Mitochondria are the “canary in the coal mine” for cellular stress - Salk Researchers Dec 2019

[Sly Saint]

LA JOLLA—Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

“Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, ‘Hey, I’m under attack, you better protect yourself,’” says Gerald Shadel, a professor in Salk’s Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.

Most of the DNA that a cell needs to function is found inside the cell’s nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds—or even thousands—of mitochondria.

Shadel’s lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus—by releasing it from mitochondria and launching an immune response that beefs up the cell’s defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell’s interior.

full article here
https://www.salk.edu/news-release/mitochondria-are-the-canary-in-the-coal-mine-for-cellular-stress/

 

[Hutan]

It's interesting.

I forget, what has been found regarding levels of mitochondrial DNA free in the cytoplasm in people with ME?

 

[Andy]

Title of paper: Mitochondrial DNA stress signalling protects the nuclear genome

The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology2,3. We showed previously that cytoplasmic release of mtDNA activates the cGAS–STING–TBK1 pathway resulting in interferon-stimulated gene (ISG) expression that promotes antiviral immunity4.

Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs that includes Parp9 remains activated by the unphosphorylated form of ISGF3 that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS–STING–dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam+/− mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting that mtDNA is a genotoxic stress sentinel.

Paywall, https://www.nature.com/articles/s42255-019-0150-8
Sci hub, https://sci-hub.se/10.1038/s42255-019-0150-8

 

[butter.]

me/cfs is a mito disorder ... in many but not all me/cfs patients and in in even more people with me/cfs with slow onset and EDS like features, pots and mcad ...

just wanted to put it out there and hope I will be still alive when it is proven ...

(existing mtdna studies for me/cfs are somewhat worthless for many reasons)

 

[Perrier]

me/cfs is a mito disorder ... in many but not all me/cfs patients and in in even more people with me/cfs with slow onset and EDS like features, pots and mcad ...

just wanted to put it out there and hope I will be still alive when it is proven ...

(existing mtdna studies for me/cfs are somewhat worthless for many reasons)

An interesting post Butter. Do we use mitochondria to think? I don't know.

You see, PEM is a result not only from physical-muscular movement ( exertion), but it can be generated from simply lying down and thinking out complex issues for say half an hour: for instance, legal arguments, or building a legal case, or doing any complex mental activity: mental exertion.

(On another topic which I don't know where to post: I have also lately been badly discouraged that Dr. Jonathan Edwards (@Jonathan Edwards) feels there is no lead in this monstrous disease. ) And I am certain Dr Edwards follows all the findings!

What are the severely ill expected to do? No one looks after them, no one helps them. This is all very 19th century.

 

[butter.]

ehhhhhhm, yes, you „use mitochondria to think“.

 

[Perrier]

ehhhhhhm, yes, you „use mitochondria to think“.

I should have looked it up before commenting, but my hands are very tied. I look after two gravely ill people. Had I searched I might not have earned: "ehhhhhhhm...."

So from what I have read this morning, they are even used to feel.

I dare say, there will be more to discover about our bodies. But for the very ill, all this is fine and dandy, but when will the chains come off.