Mitochondrial DNA

Mitochondrial DNA Dysfunction Points to Potential Therapeutic Targets against. Inflammation

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function Points to Potential Therapeutic Targets against Inflammation

Mitochondria

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. Mitochondrial DNA (mtDNA) contains 37 genes, all of which are essential for normal mitochondrial function. When mtDNA remains where it belongs (inside of mitochondria), it sustains both mitochondrial and cellular health. However, when it goes where it doesn’t belong, it can initiate an immune response that promotes inflammation.

Now, Salk scientists and collaborators at the University of California, San Diego (UCSD), have discovered a novel mechanism used to remove improperly functioning mtDNA from inside to outside the mitochondria. When this happens, the mtDNA gets flagged as foreign DNA and activates a cellular pathway used to promote inflammation to rid the cell of pathogens.

Their findings are published in Nature Cell Biology in an article titled, “Mitochondrial DNA replication stress enacts an endosomal pathway of nucleoid disposal prone to innate immune system activation.”

In their study, the researchers noted “the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS–STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria.”

“We knew that mtDNA was escaping mitochondria, but how was still unclear,” explained Gerald Shadel, PhD, senior and co-corresponding author of the study, professor, director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging, and holder of the Audrey Geisel Chair in Biomedical Science at Salk. “Using imaging and cell biology approaches, we’re able to trace the steps of the pathway for moving mtDNA out of the mitochondria, which we can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation.”

Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to the unique mtDNA stress conditions the Salk team was investigating.

“We had a huge breakthrough when we saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria—after assembling all of the puzzle pieces, we realized that structure was an endosome,” said first author Laura Newman, PhD, former postdoctoral researcher in Shadel’s lab and current assistant professor at the University of Virginia. “That discovery eventually led us to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out.”

The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. The cell then begins to remove the replication-halting nucleoids by transporting them to endosomes. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

“Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA,” added co-corresponding author Uri Manor, PhD, former director of the Waitt Advanced Biophotonics Core at Salk and current assistant professor at UCSD. “There are so many follow-up questions we cannot wait to ask, like how other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging.”

The researchers hope to further map out the mtDNA-disposal and immune-activation pathway, including what biological circumstances are required to initiate the pathway and what downstream effects there may be on human health. The findings offer new targets for therapeutics to disrupt the inflammatory pathway and  mitigate inflammation during aging and diseases, like lupus or rheumatoid arthritis.

Wandering mitochondrial DNA hint at new ways to fight disease .

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Time to rewrite the textbooks. Scientists have watched mitochondrial DNA transfer from healthy cells into tumour cells – something that everyone assumed was biologically impossible – and it could lead to completely new ways of fighting debilitating disease.

For the first time, scientists have demonstrated how DNA can move between cells in a tumour, which opens up the possibility of replacing defective genes with healthy, custom-made genes that can fight the cancer from the inside out.

The team, from the Malaghan Institute of Medical Research in New Zealand, discovered that when mitochondrial DNA was removed from mouse models of breast cancer and melanoma, after about a month or so, this DNA was naturally replaced by the surrounding healthy tissue.

This allowed the cancer to form tumours and continue spreading around the body, because mitochondrial DNA is responsible for encoding key proteins that are used in the process of converting the energy from our food into the chemical energy that we use to fuel our brain and muscle function. This is different from nuclear DNA, which is responsible for encoding characteristics such as hair colour, height and sex.

“Initially we thought the cells had learned to grow without needing mitochondrial DNA,” said lead researcher and cell biologist Mike Berridge, in a press release. “But when we presented the research at a conference, a well-known scientist asked if we had tested the growing cells to see if they contained mitochondrial DNA. We hadn’t.”

Prior to this research, it was thought that mitochondrial DNA stayed put within our cells in all situations other than in reproduction. This theory was so solid, you’ll find it in your high school biology textbooks.

“Our findings overturn the dogma that genes of higher organisms are usually constrained within cells except during reproduction,” said Berridge. “It may be that mitochondrial gene transfer between different cells is actually quite a common biological occurrence.”

Publishing their findings in the journal Cell Metabolism, the team suggests that, now knowing this, we can figure out how to turn this process against developing cancers. Defective mitochondrial DNA is known to cause around 200 diseases, characterised by the way they affect a person’s hearing, eyesight, brain and muscle function, and is being investigated for a whole lot more. The researchers suggest that perhaps synthetic mitochondrial DNA could be custom-designed to replace the defective genes and stop tumours and other diseases from developing.

“This appears to be a basic physiological mechanism in the body that no one has seen before because they lacked the exploratory tools,” said Berridge. “Whether this new phenomenon is important in tumour formation is still unclear, but we are interested in pursuing the research to see if the transfer occurs more widely in the body. Preliminary evidence indicates it may be a common occurrence in the brain.”

World’s first ‘three-parent’ babies could be born in the UK

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MPs will be asked to vote on whether to allow mitochondrial transfer technique to prevent inherited genetic diseases
A newborn baby
The IVF technique involves using healthy mitochondrial DNA from a donor to replace the defective DNA responsible for a host of debilitating inherited diseases.

A newborn baby

A further step towards creating babies using DNA from three people has been taken by the UK government with the announcement of new regulations to be put before parliament. The move was hailed as a “milestone” by the head of one charity representing those affected by mitochondrial diseases, which the controversial fertility technique aims to prevent.

MPs will be asked to vote on whether the UK should become the first country in the world to legalise the procedure, an IVF technique that uses genetic material from a mother and a father as well as a donor egg – minus its nucleus – from another woman.

The donor contributes healthy mitochondrial DNA (mtDNA) to replace defective mtDNA responsible for a host of serious inherited diseases. Housed in the mitochondria – the cell’s “power plants” – and not the cell nucleus, mtDNA accounts for only 0.1% of a person’s genetic make-up.

Mitochondrial diseases are rare, affecting around one in 5,000 of the population, but can be devastating for families. They cause a wide range of different conditions affecting muscles, nerves and organs, and can lead to blindness, deafness, autism and learning difficulties.

One of the regulations laid before parliament says that the donor would not be classed as a parent related to the child. Others say that the fertility regulator must assess each case for a significant risk of disability or serious illness, and that fertility clinics would need to obtain a special licence to offer the treatment.

In addition, any child born as a result of the technique would have no automatic right to information about the donor.

Robert Meadowcroft, chief executive of the Muscular Dystrophy Campaign, which helps people suffering from mitochondrial diseases, said: “Today’s news is an important milestone for families affected by mitochondrial disease.

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“For years, many have been hoping for access to this IVF technique and a debate in parliament is a huge step forward towards achieving this.

“This technique has moved successfully through the necessary ethical and public reviews, and a positive result in this debate is now vital to allow further progress.”

Dr Jeremy Farrar, director of the Wellcome Trust, said: “Over the past seven years, Britain has been engaged in an exemplary process for evaluating scientific, ethical and public opinion about mitochondrial donation, which has revealed broad support on all three fronts.

“A parliamentary vote is the next logical step, and we urge MPs to support regulations that will allow the law to catch up with public and scientific opinion.

“Parents who know what it means to care for a sick and suffering child with mitochondrial disease are the people best placed to decide, with proper medical advice and safeguards, whether mitochondrial donation is right for them.

“They should not have to wait any longer to be able to make this choice.”

But Dr David King, director of Human Genetics Alert, argued that there are already reliable ways of avoiding the conditions: “This is high-tech medicine at its worst and most unnecessary.

“Medical researchers are crossing the crucial ethical line that will open the door to designer babies based on scientific misinformation,” he said.

Australian and US scientists reverse ageing in mice, humans could be next.

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Laboratory mouse
PhotoAgeing process reversed: It works in mice, now humans could be nextReuters

Australian and US researchers have developed a compound which reverses muscle ageing in mice, saying it could be one of the keys to reversing ageing in humans.

When used in trials, the compound gave mice more energy, toned their muscles, reduced inflammation, and led to big improvements in insulin resistance.

Scientists say it actually reversed the ageing process, not just slowing it down, and say that for humans the effect would be similar to a 60-year-old feeling like a 20-year-old.

And they say human trials could start within the year.

The study has been published this morning in the research journal Cell.

“I’ve been studying ageing at the molecular level now for nearly 20 years and I didn’t think I’d see a day when ageing could be reversed. I thought we’d be lucky to slow it down a little bit,” University of New South Wales geneticist Professor David Sinclair said.

“The mice had more energy, their muscles were as though they’d be exercising and it was able to mimic the benefits of diet and exercise just within a week.”

Video 4:39 Dr Nigel Turner from the University of NSW explains the research

Researchers reverse symptoms of aging with 1 week of treatment ABC News

Professor Sinclair led the study from his base at Harvard Medical School in the US.

“We think that should be able to keep people healthier for longer and keep them from getting diseases of ageing,” he said.

The researchers also looked at particular diseases in the old mice.

“We looked at diabetes, we looked at muscle wasting or frailty, and we also look at inflammations as something that gives rise to many diseases like arthritis. All of those aspects of ageing were reversed within that week and that was really quite a striking result,” Professor Sinclair said.

He said the team identified a new cause of ageing that is particularly prevalent in muscle, including the heart.

Audio 3:32 Researchers discover how to wind back the clock on ageing

AM

“What we think is going on is that we have two major chromosome sets in our body,” he said.

“We have chromosomes that we all know about, we call it our genome, but there’s other DNA that we often don’t think about – the mitochondrial DNA that we get from our mothers.

“What we found is that during ageing these two genomes, the chromosomes, don’t talk to each other,” he said.

“Much like a married couple talks to each other when they’re newly married but then they stop communicating after about 20 years, at least in some cases.

I’ve been studying ageing at the molecular level now for nearly 20 years and I didn’t think I’d see a day when ageing could be reversed.

Professor David Sinclair

“Then we found that we could reverse that and get the communication going again and the animals went back to being young again.

“We used a molecule that raises a chemical in the body that goes down as we get older – its simple name is NAD (Nicotinamide adenine dinucleotide),” he added.

“When we’re young we have the high levels of NAD and if we exercise and diet, the levels of this NAD molecule are high in our body.

“But as we get older, and as these mice in our experiments got older, the levels went down about 50 per cent and then we could give this drug to bring the levels back up again.”

The next stage in the research involves trials with humans, most likely within the next year.

Professor Sinclair is reluctant to forecast how long it will be before the compound might be readily available for use but he says he has established a company to push things along.

“These trials, if we do manage to do them in patients, are millions of dollars and really I need to raise money to be able to do them and that’s the mechanism,” he said.