Water-soluble CoQ10 as A Promising Anti-aging Agent for Neurological Dysfunction in Brain Mitochondria

López-Lluch G., del Pozo-Cruz J., Sánchez-Cuesta A., Cortés-Rodríguez A.B., Navas P.

Bioavailability of supplements with coenzyme Q10 (CoQ10) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ10 supplements affect the different response to CoQ10 in humans.We tested seven different supplement formulations containing 100 mg of CoQ10 in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes.Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ10) or ubiquinol (reduced CoQ10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10. Although control measurements documented that all formulations contained 100 mg of either CoQ10 or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ10 in blood, indicating the participation of individual unknown physiological factors.This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ10 in humans.

Hernández-Camacho J.D., Bernier M., López-Lluch G., Navas P.

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and ageing, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate ageing symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of ageing based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.

Takahashi K., Ohsawa I., Shirasawa T., Takahashi M.

The oxygen consumption rate (OCR) in brain mitochondria is significantly lower in aged mice than in young mice, and the reduced OCR is rescued by administration of water-solubilized CoQ10 to aged mice via drinking water. However, the mechanism behind this remains unclear. Here, we show that the activity of respiratory complex IV (CIV) in brain mitochondria declined in aged mice than in young mice, with no significant change in individual respiratory complex levels and their supercomplex assembly. Reduced CIV activity in the aged mice coincided with reduced binding of optic atrophy 1 (OPA1) to CIV. Both reduced activity and OPA1 binding of CIV were rescued by water-solubilized CoQ10 administration to aged mice via drinking water. OCR and the activity and OPA1 binding of CIV in isolated brain mitochondria from aged mice were restored by incubation with CoQ10, but not in the presence of 15-deoxy-prostaglandin J2, an inhibitor of a GTPase effector domain-containing GTPase such as OPA1 and DRP1. By contrast, the CoQ10-responsive restoration of OCR in the isolated mitochondria was not inhibited by Mdivi-1, a selective inhibitor of DRP1. Thus, we propose a novel function of OPA1 in regulating the CIV activity in brain mitochondria in response to CoQ10.

Gupta B.K., Kumar S., Kaur H., Ali J., Baboota S.

Coenzyme Q10 (CoQ10) is a well-known antioxidant molecule which is used in the treatment of neurodegenerative disorders, but due to poor solubility it suffers with the drawback of low oral bioavailability. The aim of present study was to prepare and characterize CoQ10 loaded nanoemulsion to improve the oral bioavailability. Prepared formulation was studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology by transmission electron microscopy, and in vitro release study. Optimized formulation (A10) showed spherical droplets with mean diameter of 60.00 ± 15 nm, PDI of 0.121 ± 0.053, and zeta potential values of -24.40 ± 0.16 mV. Prepared nanoemulsion exhibited good transmittance (100.50% ± 0.86%), refractive index (1.41 ± 0.02), and viscosity (30.54 ± 2.86 cP). Various behavioral tests like forced swimming test, locomotor activity test, catalepsy, muscle coordination test, and akinesia test performed in haloperidol challenged rats and treated with CoQ10 nanoemulsion significantly improved the behavioral activities in comparison to CoQ10 suspension by reducing nigrostriatal dopamine depletion and thereby helping in the treatment of Parkinson's disease. Biochemical estimation data showed that CoQ10 nanoemulsion was helpful in elevating the decreased content of glutathione and reducing the increased content of thiobarbituric acid reactive substances. Improved CoQ10 release was obtained with nanoemulsions. Pharmacokinetic study results revealed that nanoemulsion exhibited 1.81 times enhancement in bioavailability in comparison to CoQ10 suspension.

Grimm A., Eckert A.

Aging is defined as a progressive time-related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the 'free-radical theory of aging', because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age-related mitochondrial impairments? (iii) Is there a sex difference in the age-induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may help identify therapeutic targets against neurodegeneration. This article is part of a series "Beyond Amyloid".

Abeliovich A., Gitler A.D.

Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms. Cell-extrinsic mechanisms, including inflammation and prion-like spreading, are proposed to have both protective and deleterious functions in Parkinson's disease.

Takahashi K., Ohsawa I., Shirasawa T., Takahashi M.

Brain mitochondrial function declines with age; however, the accompanying behavioral and histological alterations that are characteristic of Parkinson's disease (PD) are poorly understood. We found that the mitochondrial oxygen consumption rate (OCR) and coenzyme Q (CoQ) content were reduced in aged (15-month-old) male mice compared to those in young (6-month-old) male mice. Concomitantly, motor functions, including the rate of movement and exploratory and voluntary motor activities, were significantly reduced in the aged mice compared to the young mice. In the motor cortex of the aged mouse brain, the accumulation of α-synuclein (α-syn) phosphorylated at serine129 (Ser129) significantly increased, and the level of vesicular glutamate transporter 1 (VGluT1) decreased compared with that in the young mouse brain. The administration of exogenous water-soluble CoQ10 to aged mice via drinking water restored the mitochondrial OCR, motor function, and phosphorylated α-syn and VGluT1 levels in the motor cortex. These results suggest that early-onset motor impairment and the increased accumulation of Ser129-phosphorylated α-syn in the motor cortex are ameliorated by the exogenous administration of CoQ10.

Sun N., Youle R.J., Finkel T.

A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in mitochondria function contributes to aging. In particular, we discuss how mitochondria contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and the age-dependent decline in stem cell activity. Signaling pathways regulating the mitochondrial unfolded protein response and mitophagy are also reviewed, with particular emphasis placed on how these pathways might, in turn, regulate longevity. Taken together, these observations suggest that mitochondria influence or regulate a number of key aspects of aging and suggest that strategies directed at improving mitochondrial quality and function might have far-reaching beneficial effects.

Civiletto G., Varanita T., Cerutti R., Gorletta T., Barbaro S., Marchet S., Lamperti C., Viscomi C., Scorrano L., Zeviani M.

Increased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4(-/-)), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15(sm/sm)), with Opa1 transgenic (Opa1(tg)) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4(-/-)::Opa1(tg) mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15(sm/sm)::Opa1(tg) mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15(sm/sm)::Opa1(tg) mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease.

Zaki N.M.

Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a powerful, endogenously produced, intracellularly existing lipophilic antioxidant. It combats reactive oxygen species (ROS) known to be responsible for a variety of human pathological conditions. Its target site is the inner mitochondrial membrane (IMM) of each cell. In case of deficiency and/or aging, CoQ10 oral supplementation is warranted. However, CoQ10 has low oral bioavailability due to its lipophilic nature, large molecular weight, regional differences in its gastrointestinal permeability and involvement of multitransporters. Intracellular delivery and mitochondrial target ability issues pose additional hurdles. To maximize CoQ10 delivery to its biopharmaceutical target, numerous approaches have been undertaken. The review summaries the current research on CoQ10 bioavailability and highlights the headways to obtain a satisfactory intracellular and targeted mitochondrial delivery. Unresolved questions and research gaps were identified to bring this promising natural product to the forefront of therapeutic agents for treatment of different pathologies.

Mourier A., Matic S., Ruzzenente B., Larsson N., Milenkovic D.

Sikorska M., Lanthier P., Miller H., Beyers M., Sodja C., Zurakowski B., Gangaraju S., Pandey S., Sandhu J.K.

Although the support for the use of antioxidants, such as coenzyme Q(10) (CoQ(10)), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ(10) is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ(10) (Ubisol-Q(10)) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q(10) was delivered in drinking water. Prophylactic application of Ubisol-Q(10), started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q(10) group by day 28). Therapeutic application of Ubisol-Q(10), given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q(10) concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ(10)/kg body weight/day, showing clearly that high doses of CoQ(10) were not required to deliver these effects. Furthermore, the Ubisol-Q(10) treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q(10) was capable of halting the neurodegeneration already in progress; however, to maintain it a continuous supplementation of Ubisol-Q(10) was required. The pathologic processes initiated by MPTP resumed if supplementation was withdrawn. We suggest that in addition to brain delivery of powerful antioxidants, Ubisol-Q(10) might have also supported subcellular oxidoreductase systems allowing them to maintain a favorable cellular redox status, especially in astroglia, facilitating their role in neuroprotection. Based on this data further clinical testing of this formulation in PD patients might be justifiable.

García-Corzo L., Luna-Sánchez M., Doerrier C., Ortiz F., Escames G., Acuña-Castroviejo D., López L.C.

Coenzyme Q10 (CoQ 10 ) deficiency (MIM 607426 ) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ 10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model ( Coq9 X/X ) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ 10 . Our results show that CoQ 10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ 10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ 10 in mitochondria from cerebrum of Coq9 X/X mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum–striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ 10 therapy in primary and secondary CoQ 10 deficiencies, other mitochondrial diseases and neurodegenerative diseases. • Ubiquinol-10 has better tissue and mitochondrial uptake than ubiquinone-10. • Ubiquinol-10 is more efficient than ubiquinone-10 in improving cerebral mitochondrial function. • Ubiquinol-10 is more efficient than ubiquinone-10 in reducing oxidative damage vacuolization and astrogliosis.

Takahashi K., Takahashi M.

• Age-dependent changes in mitochondrial function and CoQ content were studied in mice. • Mitochondrial oxygen consumption reduced in the brains of aged male mice. • This decrease in oxygen consumption was accompanied by no change in CoQ content. • Oral administration of CoQ improved oxygen consumption in aged mouse brain. The level of coenzyme Q (CoQ) has been shown to decrease in an age-dependent manner in several types of animals. However, whether CoQ-dependent mitochondrial function decreases with aging remains unclear. In this study, we found that mitochondrial complexes I and II exhibited significantly reduced oxygen consumption in the brains of aged male mice relative to young male mice, although this decrease in oxygen consumption was not accompanied by a change in the CoQ 9 or CoQ 10 content. Nevertheless, the administration of exogenous CoQ 10 significantly increased the content of CoQ 10 and CoQ 9 in the brain mitochondria of aged male mice and restored complex I- and II-mediated oxygen consumption to levels comparable to those observed in young mice. These results indicate that mitochondrial oxygen consumption in the brain decreases in aged male mice. Furthermore, these results suggest that exogenous CoQ 10 restores mitochondrial oxygen use to levels equivalent to those observed in young mice.

Cogliati S., Frezza C., Soriano M., Varanita T., Quintana-Cabrera R., Corrado M., Cipolat S., Costa V., Casarin A., Gomes L., Perales-Clemente E., Salviati L., Fernandez-Silva P., Enriquez J., Scorrano L.

Loi M., Valenti F., Medici G., Mottolese N., Candini G., Bove A.M., Trebbi F., Pincigher L., Fato R., Bergamini C., Trazzi S., Ciani E.

CDKL5 deficiency disorder (CDD), a developmental encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, is characterized by a complex and severe clinical picture, including early-onset epilepsy and cognitive, motor, visual, and gastrointestinal disturbances. This disease still lacks a medical treatment to mitigate, or reverse, its course and improve the patient’s quality of life. Although CDD is primarily a genetic brain disorder, some evidence indicates systemic abnormalities, such as the presence of a redox imbalance in the plasma and skin fibroblasts from CDD patients and in the cardiac myocytes of a mouse model of CDD. In order to shed light on the role of oxidative stress in the CDD pathophysiology, in this study, we aimed to investigate the therapeutic potential of Coenzyme Q10 (CoQ10), which is known to be a powerful antioxidant, using in vitro and in vivo models of CDD. We found that CoQ10 supplementation not only reduces levels of reactive oxygen species (ROS) and normalizes glutathione balance but also restores the levels of markers of DNA damage (γ-H2AX) and senescence (lamin B1), restoring cellular proliferation and improving cellular survival in a human neuronal model of CDD. Importantly, oral supplementation with CoQ10 exerts a protective role toward lipid peroxidation and DNA damage in the heart of a murine model of CDD, the Cdkl5 (+/−) female mouse. Our results highlight the therapeutic potential of the antioxidant supplement CoQ10 in counteracting the detrimental oxidative stress induced by CDKL5 deficiency.

Fišar Z., Hroudová J.

The progress in understanding the pathogenesis and treatment of Alzheimer’s disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aβ) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

Inoue R., Miura M., Yanai S., Nishimune H.

AbstractPhysiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Phan K., He Y., Bhatia S., Pickford R., McDonald G., Mazumder S., Timmins H.C., Hodges J.R., Piguet O., Dzamko N., Halliday G.M., Kiernan M.C., Kim W.S.

Abstract Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterised by degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis, or in relation to disease progression. The present study incorporated a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum with comparison to healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared to controls, with the diglyceride(18:1/18:1) species correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and for monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Zhao S., Wu W., Liao J., Zhang X., Shen M., Li X., Lin Q., Cao C.

Coenzyme Q10 (CoQ10), an endogenous antioxidant, has been reported frequently to exert an outstanding protective effect on multiple organ injury, including acute kidney injury (AKI). In this study, we aim to summarize all the current evidence of the protective action of CoQ10 against AKI as there are presently no relevant reviews in the literature. After a systematic search, 20 eligible studies, either clinical trials or experimental studies, were included and further reviewed. CoQ10 treatment exhibited a potent renal protective effect on various types of AKI, such as AKI induced by drugs (e.g., ochratoxin A, cisplatin, gentamicin, L-NAME, and nonsteroidal anti-inflammatory drug), extracorporeal shock wave lithotripsy (ESWL), sepsis, contrast media, and ischemia–reperfusion injury. The renal protective role of CoQ10 against AKI might be mediated by the antiperoxidative, anti-apoptotic, and anti-inflammatory potential of CoQ10. The molecular mechanisms for the protective effects of CoQ10 might be attributed to the regulation of multiple essential genes (e.g., caspase-3, p53, and PON1) and signaling cascades (e.g., Nrf2/HO-1 pathway). This review highlights that CoQ10 may be a potential strategy in the treatment of AKI.

Liu J.

Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.

Mantle D., Heaton R.A., Hargreaves I.P.

The ageing brain is characterised by changes at the physical, histological, biochemical and physiological levels. This ageing process is associated with an increased risk of developing a number of neurological disorders, notably Alzheimer’s disease and Parkinson’s disease. There is evidence that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of such disorders. In this article, we review the potential therapeutic role in these age-related neurological disorders of supplementary coenzyme Q10, a vitamin-like substance of vital importance for normal mitochondrial function and as an antioxidant. This review is concerned primarily with studies in humans rather than in vitro studies or studies in animal models of neurological disease. In particular, the reasons why the outcomes of clinical trials supplementing coenzyme Q10 in these neurological disorders is discussed.

Yang S., Niu Y., Li L., Liu J., Ma M., Duan X., Zhang L., Wang L., Qu L.

Coenzyme Q10 (CoQ10) has a wide range of physiological functions and therapeutic value. However, its biomedical application as a health product or drug is limited by its insolubility and low bioavailability. Single-walled carbon nanotubes (SWCNTs) have attracted great interest for drug or therapeutic agent delivery due to their unique properties. In this study, the pristine SWCNTs are purified with different oxidizing acid, and the resulting shortened CNTs (CNTs-COOH) are conjugated with poly-(ethylene glycol) (PEG) groups. Afterwards, CoQ10 is loaded by CNTs carriers. CNTs carriers are systematically characterized and evaluated in terms of drug loading, in vitro release, cytotoxicity, and cellular uptake. The results reveal that the sizes (length) of CNTs-COOH and CNTs-PEG are 253.2 and 328.7 nm, respectively, and they have high loading capacity for CoQ10 and low cytotoxicity toward Caco-2 cells. In comparison with CNTs-COOH, CNTs-PEG exhibited better sustained-release property for CoQ10. Also, CNTs-PEG carriers loaded with CoQ10 can be effectively delivered into cells and have enhanced cellular uptake efficiency over time. Further study results of the uptake mechanism illustrate that CNTs-PEG can be internalized into cells through the broader and more efficient entry routes, including direct penetration, clathrin-mediated endocytosis and macropinocytosis pathway. In summary, the PEG-conjugated CNTs may be used as novel nanocarriers, and the findings will contribute to the rational design of multifunctional delivery vehicles for CoQ10.

Iuchi K., Takai T., Hisatomi H.

Lipid peroxidation of cellular membranes is a complicated cellular event, and it is both the cause and result of various diseases, such as ischemia-reperfusion injury, neurodegenerative diseases, and atherosclerosis. Lipid peroxidation causes non-apoptotic cell death, which is associated with cell fate determination: survival or cell death. During the radical chain reaction of lipid peroxidation, various oxidized lipid products accumulate in cells, followed by organelle dysfunction and the induction of non-apoptotic cell death. Highly reactive oxidized products from unsaturated fatty acids are detected under pathological conditions. Pathological protein aggregation is the general cause of these diseases. The cellular response to misfolded proteins is well-known as the unfolded protein response (UPR) and it is partially concomitant with the response to lipid peroxidation. Moreover, the association between protein aggregation and non-apoptotic cell death by lipid peroxidation is attracting attention. The link between lipid peroxidation and protein aggregation is a matter of concern in biomedical fields. Here, we focus on lethal protein aggregation in non-apoptotic cell death via lipid peroxidation. We reviewed the roles of protein aggregation in the initiation and execution of non-apoptotic cell death. We also considered the relationship between protein aggregation and oxidized lipid production. We provide an overview of non-apoptotic cell death with a focus on lipid peroxidation for therapeutic targeting during protein aggregation diseases.

Banun V.J., Rewatkar P., Chaudhary Z., Qu Z., Janjua T., Patil A., Wu Y., Ta H.T., Bansal N., Miles J.A., Ross B.P., Kumeria T., Popat A.

Coenzyme-Q10 (CoQ10) is a hydrophobic benzoquinone with antioxidant and anti-inflammatory properties. It is known to reduce oxidative stress in various health conditions. However, due to the low solubility, permeability, stability, and poor oral bioavailability, the oral dose of CoQ10 required for the desired therapeutic effect is very high. In the present study, CoQ10 is encapsulated into two milk derived proteins β-lactoglobulin and lactoferrin (BLG and LF) to produce self-assembled nanostructures of around 100-300 nm with high encapsulation efficiency (5-10% w/w). Both CoQ10-BLG and CoQ10-LF nanoparticles (NPs) significantly improved the aqueous solubility of CoQ10 60-fold and 300-fold, compared to CoQ10 alone, which hardly dissolves in water. Insight into the difference in solubility enhancement between BLG and LF was obtained using in silico modeling, which predicted that LF possesses multiple prospective CoQ10 binding sites, potentially enabling greater loading of CoQ10 on LF compared to BLG, which was predicted to be less capable of binding CoQ10. At pH 7.4, CoQ10-LF NPs showed a burst release between 30 min and 2 h then plateaued at 12 h with 30% of the total drug released over 48 h. However, pure CoQ10-BLG and pure CoQ10 had a significantly lower release rate with less than 15% and 8% cumulative release in 48 h, respectively. Most importantly, both BLG and LF NPs significantly improved CoQ10 permeability compared to the pre-dissolved drug across the Caco-2 monolayer with up to 2.5-fold apparent permeability enhancement for CoQ10-LF-further confirming the utility of this nanoencapsulation approach. Finally, in murine macrophage cells (J774A.1), CoQ10-LF NPs displayed significantly higher anti-ROS properties compared to CoQ10 (predissolved in DMSO) without affecting the cell viability. This study paves the way in improving oral bioavailability of poorly soluble drugs and nutraceuticals using milk-based self-assembled nanoparticles.

Jiang Q., Yin J., Chen J., Ma X., Wu M., Liu G., Yao K., Tan B., Yin Y.

Mitochondria are the main organelles that produce adenosine 5 ′ -triphosphate (ATP) and reactive oxygen species (ROS) in eukaryotic cells and meanwhile susceptible to oxidative damage. The irreversible oxidative damage in mitochondria has been implicated in various human diseases. Increasing evidence indicates the therapeutic potential of mitochondria-targeted antioxidants (MTAs) for oxidative damage-associated diseases. In this article, we introduce the advantageous properties of MTAs compared with the conventional (nontargeted) ones, review different mitochondria-targeted delivery systems and antioxidants, and summarize their experimental results for various disease treatments in different animal models and clinical trials. The combined evidence demonstrates that mitochondrial redox homeostasis is a potential target for disease treatment. Meanwhile, the limitations and prospects for exploiting MTAs are discussed, which might pave ways for further trial design and drug development.

Chaiyarit S., Thongboonkerd V.

Mitochondrion is a pivotal intracellular organelle that plays crucial roles in regulation of energy production, oxidative stress, calcium homeostasis and apoptosis. Kidney stone disease (nephrolithiasis/urolithiasis), particularly calcium oxalate (CaOx) (the most common type), has been shown to be associated with oxidative stress and tissue inflammation/injury. Recent evidence has demonstrated the involvement of mitochondrial dysfunction in CaOx crystal retention and aggregation as well as Randall’s plaque formation, all of which are the essential mechanisms for kidney stone formation. This review highlights the important roles of mitochondria in renal cell functions and provides the data obtained from previous investigations of mitochondria related to kidney stone disease. In addition, mechanisms for the involvement of mitochondrial dysfunction in the pathophysiology of kidney stone disease are summarized. Finally, future perspectives on the novel approach to prevent kidney stone formation by mitochondrial preservation are discussed.

Wu H., Fan X., Hu C., Chao Y., Liu C., Chang J., Sen Y.

• Increase of hair regrowth in rank order is P-Mito, PRP and Mito treatments. • Dermal collagen production is increased equivalently in P-Mito and PRP groups. • Only mitochondrial graft significantly increases the thickness of subcutaneous fat. • Pep-1-conjugation facilitates transdermal penetrating of mitochondria in skin. • P-Mito is as effective as PRP in skin anti-aging treatments. The mechanism of hair loss caused by aging is related to mitochondrial dysfunction. Pep-1-mediated mitochondrial transplantation is a potential therapeutic application for mitochondrial disorders, but its efficacy against hair aging remains unknown. This study compared platelet-rich plasma (PRP) therapy with mitochondrial transplantation for hair restoration and examined the related regulation in naturally aging mice. After dorsal hair removal, 100‐week‐old mice received weekly unilateral injections of 200 μg of allogeneic mitochondria-labeled 5-bromo-2′-deoxyuridine with (P-Mito) or without Pep-1 conjugation (Mito) or human PRP with a stamp-type electric injector for 1 month. The contralateral sides were used as corresponding sham controls. Compared with the control and corresponding sham groups, all treatments stimulated hair regrowth, and the effectiveness of P-Mito was equal to that of PRP. However, histology revealed that only P-Mito maintained hair length until day 28 and yielded more anagen follicles with abundant dermal collagen equivalent to that of the PRP group. Mitochondrial transplantation increased the thickness of subcutaneous fat compared with the control and PRP groups, and only P-Mito consistently increased mitochondria in the subcutaneous muscle and mitochondrial DNA copies in the skin layer. Therefore, P-Mito had a higher penetrating capacity than Mito did. Moreover, P-Mito treatment was as effective as PRP treatment in comprehensively reducing the expression of aging-associated gene markers, such as IGF1R and MRPS5, and increasing antiaging Klotho gene expression. This study validated the efficacy of mitochondrial therapy in the restoration of aging-related hair loss and demonstrated the distinct effects of PRP treatment.

Zhunina O.A., Yabbarov N.G., Grechko A.V., Yet S., Sobenin I.A., Orekhov A.N.

Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer's diseases. In this review, the discuss the current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson and Alzheimer's diseases.

López-Lluch G.

Coenzyme Q10 (CoQ10) is an essential lipid present in all cell membranes [...]