Broadening Study of Mitochondrially Targeted Compounds

Mitochondria, the cell's herd of bacteria-like power plants, occupy an important position in processes of aging, metabolism, and many age-related conditions. Mitochondria produce damaging reactive oxidative molecules as a side-effect of their operation, and these can cause all sorts of havoc - such as by damaging mitochondrial DNA in ways that can propagate throughout the mitochondrial population of a cell, causing it to run awry and harm surrounding tissue. This happens ever more often as we age, and is one of the principle contributions to degenerative aging.

It is worth noting that a greater ability of mitochondria to resist this sort of self-inflicted oxidative damage is theorized to explain much of the longevity of many species that are unusually long-lived for their size - such as bats, naked mole-rats, and so forth.

Thus the researcher community is increasingly interested in finding ways to target therapies to mitochondria: to slow oxidative damage, fix that damage, repair other issues such as genetic disorders in mitochondrial DNA, or alter mitochondrial operation as a way of manipulating cellular behavior and metabolic processes. Building such a therapy usually means attaching a payload molecule to a delivery molecule or particle that will be (a) taken up by a cell, passing through the cell membrane, and then (b) swallowed by a mitochondrion within the cell, passing through that mitochondrion's membranes.

A range of different research groups are working on varied forms of delivery technology. Compare, for example, the repurposed protein machinery of rhTFAM with various plastinquione compounds or polymer nanoparticles. Or, more deviously, genetic engineering that makes a cell nucleus produce and export proteins to that cell's mitochondria. There are many others.

Diversity is a good thing - though of course not all of these strategies are equal in the sort of interventions that they can support. There is a world of difference between introducing more antioxidants into the mitochondria so as to blunt their creation of damaging, reactive byproducts and introducing new genes to repair damage to mitochondrial DNA. The former only gently slows the inevitable, while the latter reverses and repairs the harm done.

In any case, here is a paper representative of work taking place in the targeted antioxidant camp, much of which is taking place in Moscow research centers. Given a few years of promising studies, they are going on to explore the space of possible related compounds, in search of drug candidates that might do as well or better as those discovered to date.

Novel penetrating cations for targeting mitochondria

Novel penetrating cations were used for a design of mitochondria-targeted compounds and tested in model lipid membranes, in isolated mitochondria and in living human cells in culture. Rhodamine-19, berberine and palmatine were conjugated by aliphatic linkers with plastoquinone possessing antioxidant activity. These conjugates (SkQR1,SkQBerb, SkQPalm) and their analogs lacking plastoquinol moiety (C12R1,C10Berb and C10Palm) penetrated bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria of living cells due to membrane potential negative inside.

Reduced forms of SkQR1, SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In human fibroblasts SkQR1, SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by hydrogen peroxide.

The novel cationic conjugates described here are promising candidates for drugs against various pathologies and aging as mitochondria-targeted antioxidants and selective mild uncouplers.

As a footnote I should remind folk that everyday antioxidant supplements do nothing for long-term health, and certainly don't end up in your mitochondria when you ingest them.


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