By Chong He and Karen Ring

Dr. Richard Hartley

Dr. Richard Hartley

Dr. Hartley is a Professor of Chemical Biology and Organic Synthesis at the University of Glasgow, Scotland. Dr. Hartley’s research involves using synthetic organic chemistry to unlock the secrets of biology. Specifically, his lab designs and synthesizes small molecular probes to study oxidative stress and aging. His goal is to find new ways to make drug-like compounds using titanium carbenoid chemistry and a platform technology developed in his lab called MPEG-assisted organic synthesis.

During a recent visit to the Buck Institute, Dr. Hartley discussed his cutting-edge research in the field of aging. In his seminar, he described his lab’s efforts to design chemical probes called “exomarkers” that quantify reactive oxygen species (ROS), such as hydrogen peroxide, superoxide, and hydrogen sulfide, that build up in the mitochondria of cells during the aging process. Using exomarkers to assess mitochondrial ROS is a technique that is commonly used to understand the fundamental mechanisms of aging and age-related diseases.

Dr. Hartley told the story of MitoB and MitoP, molecular probes that can quantify hydrogen peroxide levels in the mitochondria of fruit flies and other organisms. MitoB selectively reacts with hydrogen peroxide, and in the process, is converted into a different compound called MitoP. Both MitoB and MitoP can easily be detected by ESI-MS (a form of mass spectrometry), and the ratio of MitoB to MitoP can determine the amount of H2O2 present. Using MitoB and MitoP, Dr. Hartley discovered an increase in mitochondrial H2O2 with age in flies. However, H2O2 levels were not influenced by dietary restriction (which is known to extend lifespan in fruit flies and other model organisms).

Q: In the fly model, you observed an increase in mitochondrial H2O2 with age. Interestingly, dietary restriction did not affect mitochondrial hydrogen peroxide despite increasing lifespan and decreasing oxidative damage. What’s your interpretation of this?

RH: These findings do not mean that changes in mitochondrial hydrogen peroxide have no influence on aging, as changes in mitochondrial hydrogen peroxide independent of other factors may well affect lifespan. Moreover, it is important to point out that our approach measures a weighted average of mitochondrial hydrogen peroxide throughout the whole organism, and due to the greater uptake of MitoB into thoracic muscle mitochondria, our measurements are dominated by changes in this subset of mitochondria. It may be that localized changes in mitochondrial hydrogen peroxide in particular organs or in small populations of cells, for example in particular neurons, may be critical for the aging process but will not be detected by our approach. Even so, we can conclude that any causal link between the weighted average of mitochondrial hydrogen peroxide (predominantly thoracic muscle mitochondria) and aging in the two models investigated here is either absent or masked by changes in other processes that also determine aging.

Q: The small-molecule modulator, MitoDNP-SUM, can sense ROS and also uncouple mitochondria to reduce ROS. Have you tried this molecule for treatment of ischaemia-reperfusion injury?

RH: While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through the generation of mitochondrial ROS. Although mitochondrial ROS production in ischaemia reperfusion is well established, it has generally been considered a nonspecific response to reperfusion. These findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies. We haven’t tried MitoDNP-SUM, because we think it is still not good enough. The background release is a major problem right now.

Q: Do you believe in the mitochondrial free-radical theory of aging?

RH: I wouldn’t be looking at ROS if I didn’t think they would have an effect on aging. But as you can see, I am also starting to look into other areas besides ROS, such as mitophagy. I choose these areas to focus on because I think they are important. We still see that there are increases of mitochondrial hydrogen peroxide with age in the fly study. So maybe in in the condition dietary restriction, flies can cope with this increase better.

For more on Dr. Hartley’s exciting research check out the Hartley Group Website.