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MitoSENS Mitochondrial Repair Project

Engineering backup copies of mitochondrial genes to place in the nucleus of the cell, aiming to prevent age-related damage and restore lost mitochondrial function.

By Dr. Matthew "Oki" O'Connor

Funding Successful. This project reached its goal before October 26, 2015.

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  • $46,128

    Pledged of $30,000 Goal

  • 400

    Backers

  • 153% Funded

    campaign complete

Campaign  Completed

This campaign will only be funded if at least $30,000.00 is pledged by October 26, 2015.

Launched: August 17, 2015
Funding Ends: October 26, 2015
SENS Research Foundation

A big thank you to everyone for helping us hit our goal so quickly! Please check out the campaign updates tab to learn about our stretch goals for hitting $45,000 and $60,000.
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Each cell in the body is dependent on the efficient generation of cellular energy by mitochondria to stay alive. Critical to this process are genes encoded within the mitochondrial genome. Over time however, mutations in these genes occur as a result of constant exposure to reactive oxygen species produced by oxidative phosphorylation, the mitochondrial energy generation process. Unlike genes within the nucleus, mitochondria lack an efficient system to repair damaged DNA. This leads to accumulated mutations, resulting in mitochondrial defects and an increase in oxidative stress throughout the body. Closely correlated with this is the observation that organisms which age more slowly also consistently display lower rates of mitochondrial free radical damage. Thus, reversing and/or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process.

At the SENS Research Foundation, we are in the early stages of creating an innovative system to repair these mitochondrial mutations. If this project is successful we will have demonstrated, for the first time, a mechanism that can provide your cells with a modified backup copy of the entire mitochondrial genome. This genome would then reside within the protective confines of the cell’s nucleus, thereby mitigating damage to the mitochondrial genome. In fact, during the long course of evolution, this gradual transfer of genetic information into the nucleus has already occurred with the majority of mitochondrial genome, leaving behind a mere 13 protein coding genes within the mitochondria. Demonstrating the effectiveness of this technology would be a major milestone in the prevention and reversal of aging in the human body.

Edward James Olmos describes the SENS Mitochondrial Repair Plan

https://www.youtube.com/watch?v=HCbfsnV2tm8&feature=youtu.be

We are also developing a unique method for guiding the products of these nuclear encoded mitochondrial genes back into the mitochondria, where they can then properly function. Over the last decade, engineering this last step has been the major bottleneck in achieving effective results. In our novel system, the mRNA from an engineered mitochondrial gene is guided back to the mitochondrial surface, where it is then translated into a protein by the organelle’s co-translational import system (see figure below). Once imported, it is then incorporated into the correct location within the inner mitochondrial membrane.

Our precise targeting is achieved by adding a specific sequence “tag” to both ends of the mRNA. These tags then serve to guide the information containing mRNA molecule to the mitochondrial surface. Our prior research indicates that our system of tagging yields a significantly higher efficiency of import to mitochondria than any previously published research.

Visualization of engineered ATP8 expressed in mutant cellsSENS-data-slide

Successfully completing this project will mean that we have developed a groundbreaking method that will provide us with the capability to safeguard the mitochondrial genome by creating a backup copy in the nuclear genome. The overall goal will be to test this improved targeting technology so that it can be optimally refined for use in rescuing mutated mitochondrial DNA, and thus prevent and cure what may be one of the major causes of cellular aging.

In our current research, we are using cells derived from a patient suffering from a rare mitochondrial disease, that are null for the mitochondrial ATP8 gene (i.e., the ATP8 protein is completely absent). We have inserted our improved versions of the ATP8 gene, equipped with our specialized mitochondrial tagging system, into the nuclear genome. Inserting it into the nuclear genome helps to protect the gene from oxidative damage, while our tagging system will help guide the functional protein into the mitochondria where it is needed.

We need your support at this critical juncture of the MitoSENS project. The MitoSENS team has already demonstrated the rescue of cells containing mitochondrial mutations, and has recently generated highly promising preliminary data showing the rescue of the complete loss of a mitochondrial gene. Our next steps will focus on improving the effectiveness of the targeting system, so that we can repeat our success with one mitochondrial gene to all thirteen. We will then transition this work into animal models of mitochondrial dysfunction. This would be a crucial step in what may be the development of an eventual cure for aging and aging related diseases.

We have a talented team of highly trained mitochondrial biologists working on MitoSENS. Right now the rate-limiting factor is the cost of the expensive reagents that we use for these experiments. Increasing our funding with this campaign will allow us to double the pace of our research and bring results to the public that much faster. We have made preliminary progress on rescuing function with a second gene, ATP6, and your support will help us perfect our targeting of both ATP8 and ATP6. This requires more cells, more viruses, and many new synthetic gene sequences. Specifically, we will spend your generous donations on cell culture reagents, oxygen consumption measurements, virus production, quantitative reverse transcription PCR, DNA synthesis services, and publication of our results in a peer-reviewed journal.

Your support will help take us there.

Thank You.

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Mitochondria Repair Projects 1 and 2 

Posted on 05/24/2023 by Amutha Boominathan

The cellular machinery and higher-level structures of our bodies inevitably damage themselves as part of keeping us alive. While our bodies have mechanisms to prevent and repair some aspects of this damage, the repair is never complete. Over time, damage to our cells and tissues accumulates in our bodies, causing them to become increasingly dysfunctional with the eventual endpoint of aging and its many diseases.

At SENS Research Foundation, we work to develop the https://www.sens.org/our-research/intro-to-sens-research/  seven practical repair strategies into rejuvenation biotechnologies that can prevent, defang, or remove this damage to restore the health of our cells and tissues and thus maintain or restore youthful health and vigor.

The https://www.sens.org/mitosens/  MitoSENS program at SENS Research Foundation is working to develop longevity therapeutics to repair or render harmless the damage that drives the age-related decline in the function of our cellular power plants — the mitochondria. The most important kind of age-related mitochondrial damage is large deletions in the mitochondrial DNA, which are the ultimate result of the toxic byproducts of cellular energy production. Such large deletions are prime culprits in multiple specific age-related pathologies, such as Parkinson’s and Alzheimer’s diseases, as well as sarcopenia — the loss of mass and disproportionate loss of power in aging muscles. Such mutations also drive broader pro-aging effects across the body.

Using a biotechnology called allotopic expression, the Boominathan Lab at SENS Research Foundation is engineering “backup copies” of the genes normally harbored in the mitochondria into the safe environment of the nucleus, separating the damage-causing molecules in the mitochondria themselves from the genes that are essential for cellular energy production.

In 2015, SRF launched a crowdfunding campaign for the allotopic expression of mitochondrial genes with the help of Lifespan.io, which enabled us to ramp up our efforts. This additional funding was instrumental in establishing proof of concept for this strategy. In collaboration with renowned mitochondrial scientists Dr. Martin Brand and Dr. Birgit Schilling of the Buck Institute, the MitoSENS team showed that the allotopic expression of two mitochondrial DNA genes restores critical metabolic functions in cells derived from a patient with a severely disabling mutation in the mitochondrial ATP8 gene.

Subsequently, to validate the gene therapy product in a living organism, they teamed again with Lifespan.io for a second crowdfunding campaign” the Mitochondria Repair Project 2 . Using the maximally modifiable mouse model, the researchers at SRF placed a single copy of ATP8 in a safe harbor locus in the nucleus. They then crossed this allotopic ATP8 mouse with a mouse model that harbored a specific mutation in its ATP8 gene to see if their allotopic ATP8 could restore normal energy production and metabolism in the face of a mutation in the inherited mitochondrial gene. Careful breeding and genotyping confirmed that the allotopic ATP8 is robustly expressed and is passed down through at least four generations in the progeny. And on the critical question, the allotopic ATP8 gene works: the mice’s cells express the allotopic protein, its mitochondria take the protein up, and it effectively assembles into the correct Complex of the mitochondria’s energy-producing machinery without any adverse effects. Studies are ongoing to quantify how much the engineered ATP8 displaces the mutated mitochondrial version of the gene and the team hopes to publish these results soon. 

Thanks to everyone at LEAF and all the crowdfund donors who helped make this amazing advance possible! We are several large steps closer to human mitochondrial gene therapies thanks to you. 


MitoSENS Project Results to be Published in the journal Nucleic Acids Research!

Posted on 08/18/2016 by Oki

We are excited to announce that our successful work of backing up two mitochondrial genes into the nuclear genome has been accepted for publication in the journal Nucleic Acids Research! Please see the announcent from our recent Rejuvenation Biotechnology Conference here, starting at 2h15m6s:


Great Success Thus Far!

Posted on 05/18/2016 by Oki

Hi Everyone, it’s been an amazing few months. In short, we have been tremendously successful in our efforts to rescue a mutation in the mitochondrial genome!

PrintEssentially we’ve shown that we can relocate both ATP6 and ATP8 to the nucleus and target the proteins to the mitochondria. We can show that the proteins incorporate into the correct protein complex (the ATPase) and that they improve function resulting in more ATP production. Finally, we show that the rescued cells can survive and grow under conditions which require mitochondrial energy production while the mutant cells all die.

We have finished writing up our results and submitted them for review and publication. It may take a while for our results to be published (the peer review process can be lengthy) but as soon as it is I’ll post an update here so you can see the full paper.

We have also started the project that you helped us get to our stretch goal on. We have made all the combinations of MTS with ATP6 that we proposed and are now working on testing them. I’ll let you know when we know more.

Thank you so much for your support!

Oki


Updates

Posted on 10/19/2015 by Oki

MitoSENS_Oki_Thumbs_up_inside_CC

Hi everyone, thanks so much for your support in reaching our initial goal! I’m proud to announce that we have just received a donation from a local company in the form of a large quantity of free DNA primers. We used the donation to design a huge set of primers that we can use to make dozens more mitochondrial targeting sequences (MTSes) to test for their ability to target proteins to the mitochondria. So instead of the 3 that we’ve tested so far we could test many different ones that we suspect might be good candidates as stretch goals for this campaign.

If we reach a total of $45,000 we can test all of these MTSes on ATP6 and see if we can bring it up to full activity.

If we reach a total of $60,000 we can also test all of these targeting signals on a 3rd gene, Cytochrome B, which has long been a challenging gene for us and others in the field to make functional. If we can get this gene working, we should be able to make any gene in the system work.

In addition, we are excited to announce matching funds! Several of you have asked for this. For every dollar that you donate to the Mitochondrial Repair Project another dollar will go directly into the SENS Research Foundation general fund to support all the great research we do at SRF. Thanks to Reason at fightaging.org for helping to organize this fund to match your donations!


33 Comments

  1. Reply
    Reuben Tracey

    What a great Site, and its great to see SENS the first project, here, of course I had to back it.
    This is really important project and I really hope they meet there goal.

      • Reply
        John

        That analysis showed a link between using PGP to limit mitochondrial swelling in mice tissues, which is rather interesting as a topic but unhelpful long term. In addition to disputing the relevance of your source trial (which doesn’t appear to offer a duration or suggestion that the tests increase healthy lifespan of the mice in question), I’d like to point out that protection is less beneficial in the long term, because you cannot stop damage from occurring completely no matter how well you defend an organelle, and that damage will accumulate over time. The only option is to repair or replace the damaged component which is why this sort of project is rather important.

      • Reply
        Antonio

        (1) Ginseng extracts aren’t natural.
        (2) Natural products aren’t better than artificial ones.
        (3) Ginseng doesn’t protect against mitochondrial DNA damage.
        (4) This research has nothing to do with hipoxia.

  2. Reply
    Giancarlo Aguirre

    WoW, now I can feel I’m helping a good cause, good, if there is another promising project for increasing life expentancy and /or reverse aging, let us know, I’ll be glad to back it up :).

  3. Reply
    Gennady Stolyarov II

    Best wishes on the success of this important research project – another step forward in the noble and urgently necessary war against senescence and death.

  4. Reply
    Prayag Patil

    Have never seen a worthier project, clear concise goals with obvious reward in terms of improving our ability to reengineer ourselves.

  6. Reply
    Brett Bellmore

    A worthwhile project to engineer a future humanity, and I’ll see if I can’t contribute, but I’d also like to see something with more theraputic potential for existing old geezers such as myself. Mitochondria *evolve* within the cell dependent on a host of circumstances, and are quite capable of remaining functional indefinately if subject to the right evolutionary ‘incentives’.

    We need to engineer circumstances such that the working mitochondria will outcompete the disfunctional ones.

  7. Reply
    Jim

    I mentioned this over at the http://www.fightaging.org website – how about rather than just being a kickstarter style website lifespan.io could provide fundraiser tools? Rather than just chuck in whatever dollars I could afford and then send the page for this project to my friends, hoping they donate too, I could run a half marathon or something to raise money from my friends, much like people do with cancer etc?

    There are sites out there like http://www.justgiving.com that facilitate this already, but they take a fairly hefty approach to the fees they charge. How difficult would it be to add such facilities to lifespan.io?

    Not only could this help raise more money, it is also a promotional tool.

      • Reply
        Jim

        Keith, it seems like you already have most of the infrastructure ready to go. If you could just create a private page that only people with a link could view (or just not a page with hyperlinks from the rest of the website) . I can’t afford to give much to the Mitosens campaign personally, but I might be able to raise 250-500 dollars from friends & relatives for an activity.

  8. Reply
    Aaron

    Can anyone contact me to give a bit more info about the tshirt that comes with the $50 donation? I have unique fit needs so I’d like to get some details to make sure it’ll work. Thanks much. Go longevity! ;-)

  9. Reply
    Victor

    What an amazing idea! I have not contributed yet, but I will. One thing that I want to suggest is different rewards: I personally don’t care about T-shirts and all that merchandise, but I would love to receive an in-depth explanation of the problem with mitochondrial mutations and the suggested solution. This would be a great perk that would help me deepen my understanding and be more involved – as I really wish I could be (I don’t have much money to support but I could contribute my time and would love to know how to do it).

    • Reply
      Keith Comito

      Hi Victor; some of the mid-level rewards like the 30 minute video call with the team would be perfect for this sort of thing. Obviously these rewards are at higher contribution levels, but they do require the researchers to set aside time, etc.

  10. Reply
    Matthew O'Connor

    Hi everyone, in addition to all the wonderful financial support we’ve received during this campaign we’ve also had a number of inquiries about volunteering. Volunteers and interns are a huge part of SRF. If you’d like to inquire about volunteer opportunities please fill out an application so we can try to find the best way for you to help. http://www.sens.org/outreach/take-action/volunteer Please be patient as we’ve seen quite an uptick in applications this past month.

    -Oki

  11. Reply
    John

    Guys, I really don’t want to register on another site. Can you work out a way for me to just plop down 10 bucks via paypal or something and do nothing else?

    Maybe I’m the only one this is bothering; if that’s the case then forget it, obviously, I’ll suck it up and do it :)

    • Reply
      Keith Comito

      At the moment the limits paypal wanted to impose on the crowdfunding transactions made it essentially impossible to use for any real scenario. You can use paypal to donate directly to LEAF if you like, however, via the donate link in the header.

  12. Reply
    Eric Schulke

    Thank life for every one of you health extending donators. You are leaders, pure and simple. That’s no overstatement. Small donations, big donations, they all lead the way for more in a big way, and in more ways than one.

  13. Reply
    Antonio

    Less than $900 to go :) Since there are still 28 days left, will the project scope be extended and a new funding goal set?

  15. Reply
    Giancarlo Aguirre

    You have reached the goal, now I’m sure that you would be able to do more if you pass the number, you should put another project, and I’m surprise other investigations and projects about aging hasn’t appeared in the site, is it taking so long to approve? or there is no projects jet to be fund?

    • Reply
      Eric Schulke

      There are more projects lined up, but we’re waiting until we have a bit more time on our hands to jump in again. It takes a ton of effort to raise this kind of money in our relatively small, but growing communities. If you or anybody wants to join in on helping to promote the next ones then let us know.

  16. Reply
    John G

    Love the research potential, I will be adding my $100 worth – good luck.
    Question 1: Any way for me to decline material “goodies” ? I would love to have a low-cost ecopy of the book and would like to see all more go towards research (dont need a tshirt, bag, etc. as cool as they are :-) ).
    Question 2: Does this count towards the 2015 Challenge Grant shown on sens.org ? Or am I better donating directly through sens.org to help take advantage of that?

    • Reply
      Keith Comito

      Hi John, here are the answers to your questions:
      1. You could definitely email SENS and make this request. We’ll pass the info along as well.
      2. All donations made after Oct 1 on Lifespan.io will also count towards the SENS matching fundraiser.

    • Reply
      Keith Comito

      Hi Nadav, this would likely depend on the item and how SENS will be shipping. Feel free to contact them for specifics. Otherwise they would contact you after the campaign ends to figure this out. Thanks.

  18. Reply
    Rick Davis

    Where can we go to follow the progress of this research? A note every week or every other week would foster a sense of participation that might boost future donations. It might be as simple as “ordered supplies” or “started x experiment”.

  19. Reply
    tim

    Will we need to make double stranded nuclear DNA break to insert mitochondrial genes?
    If so how will we prevent nuclear DNA from ligating with other chromosomes?

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