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The mitochondria-targeted antioxidant MitoQ for mitigation of the deleterious effects of human space travel: a brief overview

The environment of space presents numerous challenges to human physiology and confers extreme stress on astronauts' cells and bodies.

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The environment of space presents numerous challenges to human physiology and confers extreme stress on astronauts' cells and bodies. A wealth of available data has elucidated the role of oxidative stress as a leading cause of these outcomes.

With numerous and varied clinical trials and independent studies demonstrating its ability to combat cell stress as a highly effective advanced antioxidant molecule, MitoQ is a prime candidate to not only further research in this pioneering field, but potentially be a key tool used to protect and maintain the health of the women and men of the world's space programs as we explore our universe. Read our white paper, written by MitoQ's Chief Scientific Officer William Stow, to learn more...

Introduction

The environment of space presents numerous challenges to human physiology and therefore our ability to live and explore there. Many of the observed, and indeed anticipated, effects of space travel on humans confer extreme stress on our cells and present as an “accelerated aging syndrome”. These effects include loss of bone density, endothelial and immune dysfunction, sarcopenia, and systemic cellular stress induced by environmental factors such as microgravity, atmospheric conditions, radiation exposure and mental and physical stress. A wealth of available data has elucidated the prominent role of oxidative stress as a common denominator in these phenomena [1] [Fig. 1]. MitoQ (mitoquinol mesylate) is a mitochondria-targeted antioxidant capable of significantly lowering systemic oxidative stress, particularly in tissues with high energy demands. A large body of research has demonstrated a wealth of such protective effects, most notably cardiometabolic, neurological, musculoskeletal, and immunological in nature [2]. With study outcomes particularly relevant to data from several recent space-flown missions [3], and an excellent safety profile [4], MitoQ should be considered as a candidate for multiple components of NASA’s Space Biology Program, and potentially as a future measure to support the health of crew members on long duration missions.

Fig 1. Effects of space missions and ROS on general physiology. (NPJ Microgravity. 2021; 7: 35.)
Fig 1. Effects of space missions and ROS on general physiology. (NPJ Microgravity. 2021; 7: 35.)

MitoQ

MitoQ is the flagship molecule in the class of compounds known as mitochondria-targeted antioxidants. MitoQ is a small-molecule mitochondria-targeted formulation of the reduced form of CoQ10, ubiquinol. The antioxidant moiety of the ubiquinol molecule is attached to the lipophilic triphenylphosphonium cation by a 10-carbon alkyl chain and stabilized for oral administration with the mesylate salt. It displays good oral bioavailability and readily crosses all biological membranes driven by the electrical gradient across the cell plasma membrane. MitoQ is then extensively absorbed to the inner surface of the mitochondrial membrane with the antioxidant head inserted into the membrane where it can most effectively fight reactive oxygen species (ROS) and preserve mitochondrial function. MitoQ has undergone extensive toxicology testing and displays an excellent safety profile. [4, 5]

Vascular function

According to the investigation entitled “Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular)”, spaceflight can cause stiffening and decreased flexibility of the arteries. A recent MitoQ clinical study found that chronic administration of MitoQ in healthy middle aged to older adults improved brachial artery flow-mediated dilation by 42% in just 6 weeks and significantly reduced aortic stiffness (measured by carotid-femoral pulse wave velocity) and plasma-oxidized LDL levels (a marker of oxidative stress). The magnitude of improvement in arterial dilation capacity is comparable to that typically seen by caloric restriction or aerobic exercise when applied for twice the duration of this study and is equivalent to measurements taken from an individual 15-20 years younger than the test subjects [6]. A larger follow up study is now underway [7].

Also of concern is the effect of the microgravity environment and elevated oxidative stress levels on the structural integrity of smaller arteries, particularly those in astronauts’ legs. Such conditions may mimic the effects of peripheral artery disease (PAD), a circulatory condition in which narrowed blood vessels reduce blood flow to the limbs. A recent clinical study by Park et al showed for the first time that MitoQ is effective in PAD for improving vascular endothelial function, increasing endogenous antioxidant levels and improving walking capacity [8].

Additional cellular stress-mediated benefits to vascular health have been demonstrated such as reductions in vascular fibrosis [9], attenuation of thrombus formation [10] and reductions in vascular inflammation and calcification [11, 12].

Radiation exposure

Exposure to solar and galactic cosmic radiation is a major limiting factor for astronauts, especially in consideration of long-duration space flights, and astronauts are typically exposed to 100 times more ionizing radiation than the general population [13]. Heavy ion radiation such as 56Fe radiation is of particular concern. A recent murine study found that following brain 56Fe irradiation, MitoQ pre-treatment greatly elevated endogenous antioxidant levels, decreased several markers of oxidative stress including ROS levels, reduced mitochondrial DNA damage and increased the expression of mitochondrial dynamics genes [14].

MitoQ has also demonstrated protection against gamma irradiation. A study by Ibrahim et al showed that MitoQ replenished endogenous antioxidant activity in gamma-irradiated testicular tissue which is particularly susceptible to ionizing radiation damage. MitoQ treatment inhibited radiation-induced apoptosis and conferred protection to steroidogenesis via significant reductions in ROS levels [15].

In a study by Sun et al, only targeted antioxidants such as MitoQ could prevent post-exposure cell death resulting from 12C6+ ion irradiation [16] and in a study by Ramsey et al, MitoQ prestored platelet production in irradiation-induced thrombocytopenia [17].

Musculoskeletal health

Sarcopenia and the corresponding loss in muscle strength and power is another known consequence of exposure to a microgravity environment. Research has shown that MitoQ improves multiple subdomains of motor function that are affected by oxidative stress. Recently MitoQ was shown to improve muscle power (as measured by leg extension 40% 1RM) by 11 % in healthy middle aged to older adults after 6 weeks of treatment [18]. In a rodent study, MitoQ improved mass normalized grip-strength (+23.1%) and completely restored endurance run time (+95.2%) and distance (+69.1%) in old animals supplemented with MitoQ [19].

A recent clinical trial by Broome et al showed that MitoQ improved both physical performance and power output compared to placebo in adult cyclists, while significantly reducing markers of oxidative stress [20]. In a second clinical trial by Williamson et al, MitoQ prevented high-intensity-exercise-induced DNA damage in both the mitochondria and nuclei of muscle tissue and lymphocytes when compared to placebo [21].

Mitochondrial dysfunction and oxidative stress are also significant contributors to the pathogenesis of intervertebral disc degeneration (IDD) which is a risk to astronauts given their elevated cellular stress levels and the effect of gravity once they return to Earth from extended stays in orbit. Work by Kang et al showed MitoQ is protective against IDD through removal of damaged mitochondria and restoration of redox balance in nucleus pulposus cells leading to reduced rates of apoptosis and increased cell survival [22].

Neurological health

Nervous tissue is particularly susceptible to oxidative stress and astronauts are at an increased risk of damage leading to short-term memory loss, psychiatric and affective disorders and neurotransmission and CNS homeostasis disruption [23]. It has been demonstrated that MitoQ is neuroprotective in a variety of models. This includes several studies displaying protection against oxidative neurotoxicity from chemotherapy [24, 25],

environmental toxins [26, 27] and physical trauma [28,29]. Additional results show that MitoQ can protect against motor neuron degeneration in a variety of settings [30, 31, 32] and can prevent loss of memory retention in models of neurodegeneration and hypoxia [33, 34, 35].

Reproductive health

As we all develop from a single cell into over 30 trillion cells, it is vital that that initial cell starts its journey in good health. Gametes are particularly sensitive to elevated oxidative stress levels and such cellular stress and mitochondrial dysfunction has been shown to reduce the quality of both oocytes and spermatazoa. MitoQ has been shown to ameliorate the mitophagy which contributes to poor cell quality and improve the blastocyst potential of stressed oocytes [36]. Elevated radiation levels are conducive to chromosomal defects in such cells however work by Al-Zubaidi et al has demonstrated that MitoQ protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and promotes nuclear maturation [37]. Similar results have emerged for sperm cells. A study by Kumar et al revealed that MitoQ attenuates the vitrification-induced ultrastructural changes and alterations in the key proteins involved in spermatozoa functions and fertilization [38]. MitoQ can also protect human sperm from post-thaw oxidative stress injury and retain cell quality [39].

Conclusion

Space missions will increasingly last longer as we look to explore Mars and other distant parts of the solar system. Astronauts will be required to endure harsh conditions for extended periods of time including microgravity, elevated radiation levels and high physical and mental stress states. These all conspire to significantly increase ROS levels and in turn cellular stress which can swiftly lead to reductions in health and function. Increased cellular stress, particularly over extended periods, leads to an acceleration in our biological age leading to musculoskeletal degradation, organ damage and neurophysiological decline [40]. Antioxidants can mitigate the damage caused by increased ROS levels and will certainly play a key role in keeping space farers healthy during extended missions or during activity in particularly harsh situations such as extra-vehicular activity. MitoQ is an ideal antioxidant due to its systemic absorption and mitochondrial targeting properties, as it is within the mitochondria where more than 90% of ROS are generated. MitoQ is an orally bioavailable, small molecule antioxidant which requires comparatively low doses and has pharmacokinetic properties making it idea for daily dosing. It accumulates primarily in tissues with high energy demands which are those with the highest risk of damage from cellular stress. The scientific knowledge of mitochondria-targeted antioxidants is led by MitoQ research and is constantly evolving, with promising data from new in vitro, in vivo, and clinical studies. While several therapeutic areas are discussed in this article, MitoQ has demonstrated benefits in many more [2]. As such, MitoQ is an excellent candidate for space biology research and has significant potential to help improve both astronaut health span and potential space mission length.

*Disclaimer: The content discussed here is for research purposes only and is not intended to confer or imply any therapeutic benefits for Earth-bound citizens.

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