Targeting Mitochondria to Combat Aging and Improve Heart Health?
Here I review a recent article titled: Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.
Via their pre-printed article, Ying Ann Chiao and colleagues demonstrate how a little peptide, four amino acids long, can restore mitochondrial function and improve heart health in aging mice. Their work has sweeping implications with respect the use of mitochondria-targeted therapeutics in the context of age-related disease.
TL;DR? Gotcha. Here’s a summary!
We exist in a state of dynamic equilibrium. To keep alive, our bodies must continually nullify deleterious processes initiated by injury, disease, and other toxic stressors. Health is thus a process, a process of persistent healing.
To heal is to live. Inevitably, however, our bodies slow as we age, and the rate at which we are capable of healing declines. Consequently, we become increasingly susceptible to perturbations that sway us from health. Within stressed cells, the things can rapidly shift from organized to chaotic; DNA becomes more prone to damage (e.g. cancer), proteins can stick together to form toxic aggregates (e.g. Alzheimer’s disease), and, most pertinent to the discussion at had, mitochondria can become dysfunctional.
Mitochondrial dysfunction is a hallmark of aging. Mitochondria are exceptionally active organelles. They are our cells’ ’power plants’, and serve as containment vessels for highly reactive processes. Mitochondrial maintenance is thus paramount to the stability of our healthful equilibrium. As such, mitochondrial dysfunction is implicated across a vast spectrum of diseases including diabetes, Alzheimer’s and heart disease. To this end, mitochondria thus present an attractive therapeutic target.
This directive, therapeutically targeting mitochondria, is being aggressively pursued in both clinical and research settings, and represents the primary motivation underlying the recent work by Ying Ann Chiao and colleagues. In particular, the Authors scientifically inquire:
How does a small peptide, one four amino acids long, go about restoring mitochondrial function in cardiomyocytes (i.e. heart muscle cells)?
Their peptide of interest, referred to elamipretide, or more tersely, as SS-31, was found to improve mitochondrial function in cardiomyocytes of aging mice. Increased health of aging cardiomyocytes was also demonstrated. From a mechanistic point-of-view, the SS-31 peptide improves mitochondrial health by making mitochondria less ‘leaky’. Accordingly, the work by Chiao et al. provides a mechanism of action as to how SS-31 can restore mitochondrial function. Pursuantly, the insightful work by Chiao et al. may have widespread implications with respect to therapeutically targeting mitochondria in the context of age-related disease.
So you want the details?
As mitochondria make ATP, protons are shuttled around in a very precise manner; the reaction that synthesizes ATP from ADP is driven by the flow of protons through a channel-containing enzyme called ATP synthase, which straddles the inner mitochondrial membrane.
At this point, it may help to view mitochondria as a ‘pouch within a pouch’. The outer mitochondrial membrane is the membrane that bounds an entire mitochondria. Within the bounds of the outer membrane lies another pouch of inner membrane; contained in this inner pouch is, what biologists like to call, the mitochondrial matrix. Visual thinkers, see below:
The inner membrane is not as smooth as is depicted above, however. At the microscopic level, it is studded with energy-harnessing proteins. ATP synthase is one such protein, and provides the primary channel through which protons flow back into the matrix. Proton flow through ATP synthase drives a molecular rotation that powers the production of ATP; ATP synthase is thus a molecular motor of the rotational variety! Returning to the view of mitochondria as cellular ‘power-plants’, ATP synthase is the turbine, and protons are the steam.
Similarly to how a leaky steam pipe can greatly diminish the efficiency of a power-plant, a leaky inner membrane can significantly impair the ability of mitochondria to manufacture ATP. In other words, a mitochondrion’s ability to produce ATP depends upon the fidelity of the inner membrane. Unto this notion, the postulated mechanism-of-action of SS-31 is to reduce the ‘leakiness’ of the inner mitochondrial membrane. By making the inner membrane less leaky, SS-31 thereby improves mitochondrial health and increases ATP output.
Purposeful movement of protons into and out of the mitochondrial matrix is thus central to ATP production. This protonic shuffle of positive charges across the inner membrane does not, however, happen without guidance. The directed movement of protons across the inner membrane is driven by a flow of electrons. The inner membrane is also studded with series of proteins that are collectively referred to as ‘electron transport chains’ (see the red ovals in Figure 2; each electron transport chain represents a functional unit; a given mitochondria can contain a multitude of these functionally distinct units along its inner membrane).
As electrons flow along these multi-protein units, protons are drawn from the mitochondrial matrix. Once electron flow comes to a halt, there is suddenly an excess of protons outside of matrix. Diffusion takes over, and pushes the protons back into the matrix (ideally through ATP synthase). Using electrons to direct the movement of protons results in a process that is dazzlingly efficient, but at the same time, terrifyingly toxic.
Before electrons can flow along the ‘electron transport chain’, they must be stripped from the nuclei to which the are bound; this creates a volatile situation, as loose electrons are an exceptionally reactive species. Luckily, electron movement along the transport chain is tightly-controlled. Electrons proceed along the transport chains until the end is reached, and are thereafter neutralized via reaction with a proton and oxygen molecule to form our ‘life juice’, water! All’s well that ends well. However, we are dealing with the flow of individual electrons here. We are thus in the ‘spooky’ realm of quantum mechanics. In this realm, the hopping of electrons along proteins of the transport chain is a probabilistic process.
Thus, even in perfectly healthy mitochondria, there is a probability that any given electron may jump off early, and not complete the course defined by the electron transport chain. Early ejection of electrons is a problematic occurrence which can produce a host of toxic species. These toxic members, termed reactive oxygen species are capable of setting off deleterious chain reactions that beget oxidative stress. Even in health, oxidative stress occurs with disturbing regularity. But worry we should not! Our ever-vigilant healing processes mitigate the unsettling occurrences below the threshold of concern–at least while we are young–with age, our once-precise mitochondria become prone to error, malfunctions become more frequent, and our once-adept healing processes become burdened to the brink.
Consider again the case of a leaky inner membrane. In addition to allowing unwanted protons into the matrix, an altered inner membrane compromises the electron transport chain. As it consists of proteins that are embedded into the mitochondria’s inner membrane, the electron transport can become faulty if the inner membrane perturbed.
Unto this notion, by restoring the fidelity of the inner membrane, faulty electron transport is less likely to occur, and the generation of reactive oxygen species is thereby reduced. Such is how Chiao et al. hypothesize SS-31 exerts its primary effect.
By shoring up the inner membrane, SS-31 improves mitochondrial function by ameliorating previously compromised electron transport processes.
An additional effect of SS-31 is increased ATP production. Via increased ATP production cardiomyocyte function is improved. Cardiomyocytes are essentially tasked with pumping blood. To accomplish this job effectively, cardiomyocytes must contract and relax in a sweeping, coordinated manner. However, when ATP production is reduced via mitochondrial dysfunction, cardiomyocytes lose their ability to fully relax. This causes the cardiac cycle to become stunted. Mitochondria dysfunction is thus an instigator in both hypertension and heart disease.
In particular, Chiao et al. demonstrate that SS-31 can relieve diastolic dysfunction, which occurs when cardiomyocytes have ‘relaxation issues’. Altered muscle filaments are to blame. The proteins regulating the tension and relaxation of cardiomyocyte fibers require a steady supply of phosphate groups to pump blood effectively. The primary donor of these phosphate groups: ATP. Thus:
By increasing ATP production, SS-31 improves cardiomyocyte function.
Tying it All Together
Chiao et al. have elucidated mechanistic details regarding how SS-31 improves mitochondrial function, and how improved mitochondrial function translates to improved health of cardiomyocytes. Their insights will undoubtedly provide both doctors and patients an expanded understanding of SS-31, a peptide that is currently involved in multiple clinical trials aimed at diseases including age-related macular degeneration and heart disease. More generally, the work by Chiao and associates serves to provide vital guidance in terms of engineering more robust and effective mitochondrial therapeutics.
