Michael Duchen Awarded the Keilin Memorial Lecture by Biochemical Society
Professor at University College London was recognized for his work connecting mitochondria to human diseases and for finding potential therapeutic targets.
MitoWorld congratulates Professor Michael Duchen on being awarded the prestigious 2024 Keilin Memorial Lecture by the Biochemical Society. Each year, the Society recognizes outstanding scientists for achievements in the study of molecular biosciences. Professor Duchen was honored for his seminal contributions to the research into mitochondria in disease.
“This award is a great honor, and I thank the Biochemical Society for it,” said Professor Duchen. “I accepted the Keilin award on behalf of the lab. I have been very lucky to work with outstanding people over the years who shaped the work that we have generated. I am not the one who is coming to work at weekends to feed the iPS cells or working late at night because that’s the only time the confocal microscope is free! Many of those people are now professors and some of the greatest pleasure comes from seeing people grow and flower and find their own scientific voice.”
Working at University College London since 1981, Duchen began his research into neurotransmitter receptors and then calcium signaling and metabolism and finally mitochondria. He has been a leader in connecting mitochondrial dysfunction to diseases and in establishing mitochondria as therapeutic targets for a variety of diseases.
MitoWorld reached out to Professor Duchen to learn more about his research. His responses to our questions are reproduced here.
How did your research evolve from signaling and metabolism to mitochondria?
The story is a bit long? My PhD supervisor, Tim Biscoe, had previously done some work on the carotid body, the structure that sits on the carotid artery and senses and reports oxygen tension in the arterial blood en route to the brain. We were using patch clamp techniques to study neurotransmitter receptors in freshly dissociated neurons and one day had a visit from an old friend of Tim’s, Jose Ponte, who suggested we try to patch cells isolated from the carotid body. We tried as a ‘Friday afternoon experiment’. No one knew anything at all about the physiology of these cells, and we discovered that they were excitable. The question then was how do they respond to low oxygen? There was some evidence from Elliott Mills that mitochondria might be involved as mitochondria are the main oxygen consumers. That made sense. I was then faced with the challenge of how to study changes in mitochondrial function in these cells in response to changing pO2, especially difficult as the structure is very tiny with a very small population of cells. That eventually led to measurements of changing mitochondrial membrane potential in response to graded changes in oxygen which were amongst the first measurements of changing mitochondrial membrane potential in living cells. That opened up a huge swathe of questions about how mitochondria behave in different cell types and in response to different physiological conditions or in disease, about which we then knew nothing at all, and those questions have kept me busy for ~30 years!
What are the main connections between mitochondria and diseases, such as PD?
We can broadly divide roles of mitochondrial dysfunction in disease into ‘primary’ where the primary defect is in the mitochondria, such as a mutation of mitochondrial DNA (mtDNA) and ‘secondary’, where mitochondria are damaged as part of a cascade of cell injury and the defect is extramitochondrial. The latter group probably includes diseases, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease and many others. It seems clear at least in familial forms of PD, that the primary genetic defects lie on pathways that have an impact on mitochondrial function. As the resulting mitochondrial dysfunction may play a critical role in defining the disease progression, this is still an interesting potential therapeutic target.
What potential therapeutic targets interest you most?
Recent work has highlighted multiple pathways that affect and are affected by mitochondrial function in a host of different ways. These include cell death pathways governed by mitochondria, mitochondrial quality control pathways that include biogenesis, mitophagy, fission, fusion and trafficking, and most recently the activation of innate immune pathways by mtDNA that is released from damaged mitochondria. All of these pathways represent potential therapeutic targets.
Is any disease “low hanging fruit” for mitochondrial treatments?
There may be low hanging fruit in relation to process rather than to one specific disease. There is quite a lot of evidence for a mitochondrial catastrophe. The opening of the mitochondrial permeability transition pore may be the cause of sudden cell death of cell dysfunction in multiple diseases. This is most interesting as the pore is an established therapeutic target, but so far, preclinical findings haven’t translated well into the clinic. I like to think that, if we could find a compound without unwanted off target effects and with good pharmacokinetic properties, this might prove valuable in multiple diseases. Mitophagy and biogenesis also appear to be a potentially powerful processes that can be modulated pharmacologically, and I suspect those will prove to be major drug targets in multiple human diseases.
For more information on Professor Duchen, please visit his UCL website at https://profiles.ucl.ac.uk/3559. More information on the Biochemical Society awards can be found at www.biochemistry.org/about-us/news-media/biochemical-society-announces-2024-award-recipients/.