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On January 12, 2023, Hu Junjie's team from the Institute of Biophysics, Chinese Academy of Sciences, Chen Bai's team from Nankai University and Hao Xiaojiang's team from the Kunming Institute of Botany, Chinese Academy of Sciences presented a presentation in Nature Chemical Biology The co-published article titled "Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction" reports S89
, a small molecule compound that specifically activates MFN1 and repairs multiclass mitochondrial damage.
Mitochondria are central
to regulating cellular energy homeostasis and fate decisions.
Mitochondria maintain normal function through continuous fusion and division, and excessive fragmentation of mitochondria caused by imbalance between division and fusion is one of the important signs of
human diseases and aging.
The molecular machines that mediate mitochondrial fusion and division are all members of the dynamin superfamily, where mitochondrial outer membrane fusion is performed
by mitochondrial fusion hormones (MFN1 and MFN2).
Mutations in MFN2 lead to a variety of inherited neurodegenerative diseases
such as peroneal muscular atrophy (CMT2A).
Therefore, the development of small molecule compounds that can promote mitochondrial fusion will help the treatment of mitochondria-related diseases, and is a cutting-edge direction that has attracted much attention and urgently needed in life science and biomedical research
.
After screening, the team found that S89, a derivative of the natural product extracted from Meadowsweet, had the effect of promoting mitochondrial fusion, and the reaction was only effective
in cells expressing endogenous MFN1.
In vitro experiments using purified MFN show that S89 binds directly to a looser region within the second helix beam (HB2) of MFN1, which binds to GTPase in its natural state to lock the molecule to an inactivating self-inhibitory
state, which is competitively relieved by the binding of S89 and HB2.
Similarly, site-specific mutations in the loose region of HB2 or binding of GTP can unlock the self-inhibition
of MFN1.
In general, the treatment of S89 can increase the enzyme activity of full-length MFN1 by about 2 times, and can also effectively promote the fusion activity
of purified MFN1 in vitro.
It is worth noting that the homologous protein MFN2 is ineffective
against it due to its strong self-inhibitory effect.
Mechanism of action of S89
Next, the team used a variety of cell models (cells from patients with MELAS syndrome, cells from CMT2A patients, cells treated with the oxidative stress inducer paraquat and the inducer of iron death RLS3) to verify the biological effects of S89, and found that S89 can repair mitochondrial functional damage
by extending mitochondria, reducing mitochondrial depolarization, alleviating mitochondrial oxidative stress, and increasing mitochondrial ATP production.
In addition, the team also found that the injection of S89 at the time of reperfusion can reduce the damage
to the myocardium caused by ischemia-reperfusion in mice.
The study of the mechanism of S89 has demystified the regulation of mitochondrial outer membrane fusion
.
The efficacy of S89 is reversible and controllable, and it also provides a new intervention idea for the treatment of related genetic diseases with multiple homologous genes, that is, defects with MFN2 mutations can be reversed
by further activating endogenous healthy MFN1.
Since mitochondrial fragmentation is ubiquitous in a variety of pathological lesions, the controllable improvement of mitochondrial fusion ability will have broad application prospects
.
Professor Chen Bai of Nankai University, researcher Hu Junjie of the Institute of Biophysics, Chinese Academy of Sciences, and Academician Hao Xiaojiang of the Kunming Institute of Botany, Chinese Academy of Sciences are the co-corresponding authors
of this paper.
Dr.
Guo Yingjie from Chen Tong's team, Dr.
Zhang Huan and Dr.
Shen Birong from Hu Junjie's team, and Dr.
Yan Chen from Hao Xiaojiang's team are the co-first authors
of this paper.
This research is supported
by the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, the Pilot B Aging Project of the Chinese Academy of Sciences, and the Stable Support for the Young Team Program in Basic Research Fields.
Article link:
(Contributed by: Hu Junjie Research Group)