecular changes associated with metabolic dysfunction.
A key focus of our research was the molecular remodelling of MAMs, in particular the protein and lipid composition of these structures. We used advanced experimental techniques, including state-of-the-art analytical tools and sophisticated data analysis methods, to deepen our understanding of the regulatory mechanisms involved.
One of the key achievements of the project is the development of advanced techniques to study organelle interactions in vivo. These cutting-edge tools have allowed us to dissect the communication between the ER and mitochondria, which is essential for maintaining cellular homeostasis. Understanding the molecular mechanisms governing MAM plasticity has laid the groundwork for identifying new therapeutic targets that could be exploited in the early stages of metabolic disease, potentially preventing progression to more severe and costly complications.
The impact of this research goes beyond the treatment of obesity and diabetes. The methods and findings from this project form the basis of a broader pipeline that can be applied to other pathological conditions where organelle communication plays a critical role. This approach also opens up new avenues for exploring various aspects of contact site biology, a rapidly growing field that is shedding light on the importance of inter-organelle communication in various cellular processes.
To identify the molecular signatures underlying metabolic disease, we used different models representing different stages of disease progression. This approach allowed us to capture both early and late molecular changes associated with metabolic dysfunction.
A key focus of our research was the molecular remodelling of MAMs, in particular the protein and lipid composition of these structures. We used advanced experimental techniques, including state-of-the-art analytical tools and sophisticated data analysis methods, to deepen our understanding of the regulatory mechanisms involved.
One of the key achievements of the project is the development of advanced techniques to study organelle interactions in vivo. These cutting-edge tools have allowed us to dissect the communication between the ER and mitochondria, which is essential for maintaining cellular homeostasis. Understanding the molecular mechanisms governing MAM plasticity has laid the groundwork for identifying new therapeutic targets that could be exploited in the early stages of metabolic disease, potentially preventing progression to more severe and costly complications.
The impact of this research goes beyond the treatment of obesity and diabetes. The methods and findings from this project form the basis of a broader pipeline that can be applied to other pathological conditions where organelle communication plays a critical role. This approach also opens up new avenues for exploring various aspects of contact site biology, a rapidly growing field that is shedding light on the importance of inter-organelle communication in various cellular processes.
This project is pushing the boundaries of our understanding of the molecular mechanisms underlying obesity and diabetes, particularly through the study of mitochondrial-associated membranes. The primary aim was to elucidate how MAMs contribute to metabolic stress, with a focus on their role in insulin resistance - a key factor in the development of these metabolic diseases. Prior to this project, the role of MAMs in these diseases was largely speculative and descriptive, lacking a solid mechanistic framework. Our research is filling this gap by providing a comprehensive dataset that, for the first time, maps the molecular events at the ER-mitochondria interface in both normal and disease conditions.
The project will provide a comprehensive dataset elucidating the molecular dynamics at the endoplasmic reticulum-mitochondrial interface. These data provide a detailed landscape of how these interactions are altered during metabolic stress, particularly in the context of insulin resistance. These findings are crucial for a deeper understanding of the pathogenesis of obesity and diabetes and offer new avenues for therapeutic intervention.
The project will provide a comprehensive dataset elucidating the molecular dynamics at the endoplasmic reticulum-mitochondrial interface. These data provide a detailed landscape of how these interactions are altered during metabolic stress, particularly in the context of insulin resistance. These findings are crucial for a deeper understanding of the pathogenesis of obesity and diabetes and offer new avenues for therapeutic intervention.