Publishing in Aging, a team of researchers has discovered how puerarin, an extract of kudzu, ameliorates chronic obstructive pulmonary disorder (COPD) signs in cellular cultures by limiting mitophagy: the consumption of mitochondria by cells.
When autophagy isn’t a good thing
Mitophagy is a subset of autophagy, the consumption of any organelle by a cell. This is a maintenance process that cells use to remove malfunctioning components, and most longevity-oriented research is oriented towards enhancing it, not suppressling it.
However, this process, like many other biological processes, can go out of control. The researchers point to prior studies showing that in COPD, mitophagy is substantially increased due to the increase in oxidative stress [1,2]. The mitochondria are the powerhouses of the cell, and these powerhouses are being destroyed in COPD.
As the kudzu root has been used in traditional Chinese medicine to treat age-related conditions similar to COPD, these researchers sought to discover what actual biochemical effects that its active compound, puerarin, has on cells.
Stopping cells from having too much FUN
Prior research has shown that the FUN14 domain protein 1 (FUNDC1) gene is strongly linked to the enhanced mitophagy associated with COPD [3] and that silencing this gene ameliorates the symptoms of COPD in cellular cultures [4]. The researchers put together a series of experiments linking puerarin to FUNDC1 inhibition.
First, they administered cigarette smoke extract (CSE) to human bronchial epithelial cells (HBECs) alongside differing concentrations of puerarin and examined multiple biochemical markers, including cellular apoptosis (death). Their results show that treatment with puerarin restored these markers back to that of the control group. There was a smooth dose-response curve; the more puerarin the researchers administered, the more the cells looked like cells that had never been exposed to CSE at all.
Looking more closely, the researchers found that puerarin was having the desired physiological effects: the concentration of reactive oxygen species (ROS), which was dramatically increased with CSE, was decreased to approximately the level of the untreated control group with the highest dose of puerarin administered. Proteins associated with mitophagy were similarly decreased, and ATP generation was restored.
Next, the researchers investigated the expression of FUNDC1 and a related protein, DRP1. Similar to the previous results, FUNDC1 and DRP1, increased by CSE, were decreased back to normal levels with puerarin on a smooth dose-response curve. The phosphorylated form of FUNDC1, however, was decreased with CSE and increased with puerarin. These results were further explored and confirmed with the additional administration of PH0321, a protein phosphatase inhibitor that directly counteracted many of the positive effects of puerarin.
The mTOR pathway and mitophagy
To confirm the effects of mitophagy, the researchers also compared the effects of puerarin with those of the mitophagy inhibitor Mdivi. They found that the two compounds performed nearly identically in multiple metrics, including apoptosis and protein expression.
In their very last experiment, the researchers examined the pathways responsible. Pl3K, AKT, and mTOR are part of an important biochemical pathway that is inhibited by CSE and restored by puerarin. By blocking the PI3K/AKT/mTOR signaling pathway with a compound called 3-MA, the researchers were able to completely stop the positive effects of puerarin as shown by other metrics.
Conclusion
While these results are very promising, even to the point of being suspiciously too good, this is simply an intriguing cellular culture study that shows increased performance on specific cellular metrics. Puerarin has not been shown to completely ameliorate the long-term effects of COPD, even in cells, and this study needs to be confirmed by other research laboratories and followed up by animal and human studies before any real conclusions can be drawn about its effectiveness as a treatment.
This study also serves as an implicit public health reminder. COPD and cigarette smoking are so tightly linked that the researchers of this study, just as many previous researchers did [5], used CSE to induce it. As any long-time Star Trek fan knows, even smoking in early life can cause lingering damage that is not naturally healed, thus depleting both healthspan and lifespan. if you truly want to live long and prosper, staying away from things that will increase cellular damage is an obvious step towards that goal.
Literature
[1] Jiang, Y., Wang, X., & Hu, D. (2017). Mitochondrial alterations during oxidative stress in chronic obstructive pulmonary disease. International journal of chronic obstructive pulmonary disease, 12, 1153.
[2] Ryter, S. W., Rosas, I. O., Owen, C. A., Martinez, F. J., Choi, M. E., Lee, C. G., … & Choi, A. M. (2018). Mitochondrial dysfunction as a pathogenic mediator of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Annals of the American Thoracic Society, 15(Supplement 4), S266-S272.
[3] Yao, R. Q., Ren, C., Xia, Z. F., & Yao, Y. M. (2021). Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy, 17(2), 385-401.
[4] Wen, W., Yu, G., Liu, W., Gu, L., Chu, J., Zhou, X., … & Lai, G. (2019). Silencing FUNDC1 alleviates chronic obstructive pulmonary disease by inhibiting mitochondrial autophagy and bronchial epithelium cell apoptosis under hypoxic environment. Journal of Cellular Biochemistry, 120(10), 17602-17615.
[5] Chen, X., Li, Y., Hua, C., Jia, P., Xing, Y., Tian, X., … & Xie, F. (2019). Establishment of rapid risk assessment model for cigarette smoke extract exposure in chronic obstructive pulmonary disease. Toxicology letters, 316, 10-19.
