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MitoSENS Update August 2017

The following is an update from MitoSENS scientist Dr. Matthew “Oki” O’Connor:

Hi, everyone! Long time, no update – my fault!

As you all saw, our manuscript that was supported by donors was published last fall. Dr. Boominathan and I have been presenting our results at conferences around the world, and I can tell you that they have been very well received.

The second part of the project has been completed (testing a library of MTSes on ATP6), and that does not seem to have solved the problem of substantially increased ATP6 expression and import.

We have, however, learned more about the problem and have made progress on solving it. We’ve discovered that there was a problem at both the mRNA expression level and at the protein level.

We think we’ve solved the mRNA problem, but we’re still working on the protein problem. The mRNA solution is a bit of a long story, so I’m going to save the details for a future update, but it’s pretty cool.

Additionally, it’s been an exciting summer. The highlight of our summer is always the SRF Summer Scholars program, in which talented undergraduate biology students join our various projects for 12 weeks.

This summer has been twice as special for the Mito project because we got not one but two amazing interns to pioneer new work. This is due to a timely grant from Michael Antonov (one of the visionary co-founders of Oculus) that allowed us to expand operations this summer to push a new project that I’ll talk about in my next update. But first…

Optimizing the Allotopic Expression of ATP6 to Mitochondria in Mutant Cells

Jasmine Zhao joined us this summer from UCLA, where she will be a senior this fall. In Jasmine’s words:

This summer, my project will be conducted under the mentorship of Dr. Amutha Boominathan and Dr. Matthew O’Connor at the SRF Research Center in Mountain View. The goal of this project is to design and test different constructs that can potentially improve the allotopic expression of ATP6 to mitochondria in mutant cell lines.

Mitochondria are double-membrane bound organelles that provide energy in the form of ATP to power the biochemical reactions of a cell. Unlike other organelles, however, mitochondria have their own DNA separate from the nucleus, and 13 out of those 37 genes encode for oxidative phosphorylation complex proteins.

Due to possible leakage of the high-energy electrons of the respiratory chain, which results in the formation of reactive oxygen species, the oxidative stress mitochondrial-DNA (mtDNA) is subjected to can lead to mutations, aging, and cell death. For instance, the ATP6 gene encodes for subunit a of the Fo structural domain of ATP synthase, also known as Complex V. The Fo structural domain is embedded in the inner membrane of the mitochondria and contains the membrane proton channel that allows for the synthesis of ATP.

Mutations of ATP6 have been implicated in different human diseases that affect neural development, vision, and motor movement, such as Leigh syndrome and Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP).



Want to know more?

You can learn more about this project at the SENS website here!

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. jimofoz
    August 29, 2017

    “We think we’ve solved the mRNA problem, but we’re still working on the protein problem.”

    On the SENS website it states that Jasmine will be using a gene sequence from a thermophilic bacterium to increase the solubility of the hydrophobic ATP6 protein to try an prevent it unfolding before it can imported into the mitochondria (I assume at the mitochondria surface where it is expressed).

    Jasmine Zhao is also taking a second approach of deleting or mutating the first transmembrane domain of the ATP6 protein (theorized to not be that important) to see if this improves solubility.

    “Dr. Boominathan et al. has previously shown that stable allotopic co-expression of ATP8 and ATP6 is able to rescue a patient cybrid cell line that is null for the ATP8 protein and has significantly lowered ATP6 protein levels (Boominathan et al., 2016). However, improving the exogenous amount of ATP6 that can be expressed or targeted to the mitochondria may be necessary in order to achieve complete restoration of ATP synthase activity and structure. Therefore, my project will investigate whether appending an additional gene sequence, the soluble tag, can help stabilize ATP6 and prevent unfolding before it is inserted into mitochondria. Derived from a thermophilic bacterium, this additional gene sequence might be able to enhance the expression of low but expressible proteins such as ATP6. Two constructs have been designed to address this hypothesis. As shown in Figure 1A and 1B, these two constructs will be cloned into pCMV and pENTR vectors and help us evaluate if the tag can be expressed in mammalian cells and if proper targeting and import of ATP6 to the mitochondria is possible, respectively. The last construct, which is depicted in Figure 1C will be focused on decreasing the mean hydrophobicity of the ATP6 protein. High mean hydrophobicity, especially in the first 100 amino acids is one of the largest barriers for successful allotopic expression of membrane proteins (Oca-Cossio et al. 2003). We hypothesize that the first transmembrane domain of ATP6 is not involved in critical functions for the protein and can be manipulated to diminish the mean hydrophobicity. As such, we also will utilize both deletion and site-directed mutagenesis of the first transmembrane domain of ATP6 to determine if ATP6 expression can be enhanced. If these constructs can provide more efficient expression of ATP6, similar methods can be applied to other mitochondrial genes to improve the rescue of mitochondrial function by allotopic expression.”

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