The mechanistic coupling between (ultra)structure and function
Werner Koopmans' research group focuses on understanding the mechanistic coupling between mitochondrial (ultra)structure and function (“morphofunction”) in patients with (mitochondrial) metabolic disorders.read more
The mechanistic coupling between (ultra)structure and function
Mitochondria are cellular organelles that generate cellular energy in the form of ATP. Importantly, mitochondria play a key role in various cellular processes like adaptive thermogenesis, innate immune responses, calcium and redox signalling, and cell death. OXPHOS and mitochondrial dysfunction are not only associated with relatively rare monogenic mitochondrial disorders but also observed during more common pathologic conditions, such as Alzheimer’s, Huntington’s and Parkinson’s disease, cancer, cardiac disease, diabetes, epilepsy, and obesity. In addition, a progressive decline in the expression of mitochondrial genes is observed during normal human aging and mitochondrial function is inhibited by environmental toxins and frequently used drugs. Mutations in OXPHOS structural genes are associated with neurodegenerative diseases including Leigh Syndrome, which is probably the most classical OXPHOS disease during early childhood.
Within the Radboudumc my research aims to unravel the interconnection between cell metabolism and mitochondrial morphofunction in single living cells, primarily using cellomics strategies. To this end I focus on gaining a quantitative mechanistic understanding of mitochondrial (patho)physiology at the (sub)cellular level in cells with mitochondrial dysfunction. Given the tight integration of mitochondrial and cellular metabolism, the above questions are addressed in living cell systems. As a key technology, protein-based and chemical fluorescent reporter molecules are introduced in healthy and patient-derived primary cells, as well as established cell lines to allow analysis of live-cell biochemistry and physiology. Reporter signals are read out using state-of-the-art quantitative (sub)cellular life cell microscopy and quantified using image processing, image quantification and machine learning techniques. Intra-mitochondrial protein diffusion is studied by combining photobleaching strategies with single-molecule spectroscopy and mathematical modelling and systems biology approaches. With respect to the latter, the (tissue-specific) consequences and adaptation programmes during mitochondrial dysfunction are studied in a mouse model of human CI deficiency and cancer cells by transcriptomics, proteomics and metabolomics.
My fundamental research stands at the basis for drug development within the SME Khondrion B.V., which aims to develop a cure for patients suffering from mitochondrial diseases. In Sept-Nov. 2014, the Committee on Medicinal Products (COMP) of the European Medicines Agency (EMA) and of the Food and Drug Administration (FDA) granted Khondrion the Orphan Drug Designation for treatment of inherited mitochondrial respiratory chain diseases. In 2016 first in-human trials (phase-I) were successfully concluded with the Khondrion frontrunner compound KH176. In 2017 a phase-II clinical trial was concluded (results pending).
In addition to disease and drug-related research I also have a strong interest in how functional food and feed components affect mitochondrial physiology. More specifically, I aim to understand how these components affect the mechanistic relationship between mitochondrial internal and external structure and thereby mitochondrial and cellular functioning. Understanding this relationship is particularly important to understand the (patho)physiological effects of mitochondrial (dys)function in whole animal models.
Towards synthetic mitochondria
It is still not understood how mitochondrial internal and external structure are coupled to mitochondrial function and vice versa. Addressing this question critically requires integration with synthetic biology/bio-engineering as well as computational approaches, because synthetic biology allows mimicking and testing of mechanisms and biophysical modelling allows validating them. At the same time, bioengineering is the necessary approach to translate our understanding of morphofunction to practical applications. Thus, bringing these disciplines together will not only yield scientific progress in the short run but also fuel many potential breakthrough applications (in science, industry, and society) during the coming decades. For instance, mitochondria could be targeted for metabolic ‘rewiring’ to create cells with engineered pathways and improved bioenergetic performance.
AimsThe following research questions are addressed:
- How can we quantify mitochondrial morphofunction at the single cell level?
- How are mitochondrial (ultra)structure and (dys)function connected?
- How is mitochondrial (dys)function linked to cellular (dys)function?
- How does mitochondrial (ultra)structure affect mitochondrial bioreactions?
- How do cells adapt to mitochondrial dysfunction?
- Can we create artificial mitochondrial with a biomimetic structure?
- Are mitochondrial morphofunctional phenotypes patient-specific?
- How can we use machine learning and deep learning for image analysis?
- How can mitochondrial (ultra)structure be therapeutically targeted?
- Mitochondrial dysfunction alters ROS/redox/calcium/glucose/ATP homeostasis
- Antioxidants mitigate mitochondrial dysfunction at the cellular level
- Mitochondrial internal structure affects biomolecular diffusion
- Inhibition of mitochondrial function can be used to target melanoma cells
- Cell metabolism rapidly adapts to mitochondrial dysfunction
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