PUM2 and MFF in the Dysregulation of Mitochondrial Fission in Aging

Mitochondria, the power plants of the cell, become dysfunctional over the course of aging. This is a general process in all mitochondria, and not the same thing as the severe mitochondrial DNA damage that occurs in only a few cells, but that has a widespread detrimental effect. In this more general mitochondrial malaise, there are changes in shape and important functions decline; energy-hungry tissues such as brain and muscle suffer as a consequence.

Mitochondria are the descendants of ancient symbiotic bacteria, and thus act much like bacteria in carrying out fission and fusion, and passing component parts around between one another. In recent years, researchers have found that imbalances between fission and fusion appear in aging, this impairs the ability of autophagic processes to remove damaged mitochondria, and that provoking more fission or less fusion slows aging in short-lived species. Researchers continue to investigate the mechanisms underlying this imbalance; the results noted here are an illustrative example of the progress taking place in this part of the field.

Mechanisms based on mRNA transcription, a very important step in gene expression, are a part of the complex regulatory mechanisms in our cells. RNA-binding proteins (RBPs) bind mRNA molecules and regulate their fate after gene transcription. In this study, scientists screened cells from old animals to identify any RBPs that change upon aging. The screening showed that one particular protein, Pumilio2 (PUM2), was highly induced in old animals. PUM2 binds mRNA molecules containing specific recognition sites. Upon its binding, PUM2 represses the translation of the target mRNAs into proteins.

Using a systems genetics approach, the researchers then identified a new mRNA target that PUM2 binds. The mRNA encodes for a protein called Mitochondrial Fission Factor (MFF), and is a pivotal regulator of mitochondrial fission - a process by which mitochondria break up into smaller mitochondria. Having high levels of MFF also allows the clearance of broken up, dysfunctional mitochondria, a process called mitophagy.

The study found that this newly identified PUM2/MFF axis is dysregulated upon aging. Evidence for this came from examining muscle and brain tissues of old animals, which were found to have more PUM2, and, consequently, fewer MFF proteins. This leads to a reduction of mitochondrial fission and mitophagy, and without the ability to chop up and remove smaller mitochondria, the aged tissues start accumulating bigger and unhealthy organelles.

But removing PUM2 from the muscles of old mice can reverse this. "We used the CRISPR-Cas9 technology to specifically target and inactivate the gene encoding for Pum2 in the gastrocnemius muscles of old rodents. Reducing Pum2 levels, we obtained more MFF protein and increased mitochondrial fragmentation and mitophagy. Notably, the consequence was a significant improvement of the mitochondrial function of the old animals."

Link: https://actu.epfl.ch/news/targeting-an-rna-binding-protein-to-fight-aging/


This is interesting. I've been reading lately about mitochondrial fission and fusion and how it comprising the mitophagy process. There is a discussion thread about this fission/fusion process on about this over on the Longecity forums.

I'm wondering if the mitochondrial dysfunction component of aging is nothing more than an imbalance between these two processes. The evidence for mtDNA damage has always been minimal despite the intuitive nature of mtDNA damage being a cause of aging. This has always bothered me about the mtDNA damage cause of aging even though this theory is so intuitive from a general bio-engineering standpoint.

Perhaps the fission/fusion balance is something analogous to the anabolism/catabolism balance which an imbalance of the latter is the cause of the AGE crosslinks.

Posted by: Abelard Lindsey at January 14th, 2019 10:25 AM

Does anyone have any suggestions on how to reduce PUM2, other than via crisper?
Is there a way to increase MFF protein if PUM2 can' be reduced?

Also Abelard, how do you balance anobolism/catabolism?

Posted by: August at January 14th, 2019 11:31 AM

Very interesting and also very promising for future medical intervention!

Posted by: Thomas at January 14th, 2019 12:16 PM

The study ("Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins") may be helpful. Noncoding RNA Activated by DNA Damage, or NORAD.
The following report indicates that activating Norad is key.
"Cells lacking NORAD are unable to properly pass on chromosomes as they divide. NORAD controls chromosome segregation during cell division by regulating the activity of a family of PUMILIO proteins. In cells lacking NORAD, overactivity of PUMILIO leads to an unstable genome."
Also of interest
PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Norad is upregulated in response to DNA damage and binds PUMILIO proteins. So many questions to learn about this great gene. I'll be looking for future studies from Mendell lab.
The best thing I can find regarding Norad upregulating supplements is supplementing with exogenous Sam68. Where one gets that I don't know.
In the meantime, Perhaps this study is a place to start


Posted by: August at January 14th, 2019 12:24 PM

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