Periodic Reporting for period 2 - MitoCure (Molecular and metabolic mechanisms underlying mitochondrial dysfunction)
Reporting period: 2022-07-01 to 2023-12-31
Mitochondria are special and intricate structures inside our cells that play vital roles in various aspects of cell biology. Unfortunately, mutations that disrupt their proper function lead to a diverse group of genetic inherited disorders known as mitochondrial diseases. These diseases are quite common, affecting at least 1 in 5000 adults, and can range from mild symptoms like exercise intolerance to severe, life-threatening forms causing organ failure and even death.
Currently, there are no cures for mitochondrial diseases, and the available treatments mainly focus on easing symptoms through vitamin cofactors, nutritional adjustments, and exercise. However, there's a pressing medical need to delve deeper into the molecular mechanisms driving these devastating disorders and use that knowledge to develop effective therapies.
The primary aim of this project is to address long-standing questions concerning mitochondrial metabolism and gain a better understanding of the diseases linked to mitochondrial dysfunction. Until now, developing treatments for diseases caused by mitochondrial problems has been hindered by a lack of clear molecular targets. Through MitoCure, we hope to uncover new insights into potential targets, paving the way for drug development programs and clinical studies. This groundbreaking work will provide a comprehensive view of how molecular mechanisms regulate mitochondrial function in both health and disease, serving as a vital foundation for future research into the molecular basis of mitochondrial disorders.
Currently, there are no cures for mitochondrial diseases, and the available treatments mainly focus on easing symptoms through vitamin cofactors, nutritional adjustments, and exercise. However, there's a pressing medical need to delve deeper into the molecular mechanisms driving these devastating disorders and use that knowledge to develop effective therapies.
The primary aim of this project is to address long-standing questions concerning mitochondrial metabolism and gain a better understanding of the diseases linked to mitochondrial dysfunction. Until now, developing treatments for diseases caused by mitochondrial problems has been hindered by a lack of clear molecular targets. Through MitoCure, we hope to uncover new insights into potential targets, paving the way for drug development programs and clinical studies. This groundbreaking work will provide a comprehensive view of how molecular mechanisms regulate mitochondrial function in both health and disease, serving as a vital foundation for future research into the molecular basis of mitochondrial disorders.
Up to this point, we've made significant strides in achieving several project objectives, particularly in the first two focal areas (AIMs).
1) One of the central questions we're addressing is: Why do cells and tissues with faulty mitochondria experience reduced fitness? Additionally, how do mutations that compromise mitochondrial function negatively impact the ability of specific tissues, like the brain, to carry out their functions? By utilizing advanced techniques, we've uncovered new metabolic pathways that become impaired when mitochondria aren't functioning correctly. Contrary to previous beliefs that energy production deficits were solely responsible for observed symptoms in patients, our data challenges this notion. Our research has enabled us to analyze various brain cell types and understand how each one activates distinct adaptive mechanisms to cope with faulty mitochondrial function. This is a crucial finding because it allows us to target these adaptive mechanisms to promote survival and enhance the fitness of neuronal populations, which could potentially benefit individuals affected by mitochondrial diseases.
2) Mitochondrial diseases have a genetic basis. While many genes responsible for these disorders have been identified, we're still working to create a comprehensive catalog of all the genes involved, which currently poses challenges in diagnosing these conditions. To tackle this issue, we've implemented cutting-edge genetic screens to identify previously unknown genes associated with mitochondrial diseases. As of now, we've uncovered two promising candidate genes, and we're in the process of validating them through a wide range of biochemical and bioenergetic tests. These discoveries are vital steps toward a better understanding and diagnosis of mitochondrial diseases.
3) We have created several mice models to study the metabolic communication between brain cell types and how this communication is impaired when mitochondria are not properly working. We are mainly focusing on two types of cells, neurons and astrocytes, a type o glia cell.
1) One of the central questions we're addressing is: Why do cells and tissues with faulty mitochondria experience reduced fitness? Additionally, how do mutations that compromise mitochondrial function negatively impact the ability of specific tissues, like the brain, to carry out their functions? By utilizing advanced techniques, we've uncovered new metabolic pathways that become impaired when mitochondria aren't functioning correctly. Contrary to previous beliefs that energy production deficits were solely responsible for observed symptoms in patients, our data challenges this notion. Our research has enabled us to analyze various brain cell types and understand how each one activates distinct adaptive mechanisms to cope with faulty mitochondrial function. This is a crucial finding because it allows us to target these adaptive mechanisms to promote survival and enhance the fitness of neuronal populations, which could potentially benefit individuals affected by mitochondrial diseases.
2) Mitochondrial diseases have a genetic basis. While many genes responsible for these disorders have been identified, we're still working to create a comprehensive catalog of all the genes involved, which currently poses challenges in diagnosing these conditions. To tackle this issue, we've implemented cutting-edge genetic screens to identify previously unknown genes associated with mitochondrial diseases. As of now, we've uncovered two promising candidate genes, and we're in the process of validating them through a wide range of biochemical and bioenergetic tests. These discoveries are vital steps toward a better understanding and diagnosis of mitochondrial diseases.
3) We have created several mice models to study the metabolic communication between brain cell types and how this communication is impaired when mitochondria are not properly working. We are mainly focusing on two types of cells, neurons and astrocytes, a type o glia cell.
In our research project, we have been studying a group of diseases called mitochondrial diseases, which affect the tiny powerhouses inside our cells known as mitochondria. These diseases are caused by changes in the genes responsible for keeping our mitochondria working correctly. Unfortunately, these changes can lead to a range of health problems. We have achieved notable milestones in each of our aims, shedding new light on the complex molecular mechanisms governing mitochondrial function and their impact on cellular and brain health.
What We've Achieved So Far:
We've made some exciting discoveries that go beyond what was previously known about mitochondrial diseases. Here are the main things we've accomplished:
1. Unraveling Mystery Genes: Imagine our cells as little factories with many workers, and mitochondria are like the engines that power these factories. We found some new "mystery" genes that play crucial roles in making sure these engines function properly. Understanding these genes is essential because when they don't work as they should, it can lead to serious health issues.
2. Unlocking the Secrets of Cellular Health: We've learned a lot about how our cells stay healthy and work well. We found that a specific pathway, called the "Pentose Phosphate Pathway," is vital for keeping cells strong during difficult times when they lack energy. Understanding this pathway can help us find new ways to treat diseases related to mitochondrial problems.
3. Glial Cells and Brain Health: Our brains are like supercomputers, and they need healthy cells called "glial cells" to support the neurons that do all the thinking. We've been studying how problems in these glial cells can affect brain health, which could help us develop treatments for brain-related issues caused by mitochondrial diseases.
Conclusion:
Our research has brought us closer to understanding the complex world of mitochondrial diseases. By discovering new genes, pathways, and ways to protect brain health, we are laying the groundwork for better treatments and hope to improve the lives of people living with mitochondrial diseases in the future.
What We've Achieved So Far:
We've made some exciting discoveries that go beyond what was previously known about mitochondrial diseases. Here are the main things we've accomplished:
1. Unraveling Mystery Genes: Imagine our cells as little factories with many workers, and mitochondria are like the engines that power these factories. We found some new "mystery" genes that play crucial roles in making sure these engines function properly. Understanding these genes is essential because when they don't work as they should, it can lead to serious health issues.
2. Unlocking the Secrets of Cellular Health: We've learned a lot about how our cells stay healthy and work well. We found that a specific pathway, called the "Pentose Phosphate Pathway," is vital for keeping cells strong during difficult times when they lack energy. Understanding this pathway can help us find new ways to treat diseases related to mitochondrial problems.
3. Glial Cells and Brain Health: Our brains are like supercomputers, and they need healthy cells called "glial cells" to support the neurons that do all the thinking. We've been studying how problems in these glial cells can affect brain health, which could help us develop treatments for brain-related issues caused by mitochondrial diseases.
Conclusion:
Our research has brought us closer to understanding the complex world of mitochondrial diseases. By discovering new genes, pathways, and ways to protect brain health, we are laying the groundwork for better treatments and hope to improve the lives of people living with mitochondrial diseases in the future.