Nat Commun︱Guo Ming's team discovered a new mechanism of mitochondrial fission and a new target for the prevention and treatment of Parkinson's disease

Written by ︱ Huan Yang, edited by Ming Guo ︱ Sizhen Wang With the advancement of medicine and the continuous increase in life expectancy, the number of people suffering from aging-related diseases, such as Parkinson's Disease (PD) and other neurodegenerative diseases, continues to increase
.

The development of pathogenic mechanisms and drug targets by establishing animal and cell models of PD has been one of the hot topics in basic and clinical medical research and drug development in recent years
.

 The team of Ming Guo, MD, Ph.
D.
, a Chinese professor and doctor from the Department of Neurology and Molecular Pharmacology at the University of California, Los Angeles, and the California Nanosystem Institute, established a Drosophila model that knocked out the PD genes PINK1 and parkin.
It was found that mitochondrial damage caused by deletion of PINK1 and parkin is a key molecular pathway leading to PD[1]
.

In the follow-up research to further explore the functions of PINK1 and parkin, Professor Guo Ming's team found that PINK1 and parkin regulate mitochondrial morphology[2], and combined with the Drosophila model and human cell model, they successively found that the genes MUL1, VCP/p97, Atg1 can effectively inhibit the The mitochondrial damage caused by the deletion of PINK1 and parkin provides multiple potential drug targets for the prevention and treatment of PD[3-5]
.

 Mitochondria, as the "dynamo" of human cells, not only provide energy for cells, but also play a key role in regulating metabolism and programmed cell death
.

Therefore, maintaining the health and normal morphological function of mitochondria is crucial for maintaining cellular homeostasis, preventing disease occurrence, and delaying aging
.

The shape of mitochondria is regulated by two opposing pulls: mitochondrial fission (a mitochondrial split into two) and mitochondrial fusion (two mitochondrial fusions)
.

Problems with any of these pull forces can throw mitochondrial shape and function out of balance.

.

The accumulation of damaged mitochondria out of balance in cells will further cause cellular metabolic disorders, damage and even apoptosis of cells such as nerves and muscles, resulting in the occurrence of neurodegenerative diseases such as Parkinson's disease
.

PINK1 and Parkin exert their functions of regulating mitochondrial morphology, maintaining mitochondrial health, and inhibiting PD by promoting the degradation of Mitofusin (Mfn, the core protein that regulates mitochondrial fusion) and promoting the removal of damaged mitochondria through the mitophagy pathway
.

 Drp1 is a core protein that regulates mitochondrial fission and is also a GTP hydrolase
.

Drp1 is mainly distributed in the cytoplasm, and once in response to a signal that promotes mitochondrial fission in the cell, Drp1 is recruited to the mitochondrial surface by receptor proteins located on mitochondria, and then aggregates into a ring structure surrounding the mitochondria, and utilizes the GTP hydrolysis process.
The released energy splits the mitochondria in two
.

However, the signaling pathways and other key factors regulated by the core protein of Drp1 are still unclear in the field, and there is a lot of room for exploration
.

 On March 24, 2022, Professor Ming Guo's team at UCLA published an article entitled "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria" in Nature Communications[6]
.

Professor Guo Ming is the corresponding author of the paper, and Dr.
Yang Huan is the first author of the paper
.

The study found that the human gene CLUH and its Drosophila homologous gene clusterless can effectively inhibit the mitochondrial and tissue damage caused by the loss of PINK1 and parkin by regulating the core factor Drp1 responsible for mitochondrial fission
.

Therefore, CLUH also has great potential to become a new drug target for the prevention and treatment of Parkinson's disease
.

The authors found that the human CLUH gene and its Drosophila homolog, clubless, play the same role in human cell lines and Drosophila models, promoting the recruitment of Drp1 to the mitochondrial surface by the receptor, which in turn promotes mitochondrial fission
.

Importantly, the pulling force that promotes mitochondrial fission formed by overexpression of CLUH/clueless can precisely balance and repair the blocked Mfn degradation, excessive mitochondrial morphology, and accumulation of mitochondrial damage caused by the loss of PINK1 and parkin, thereby effectively inhibiting the Mitochondrial and tissue damage caused by loss of PINK1 and parkin (Figure 1-2)
.

In both human and Drosophila cells, deletion of CLUH/clueless resulted in markedly enlarged mitochondria (the balance tilted towards mitochondrial fusion due to reduced mitochondrial fission), whereas overexpression of CLUH/clueless resulted in markedly reduced mitochondrial morphology (due to reduced mitochondrial fission).
fission increases and the balance tilts toward the mitochondrial fission end) (Fig.
3)
.

Fig.
1 Overexpression of clueless can effectively repair mitochondrial and tissue damage caused by the loss of PINK1 or parkin (Image source: Yang H, et al.
, Nat Commun, 2022) Fig.
2 The gene interaction model between clueless and PINK1-parkin (Image source) : Yang H, et al.
, Nat Commun, 2022) Figure 3 CLUH/clueless regulates mitochondrial morphology and promotes mitochondrial fission (Source: Yang H, et al.
, Nat Commun, 2022) It is particularly noteworthy that CLUH/clueless It is an important gene with evolutionary conservation that regulates many basic life processes
.

Therefore, in the Drosophila model, the deletion of clueless causes the flies to survive only up to 6 days, while the lifespan of wild-type flies can exceed 3 months; when drp1 is overexpressed in flies with the deletion of the clueless mutation, it can be Extend the lifespan of Drosophila by as much as 4 times (up to more than 25 days) (Fig.
4); mitochondrial and tissue damage caused by clueless deletion can also be repaired by drp1 overexpression
.

These gene interaction data indicated that an important part of the regulation function of CLUH/clueless on mitochondria is achieved through Drp1 as a downstream factor
.

Figure 4 Overexpression of drp1 can significantly prolong the lifespan of Drosophila with clueless deletion mutations (Source: Yang H, et al.
, Nat Commun, 2022) In the process of further exploring the molecular mechanism of CLUH regulation of Drp1, the authors found that, CLUH can promote the recruitment of Drp1 to the mitochondrial surface by the Drp1 receptor protein (Figure 5-6) without changing the intracellular expression level of Drp1 Figure 5 In a Drosophila model, Clueless promotes the recruitment of Drp1 to the mitochondria by the Drp1 receptor protein Figure 6 In the human HeLa cell line, CLUH promotes the recruitment of Drp1 to the surface of mitochondria by the Drp1 receptor protein, thereby promoting mitochondrial fission (Source: Yang H, et al.
, Nat Commun, 2022) The reason why CLUH can achieve this regulatory function of Drp1 is that CLUH, as an RNA-binding protein, can directly bind to Drp1 receptors (MiD49 and Mff) messenger RNA and promote its protein synthesis (Figure 7)
.

There are more receptor proteins synthesized in the cell, which means that more Drp1 can be recruited to the mitochondria; insufficient Drp1 receptors in the cell will hinder the recruitment of Drp1 to the mitochondrial surface
.

Figure 7 CLUH regulates the translation process of the Drp1 receptor: the protein synthesis of the Drp1 receptors MiD49 and Mff was significantly decreased in the human HeLa cell line knocked out of CLUH (Source: Yang H, et al.
, Nat Commun, 2022) Figure 8 The functional interaction model of CLUH/Clueless-Drp1 and PINK1-Parkin-Mfn (Source: Yang H, et al.
, Nat Commun, 2022) Conclusion and discussion, inspiration and prospect Drp1 acts as a downstream factor to regulate mitochondrial fission, while PINK1-Parkin uses Mfn as a downstream factor to regulate mitochondrial fusion.
The two pathways, CLUH/Clueless-Drp1 and PINK1-parkin-Mfn, work together to regulate mitochondrial morphology and function, maintain tissue and body health
.

This study not only found that CLUH/Clueless is a key upstream factor regulating Drp1 and mitochondrial fission, and further elaborated the regulatory mechanism, but also indicated that the human CLUH gene is a potential novel drug target for the prevention and treatment of Parkinson's disease (PD) (Figure 8)
.

 Professor Guo Ming's team mainly focuses on the pathological research and drug development of neurodegenerative diseases and other aging-related diseases
.

Drp1 has also been a hot spot in the entire basic and clinical research field
.

Mutations in the drp1 gene and abnormalities in the process of mitochondrial fission can cause cancer, diabetes, heart disease and childhood developmental diseases, and even lead to neonatal death
.

Professor Guo Ming said that this study not only provides new discoveries for basic research to explore the basic principles of life phenomena, but also provides new ideas for the prevention and treatment of PD and other diseases and drug development, as well as medical research to promote human health
.

In addition, the article deeply explores the molecular mechanism of CLUH regulation of Drp1
.

Professor Guo Ming said that the significance is that Drp1 is a key protein that plays many important roles in cells.
If Drp1 is directly used as a drug target to treat a disease, it may disrupt other signaling pathways in cells.
Cause side effects of drugs, making it difficult to achieve precise treatment
.

The precise regulation of the Drp1 receptor through CLUH as an upstream factor is expected to make it possible to treat PD specifically
.

 The homologous genes of CLUH/clueless can be traced back to the simplest and oldest eukaryotes, such as yeast, amoeba, etc.
The homologous genes maintain structural and functional conservation
.

The research team demonstrated the evolutionary conservation of the CLUH/clueless gene in regulating Drp1 and mitochondrial functions through human cell models and Drosophila models, and further emphasized that this specific function of CLUH/clueless is indispensable for cell and body health.
effect
.

In the future, the team will further explore the regulation mechanism of CLUH on mitochondrial function, and study how to improve the health of cells and organisms by finely regulating the function of CLUH
.

Link to the original text: https:// The first author of the article, Dr.
Yang Huan (left), the corresponding author, Professor Guo Ming (right) (Photo courtesy of: UCLA Professor Guo Ming Laboratory) Professor Ming Guo from the University of California, Los Angeles (UCLA) is the corresponding author of the paper, and Yang Huan, a postdoctoral fellow in the research group, is the first author of the paper
.

Other co-authors include: Dr.
Jina Yun (former postdoc in Prof.
Ming Guo’s group at UCLA), Dr.
Caroline Sibilla (former NIH PhD student), Dr.
Raymond Liu, Prof.
Bruce Hay and Prof.
David Chan from Caltech , Professor Craig Blackstone, Physician, Harvard Medical School (former NIH Professor, Physician), Professor Robert Harvey, University of Sunshine Coast, Australia
.

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Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Edition ︱Sizhen Wang End of this paperPlate making︱Wang Sizhen End of this articlePlate making︱Wang Sizhen End of this articleMUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
Elife 3, e01958 (2014).
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6, e17834 (2017).
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Atg1-mediated autophagy suppresses tissue degeneration in pink1/parkin mutants by promoting mitochondrial fission in Drosophila.
Mol.
Biol.
Cell 29, 3082-3092 (2018).
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Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Published by ︱Sizhen Wang End of this paperMUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
Elife 3, e01958 (2014).
4.
Zhang, T.
et al.
Valosin-containing protein (VCP/p97) inhibitors relieve relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.
Elife.
6, e17834 (2017).
5.
Ma, P.
et al.
Atg1-mediated autophagy suppresses tissue degeneration in pink1/parkin mutants by promoting mitochondrial fission in Drosophila.
Mol.
Biol.
Cell 29, 3082-3092 (2018).
6.
Yang, H.
et al.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Published by ︱Sizhen Wang End of this paperValosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.
Elife.
6, e17834 (2017).
5.
Ma, P.
et al.
Atg1-mediated autophagy suppresses tissue degeneration in pink1/ parkin mutants by promoting mitochondrial fission in Drosophila.
Mol.
Biol.
Cell 29, 3082-3092 (2018).
6.
Yang, H.
et al.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Plate making︱Wang Sizhen End of this articleValosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.
Elife.
6, e17834 (2017).
5.
Ma, P.
et al.
Atg1-mediated autophagy suppresses tissue degeneration in pink1/ parkin mutants by promoting mitochondrial fission in Drosophila.
Mol.
Biol.
Cell 29, 3082-3092 (2018).
6.
Yang, H.
et al.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Plate making︱Wang Sizhen End of this articleClueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Edition ︱Sizhen Wang End of this paperClueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Nat Commun 13, 1582 (2022).
Edition ︱Sizhen Wang End of this paper