What is MitoQ

MitoQ also known as mitoquinone mesylate, mitochondrial-targeted coenzyme Q or 10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl triphenyl phosphonium methanesulfonate, is a mitochondrial targeted anti‐oxidant composed of ubiquinone, a component of the electron transport chain (ETC), covalently bound via a ten carbon chain to triphenylphosphonium (TPP+), a lipophilic cation that targets the ubiquinone moiety to the inner mitochondrial membrane driven by the high electrochemical potential across that membrane 1). MitoQ is an orally active antioxidant developed by the pharmaceutical industry to potentially treat several diseases. MitoQ retains the antioxidant activity of coenzyme Q10 and the triphenylphosphonium cation (TPP+) substituent directs this agent to mitochondria 2). MitoQ or mitoquinone is a derivative of coenzyme Q, is produced by covalently binding ubiquinone, an endogenous antioxidant and component of the mitochondrial electron transport chain to a triphenylphosphonium (TPP+) cation. MitoQ rapidly crosses the blood–brain barrier (BBB) and neuronal membranes and concentrates several hundred-fold in mitochondria driven by the high membrane potential across the inner mitochondrial membrane 3). The ubiquinone moiety is delivered to the matrix side of the inner mitochondrial membrane, placing it at the site of most cellular reactive oxygen species (ROS) generation and was proven to be effective in reducing reactive oxygen species (ROS) generated in mitochondria 4). The triphenylphosphonium(TPP+) moiety adsorbs to the matrix side of the inner mitochondrial membrane and the ubiquinone penetrates into the membrane in which it is reduced to the active antioxidant ubiquinol by respiratory complex II 5). The ubiquinol acts as an antioxidant when oxidized to ubiquinone by reactive oxygen species. Complex II then reduces the ubiquinone to ubiquinol. MitoQ is a poor substrate for complex I and is negligibly oxidized by complex III. Therefore, it cannot substitute for endogenous ubiquinone in the electron transport chain (ETC) but primarily acts as an antioxidant capable of continuous regeneration by complex II 6). Because MitoQ is a poor substrate for complex I and III, it cannot substitute for endogenous ubiquinone and thus does not take part in mitochondrial respiration 7). It instead acts as a renewable antioxidant 8).

Mitochondrial dysfunction is associated with a diverse array of diseases ranging from dystrophy and heart failure to obesity and hepatosteatosis 9). One of the major biochemical consequences of impaired mitochondrial function is an accumulation of mitochondrial superoxide (O2) or reactive oxygen species (ROS). Excessive ROS can be detrimental to cellular health and is proposed to underpin many mitochondrial diseases. Accordingly, much research has been committed to understanding ways to therapeutically prevent and reduce ROS accumulation. MitoQ (mitoquinone) was designed by Kelso et al. 10) as a potential therapeutic to target mitochondrial ROS. A large proportion of ROS is generated by the mitochondrial electron transport chain (ETC), which produces superoxide via the reduction of oxygen 11).

Reactive oxygen species (ROS) damage cellular structures and cause oxidative stress, but they also function as signaling molecules that regulate biological and pathological processes 12). Mitochondria produce a substantial portion of cellular ROS, in particular superoxide (O2), as a byproduct of oxidative phosphorylation in complexes I, II, and III of the electron transport chain (ETC) 13). Superoxide (O2) is then rapidly converted to form the ROS, hydrogen peroxide (H2O2), by the enzymatic activity of superoxide dismutases (superoxide dismutase 1, 2, and 3 [SOD1, SOD2, and SOD3]) located in the mitochondrial matrix 14). An accumulation of both superoxide (O2) and hydrogen peroxide (H2O2) causes oxidative damage, which can lead to cellular dysfunction, and death 15), often via the formation of reactive lipid species formed by lipid peroxidation 16). The mitochondria-associated H2O2 can in turn stimulate intracellular signaling pathways by reversibly oxidizing cysteine residues in key proteins 17). Indeed, mitochondria-associated ROS can move into the cytosol and subsequently into the extracellular environment, where they can trigger different signaling cascades and pathways 18). Furthermore, mitochondrial ROS can target and mutate mitochondrial DNA and thereby contribute to carcinogenesis 19). However, several reports show conflicting results on the efficiency of MitoQ to limit tumor growth and metastasis 20). In this study in mice 21), the authors found that MitoQ administration had no impact on the number of primary tumors and lymph metastases in mice with BRAF-induced malignant melanoma and no impact on tumor burden in mice with KRAS-induced lung cancer. These results question the rationale of using these mitochondria-targeted antioxidants in anti-cancer therapy. Furthermore, manipulating mitochondrial ROS has been an area of therapeutic interest for conditions such as obesity, multiple sclerosis (MS) and type 2 diabetes, albeit with little success 22).

Previous lab studies and animal experiments have revealed mitoQ exerted its protective effects on diseases like traumatic brain injury 23), cardiovascular disease 24), inflammation 25), neurodegenerative disorders 26), intestinal ischemia reperfusion 27), diabetes 28) and diabetic kidney disease 29) through regulation of NF-E2-related factor 2 (Nrf2). In db/db mice, mitoQ partially rectified mitochondrial dysfunctions, such as defective mitophagy, mitochondrial reactive oxygen species (mtROS) overexpression and mitochondrial fragmentation in tubular cells and inhibited tubular cells apoptosis 30). In in vitro study mitoQ decreased deficiency of mitophagy, mitochondrial dysfunction and apoptosis in high glucose induced HK-2 cells via Nrf2/PINK pathway 31).

NF-E2-related factor 2 (Nrf2) is retained in the cytosol bounding to Kelch-like ECH-associated protein 1 (Keap1), which represses activity of Nrf2 by promoting the proteasomal degradation of Nrf2 32). Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival 33). In the presence of reactive oxygen species (ROS), Nrf2 will dissociate from Keap1, translocate to the nucleus, dimerize with a small protein Maf, namely MafF, MafG and MafK, and initiate transcription of many cytoprotective genes at antioxidant response elements (AREs) loci, including glutathione peroxidase (GPX), GSH-S-transferase, heme oxygenase (HO)-1, NADPH quinine oxidoreductases (NQO)-1, etc. 34).

Activation of Nrf2 and antioxidant response element (ARE) signaling is a crucial process in protecting cells from oxidative insults 35). However, there remain controversies in the mechanism how Nrf2 is exactly activated. Several studies reported that the gene expression of Nrf2 might be determined by complex I activity via an ERK5-myocyte enhancer factor 2 (MEF2) signaling pathway independent of ROS 36). While other studies reported changes in mitochondrial reactive oxygen species (mtROS) generation actually altered the cellular response, where changes of mtROS actually influenced the activation of Nrf2 through unknown mediators or signaling cascades 37). In a recent study from Ping Wang et al. 38) the stability of Nrf2 was modulated by kinases Mst1 and Mst2 (Mst1/2) which can sense site-specific ROS release and maintain cellular redox homeostasis. Activated Mst1/Mst2 by mtROS could phosphorylate Keap1 at four Ser/Thr residues in the N-terminus, which inactivated Keap1 and decreased the degradation of Nrf2. Thus, these results suggested that mtROS activated Nrf2 mainly by indirect and kinase-dependent way 39). Accumulating evidence also suggests that the Nrf2 and antioxidant response element (ARE) pathway reduces apoptosis and alleviates the inflammatory response, resulting in a significant improvement in tissue retention and beneficial role in coordination 40). It is also reported that oxidative signaling and Nrf2 were tightly linked with cellular responses 41).

Figure 1. MitoQ (chemical structure of triphenylphosphonium-substituted coenzyme Q)

MitoQ chemical structure

Footnote: MitoQ (mitoquinone or mitochondrial-targeted coenzyme Q), is a mitochondrial targeting antioxidant with an antioxidant ubiquinone, which is identical to the active antioxidant in Coenzyme Q10, attached to a triphenylphosphonium (TPP+) cation

MitoQ health benefits

MitoQ is an orally active antioxidant developed by the pharmaceutical industry to potentially treat several diseases. MitoQ retains the antioxidant activity of coenzyme Q10 and the triphenylphosphonium cation (TPP+) substituent directs this agent to mitochondria 42). Mitochondria are the major resource of reactive oxygen species (ROS) and mitoQ is a mitochondria targeted antioxidant composed of lipophilic triphenylphosphonium (TPP+) cation which can easily move through phospholipid bilayers driven by mitochondrial membrane potential and an ubiquinol antioxidant 43). Once accumulating within mitochondria, mitoQ will be adsorbed to the surface of the inner membrane where it will be continually transformed to the antioxidant quinol form in the respiratory chain by complex II 44), which may react directly with superoxide (O2) 45). In cultured cells MitoQ was able to accumulate into mitochondria and act against oxidative stress 46). It was also demonstrated a protective effect of MitoQ in a sepsis model by decreasing the oxidative stress and protecting mitochondria against damage as well as by suppressing proinflammatory cytokine release 47). It was proposed that the antioxidant action of MitoQ may be useful in the treatment of diseases associated to the impairment of mitochondrial Complex I 48). On the other hand, it was recently showed that MitoQ may be prooxidant and present proapoptotic action due its quinone group that may participates in redox cycling and superoxide production 49). It is also shown that mitoQ is able to protect cells against peroxynitrite damage but it can hardly eliminate hydrogen peroxide (H2O2) like other quinols 50).

Growing evidence shows that MitoQ exerts beneficial effects on a wide range of diseases including Parkinson’s disease 51), diabetes 52) and cardiac ischemia-reperfusion injury 53) where mitochondrial oxidative damage plays a crucial role in the pathology. In addition, in some inflammatory diseases, such as sepsis, mitoQ is also proved to be effective both in vitro and in vivo 54). Previously it was reported that mitoQ improved neurological deficits, attenuated brain edema and decreased cortical neuronal apoptosis through activating the NF-E2-related factor 2 (Nrf2) and antioxidant response element (ARE) pathway 55). Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses 56).

Alzheimer’s disease

MitoQ may reduce the burden of oxidative stress in Alzheimer’s disease, though there is not strong evidence it would change clinical outcomes in patients.

In vitro, MitoQ prevented amyloid β (Aβ)-induced neuronal death, ROS production and change in mitochondrial membrane depolarization. In Alzheimer’s mice treated with MitoQ from a young age for five months, treatment improved cognition, reduced oxidative stress, increased synaptic markers, reduced gliosis, and reduced levels of amyloid 57). In older Alzheimer’s mice (beginning treatment at 12 months of age), MitoQ treatment for five months improved cognitive performance, increased markers of synapses, reduced oxidative stress, reduced astro-and micro-gliosis, and reduced tau and ptau levels. MitoQ also increased lifespan of Alzheimer’s mice to a similar extent as control mice –although the study was not long enough to test the full extent of an increase in lifespan 58). In vitro studies suggest that MitoQ can increase neurite outgrowth in neurons from an Alzheimer’s mouse model and protect against Aβ toxicity in cells 59).

In a Caenorhabditis elegans (roundworm) model of Alzheimer’s disease, MitoQ extended lifespan by 15% and delayed paralysis (a marker of healthspan in these worms) 60). MitoQ had no effect on oxidative stress, mitochondrial DNA (mtDNA) damage, or oxygen consumption rate and ATP levels (measures of mitochondrial metabolism). However, MitoQ increased mitochondrial complex I and IV activity and increased the level of certain cardiolipin species 61).

Amyotrophic lateral sclerosis (ALS)

In a mouse model of amyotrophic lateral sclerosis (ALS), treatment with MitoQ early in the disease improved mitochondrial function in the muscle and spinal cord, reduced levels of 3-nitrotyrosine and gliosis in the spinal cord, improved motor unit integrity at the neuromuscular junction, and increased lifespan 62).

Multiple sclerosis

In a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis injection), pretreatment with MitoQ delayed the onset of neurological symptoms and treatment with MitoQ after experimental autoimmune encephalomyelitis injection reduced the severity of neurological symptoms 63). In the spinal cord, MitoQ reduced microgliosis, IL-6 expression, and neurodegeneration 64).

Traumatic brain injury

When administered 30 minutes after a traumatic brain injury in mice, MitoQ (4mg/kg and 8mg/kg, but not 2mg/kg) improved neurological outcomes and reduced brain edema 65). It increased the activity of antioxidant enzymes (superoxide dismutase –SOD, and glutathione peroxidate) and reduced a marker of oxidative stress (malondialdehyde). In addition, it reduced neuronal apoptosis and increased nuclear Nrf2 levels and the expression of proteins downstream of Nrf2 66).

Subarachnoid hemorrhage

In a rat model of subarachnoid hemorrhage, administration of MitoQ 1 hour after hemorrhage improved neurological outcomes andreduced brain edema (in the 3mg/kg but not 1mg/kg or 9mg/kg groups) 67). This was accompanied by an increase in Nrf2 expression, improved mitochondrial morphology, and improved blood brain barrier integrity (measured by increased claudin-5 expression and reduced brain albumin levels) 68).

Angelman syndrome

In a mouse model of Angelman Syndrome, MitoQ increased synaptic plasticicy and improved memory 69).

Heart failure

In a model of pressure overload-induced heart failure, MitoQ (100μM in drinking water) failed to improve cardiac functioning 70). MitoQ had a few minor benefits in some measures of mitochondrial function, but not all 71). In aged mice, 4-week treatment with MitoQ (250μM) reduced aortic stiffness (aortic pulse-wave velocity) and increased elastin expression, but had no effect on collagen expression or the expression of pro-inflammatory cytokines (e.g. IL-6, IL-10, IFN-γ, IL-1β) in the aorta 72). Another study from the same group showed that 4-week treatment with MitoQ increased endothelium-dependent (but not independent) dilation, reduced mitochondria-specific superoxide production, and reduced 3-nitrotyrosine levels. It also increased the aortic expression of PGC-1α, superoxide dismutase (MnSOD), and reduced expression of COX-IV 73).

Aging and related health concerns

MitoQ shows consistent antioxidant properties, though whether it would have beneficial effects on clinicaloutcomes in humans is not known.

In aged rats, 5-week treatment with MitoQ (500μM in drinking water) reduced markers of oxidative damage (malondialdehyde, protein carbonylation, and nitrosative stress), improved mitochondrial complex I and IV activity, increased the mitochondrial membrane potential, and increased mitochondrial ATP levels 74).

In a meta-analysis of aging-related biomarkers from preclinical studies, Braakhuis et al 75) reported that three biomarkers were included in enough studies to conduct a meta-analysis (3-nitrotyrosine, 8 studies; mitochondrial membrane potential, 4 studies; and protein carbonyls, 8 studies). MitoQ significantly reduced 3-nitrotyrosine levels, increased mitochondria membrane potential, and non-significantly reduced protein carbonyl levels 76).

Kidney ischemia-reperfusion injury

In a mouse model of ischemia-reperfusion of the kidney, administration of MitoQ 15 minutes prior to ischemia reduced kidney damage (as measured by creatine levels) and reduced oxidative damage (as measured by protein carbonyl content and mtDNA damage) 77). In a model of hemorrhagic shock with reperfusion, administration of MitoQ had mixed effects with a reduction in morbidity, no effect on liver necrosis, a trend toward increased lipid peroxidation, elevated glutathione peroxidase (GPx) activity, reduced catalase activity, and a reduction in inflammation (hepatic IL-6 and TNFα) 78).

Diabetes and diabetic kidney disease

In an ex vivo study of leukocytes from patients with type 2 diabetes, MitoQ reduced mitochondrial ROS levels, leukocyte adhesion properties, and reduced the expression of inflammatory markers (NFkB and TNFα) 79). In a mouse model of diabetic kidney disease, MitoQ (0.6mg/kg/day) over 12 weeks had no effects on plasma glucose or insulin levels. Beneficial effects on renal function were similar to an ACE inhibitor (ramipril), but there were no additive effects when given together 80). In a mouse model of metabolic disease, 14-week treatment with MitoQ prevented an increase in fat, improved energy expenditure, reduced liver lipid content, reduced serum liver enzymes, and reduced serum lipid markers (cholesterol, triglycerides, and LDL [low density lipoprotein or “bad” cholesterol]). Although it had no effect on atherosclerotic plaque size, it did reduce the proliferation of plaque-associated macrophages. It reduced mitochondrial DNA (mtDNA) damage in the liver but had no effect on protein carbonyl content 81).

MitoQ clinical trials

One pilot study of MitoQ in Alzheimer’s disease patients is underway. It is a 2-day cross-over trial in 12 patients looking at carotid artery blood flow, oxidative stress, cerebrovascular oxygenation, EEG, and endothelial function 82). Other clinical trials are ongoing including fatigue in multiple sclerosis, cardiovascular function, peripheral artery disease, and chronic kidney disease (

Parkinson’s disease

In a mouse model of Parkinson’s disease, 14-day treatment with MitoQ increased the number of dopaminergic neurons and increased the expression of PGC-1α (a gene involved in mitochondrial fusion) 83). However, in 128 patients with newly diagnosed Parkinson’s disease, MitoQ (40mg or 80mg/day) had no effect on clinical outcome measures [Unified Parkinson’s Disease Rating Scale (UPDRS)] over 12 months. More patients discontinued in the MitoQ group (13 in 80 mg, 2 in 40 mg, and 1 in placebo), mostly due to gastrointestinal side effects 84). Reasons suggested for the failed trial include treating patients too late in the disease progression and insufficient brain penetration of MitoQ.

Age-related diseases

In 20 healthy older adults (average age 68) with impaired endothelial function (brachial artery flow-mediated dilation <60%), 6-week cross-over treatment with MitoQ (20mg/day) improved endothelial-dependent flow-mediated dilation by 42% (but had no effect on endothelial-independent flow-mediated dilation) and reduced aortic stiffness (carotid-femoral pulse wave velocity) in patients with elevated aortic stiffness 85). MitoQ reduced oxidized-LDL (low density lipoprotein or “bad” cholesterol) but had no effect on circulating inflammatory markers (CRP or IL-6) 86).

MitoQ supplement dosage

MitoQ is being developed by Antipodean Pharmaceuticals. It is also sold as a supplement by MitoQ. Recommended doses are 10mg/day with therapeutic doses in the Parkinson’s disease trial at 40mg or 80mg/day.

MitoQ side effects

Some evidence from clinical studies suggest there are gastrointestinal side effects of MitoQ at higher doses, though no large, extended clinical trials have been conducted.

MitoQ has been tested in 128 Parkinson’s patients over 12 months (40mg or 80mg/day) 87), 20 healthy patients over 3 weeks (10mg/day) 88), in 20 healthy older adults with endothelial dysfunction over 6 weeks (20mg/day) 89) and in 30 patients with chronic hepatitis C over 28 days (40mg or 80mg/day) 90). The only adverse effects so far reported are gastrointestinal side effects (at 40mg and 80mg doses).

Drug interactions

Not currently known. Although, theoretically, MitoQ may interact with other mitochondria-targeted antioxidants (e.g Skq1 andSS-31).

MitoQ summary

Consistent evidence suggests that MitoQ can reduce oxidative stress in mitochondria; though whether this will impact clinical outcomes in humans is unknown.

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