Complete mitochondrial control for the ultimate anticancer biohack

Since mitochondrial disease variants are said to be rare in the genome, don’t even think for a minute that this can’t happen to you. In fact, the closer we look at the complete mitonuclear genomes of normal people, the more we realize that no one is really normal – we are all, shall we say, temporarily asymptomatic.

But over time, many asymptomatic people develop the hallmarks of mitochondrial disease. While mitochondrial underperformance is ultimately the root cause of many specific disease processes such as the buildup of unburnt fatty acids in fatty liver disease or clogging debris in degenerative tubules in kidney disease, cancer is the entropic cellular eventuality that we all need to prepare for. Depending on which organ, and what type of tumor, cancer can be both a big bang and a thermal death in our existence – and both are controlled by mitochondrial energy.

Fully aware of these universal truths, researchers have long sought ways to control the spread of cancer by limiting specific mitochondrial activities. In other words, reducing energetic and synthetic processes just enough to block the exuberant replication and motility of cancer cells without wiping out our normal, less proliferating and lethargic cells. One way to do this was recently suggested by researchers at Sichuan University in Chengdu. The results were published in Advanced science.

Their idea was to target an elusive pore complex found in the inner mitochondrial membrane known as MPTP, for “mitochondrial membrane permeability transition pore.” At this point, all neurochemists should be in the arms because the acronym MPTP is already taken by a molecule called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. It is the well-known prodrug of the neurotoxin MPP +, which causes permanent symptoms of Parkinson’s disease. Although the actual protein identities of mitochondrial MPTP have not yet been fully verified, it has been experimentally found to contain a pore that allows entry of molecules smaller than 1.5 kDa, which corresponds to a diameter of ≈3 nm.

When enough pores are tilted to the open state due to cell stress or other pathology, mitochondria swell and cell death by necrosis quickly follows. If no pore is open, cancer drugs like doxorubicin, which could potentially pack down overactive mitochondria, cannot enter. In order to control MPTP, researchers turned to a magical ingredient known to affect pore permeability: licorice. Real licorice, unlike the fake news substitutes sold by most candy stores, contains all the cortisol-inhibiting, potassium-wasting glycyrrhetinic acid (GA) that your kidneys can handle.

How many GAs, exactly, are you talking about? Fortunately – or unfortunately, as the case may be – we already have an upper bound from actual toxicology reports from self-enrolled test subjects. For example, a man who purposely ate breakfast with 2 pounds of real licorice candy each day, persisted in his habit for three weeks before falling ill. When enzymatically relieved of its supernumerary sugar groups, cholesterol-like GA blocks the breakdown of cortisol, causing the patient to urinate quickly to remove all of their potassium. The secret sauce is that GA also works through the respiratory chain to generate hydrogen peroxide, which then opens up MPTPs.

The researcher’s strategy was to perform a two-in-one shot by combining GA and doxorubicin on a nanoparticle shell, with a TPP-doxorubicin combo in the nucleus. TPP, or triphenyl phosphonium, is a lipophilic cation that can help electrostatically transport compounds across the hard negative potential barrier of the mitochondrial membrane ΔΨ, typically oscillating between -150 and -180 mV). The plan worked, and the nanoparticles were successful in inhibiting the growth of primary lung tumors and suppressing their metastases.

Targeting MPTP isn’t the only way to stop cancer. Other recent research has suggested that inhibition of mitochondrial RNA polymerase (POLRMT) kills several tumor cell lines but is not cytotoxic to normal but active human cell types like hepatocytes or peripheral blood mononuclear cells. . The researchers found that normal cytosolic ribosomes were unaffected by the POLRMT inhibitor, while mitoribosomes were specifically depleted, corresponding to a lack of transcription of mitochondria-encoded rRNA subunits. Importantly, the inhibitor did not interfere with other necessary RNA polymerases in the nucleus of cells.

This type of specificity would be quite useful as a counterbalance to the new mitochondrial transplant therapies currently being offered as treatments for various conditions. While the concern would be to create new cancers from the extra mitochondrial supply, artfully applied inhibitors could bypass these risks. All of this is quite timely and convenient, as new hardware advancements in the delivery of products via mitochondrial replacement therapies are now in sight. A few early examples, the so-called photothermal nanoblade and biophotonic laser-assisted cell surgery (BLAST) technologies, initially appeared promising after successfully transferring isolated mitochondria into osteosarcoma cells. However, they were laborious and low throughput, and did not always meet the goal of resetting cellular metabolomes.

Enter the new and improved mitochondrial downloader – the
MitoPunch. This pressure vessel uses tiny mechanical divers to deliver much larger cargoes using massively parallel arrays in various cell types. The plunger deforms a collapsible polydimethylsiloxane (PDMS) reservoir containing isolated mitochondria and propels itself through a porous membrane containing numerous 3 μm diameter holes and into the cell cytoplasm. The scheme would be to remove certain cells, take them off, then put them back in strategic places. One could even envision future improvements to the device that could be introduced via catheters into the circulatory system to reach targets deep in the heart, lungs, muscles or even the brain.

The natural phenomenon underlying the utility of such mitochondrial manipulations is the remarkable ability of the mitochondrial network to continually remodel itself through fusion and fission events by which mitochondrial RNA granules are processed and exchanged. Not only would newly introduced recruits be expected to participate in these events, but now scientists can even watch them. For example, researchers at EPFL’s Experimental Biophysics Laboratory recently constructed a super-resolution living cell microscope that can directly image newly struck granules of mitochondrial RNA.

Incredibly, they found out that what the RNA granules were doing, the whole network had done. In other words, they could predict when the network would branch off or merge based on what the RNA granules were doing inside. They even went so far as to call the coordinated display a fluid condensate. In addition, they could control the granules with specific inhibitors. While we are still a long way from full mitochondrial control, these developments suggest continued promise and progress.

© Science X Network 2021