Mitochondrial DNA Mutation as a Contributing Cause of Aging, and the Prospects for Therapies

Mitochondria are the power plants of the cell. They are deeply integrated into many core cellular processes, but their primary responsibility is to generate adenosine triphosphate (ATP), an energy store molecule used to power cellular activities. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and carry a small remnant genome encoding a handful of genes vital to ATP production. Each cell contains hundreds of mitochondria. Worn mitochondria are destroyed by the quality control process of mitophagy, while other mitochondria replicate much like bacteria to make up numbers.

The mitochondrial genome is less well protected than the nuclear genome, and some forms of mutational damage can cause mitochondria to become both dysfunctional and in some way able to outcompete their peers, either resistant to mitophagy or better able to replicate, or both. It is an open question as to how much of the age-related decline in mitochondrial function is a result of stochastic mitochondrial DNA damage, both modest and severe, versus the characteristic epigenetic changes of age that impair mitophagy and mitochondrial function in other ways.

To answer that question, it would be necessary to repair mitochondrial DNA damage in isolation of other processes. This is the goal of the MitoSENS project at the SENS Research Foundation, and their approach is to place mitochondrial genes into the nuclear genome, suitably altered such that the proteins produced are transported into the mitochondria where they are needed. This has been achieved for a few of the necessary genes, and if achieved for all it would, in principle, make mutational damage to the mitochondrial genome a non-event. It would then be possible to observe the outcome of this intervention in animal models, to see how much of a gain in health and life span was achieved.

SRF Publication on Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

The MitoSENS team continue to make progress in developing rejuvenation biotechnologies to prevent, reverse, or remove mutant mitochondria from aging cells. The center of their work continues to be allotopic expression, placing "backup copies" of the mitochondrial DNA into the nucleus, which would supply the proteins that mutation-bearing mitochondria can no longer produce for themselves, and thus keep them (and our cells) functioning normally over time. The MitoSENS team's 2016 breakthrough with allotopic expression of the mitochondrial genes ATP8 and ATP6 marked an important milestone. Since then, they've continued to work to advance the field, including showing how the distinct way that mitochondria encode genetic instructions into their DNA can be better "translated" for use in the nuclear genome, resulting in robust but transient protein production for all of the 13 genes. The team is now working on creating stable expression for these proteins and in achieving functional relevance.

In a new peer-reviewed scientific paper, the MitoSENS team gives an overview of where the field is at and the obstacles that are holding us back. They first highlight some of the drugs, supplements, and stem cell treatments that have been tried and failed (or only had modest effects) to treat inherited mitochondrial diseases. But then they get to the heart of the matter: the challenges that now need to be overcome in order to move allotopic expression towards the clinic. These include mastering the targeting of allotopically-expressed proteins to the right place in the mitochondria; modifying either the protein products themselves or the way we deliver them to prevent these proteins being incorrectly assembled in places other than their intended location; and controlling the level of protein production and its regulation by the cell (since too little protein production wouldn't have a therapeutic effect, and too much might be harmful).

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

Mitochondria are at the interface between several critical functions in the cell, including metabolism, signaling, and immune surveillance. Advances in our understanding of mitochondrial biology and function have illuminated the role of mitochondrial dysfunction in pathology and aging. The unique properties of the organelle predispose its genome to mutations and compromised functions leading to several diseases collectively called mitochondriopathies. Researchers have exploited various technologies, including small-molecule drugs, allogeneic hematopoietic stem cell transplantation, mitochondrial replacement, as well as gene-editing tools, such as nucleic acid therapy and mitochondria-targeted restriction endonucleases, in alleviating these diseases. While modulating organelle function using small molecules is attractive at the outset and benefits from ease of administration, few leads have been identified that hold curative promise, and this treatment modality leaves the root cause of pathology unaddressed.

Recent gene editing approaches, such as targeted restriction endonucleases and base-editing enzymes show promise, though they are limited by their narrow specificity and may require patient-to-patient customization. Gene therapy in the form of allotopic expression has received the most attention for its potential as a robust method for reversing the symptoms of mitochondrial DNA (mtDNA) mutations. Synchronizing allotopic expression for the 13 mtDNA genes with the nuclear-mitochondrial transcription and translation machinery can overcome limitations in competing with pre-existing mutant proteins in the respiratory chain complexes due to heteroplasmy, a condition commonly observed in known mtDNA pathologies. Furthermore, advances in technologies capable of inserting large DNA cargos into the nuclear genome, such as safe harbor expression or mini chromosomes, will allow for testing multiple allotopic genes simultaneously. While validating the technology in vivo has its challenges due to inadequate animal models for all the protein coding genes, the ease of generating precise human iPSCs, particularly from patients with specific mtDNA mutations, may allow us to test these gene therapy approaches on a case-by-case basis in vitro.

Comments

This is a very impressive work and progress. However, I think that boosting mitophagy and delivering replacement mitochondria tough extracellular vesicles is more promising and much easier to achieve.

Posted by: Cuberat at March 15th, 2022 6:41 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.