Hypoxia differentially regulates muscle oxidative fiber type and metabolism in a HIF-1α-dependent manner

Loss of skeletal muscle oxidative fiber types and mitochondrial capacity is a hallmark of chronic obstructive pulmonary disease and chronic heart failure. Based on in vivo human and animal studies, tissue hypoxia has been hypothesized as determinant, but the direct effect of hypoxia on muscle oxidative phenotype remains to be established. Hence, we determined the effect of hypoxia on in vitro cultured muscle cells, including gene and protein expression levels of mitochondrial components, myosin isoforms (reflecting slow-oxidative versus fast-glycolytic fibers), and the involvement of the regulatory PPAR/PGC-1α pathway. We found that hypoxia inhibits the PPAR/PGC-1α pathway and the expression of mitochondrial components through HIF-1α. However, in contrast to our hypothesis, hypoxia stimulated the expression of slow-oxidative type I myosin via HIF-1α. Collectively, this study shows that hypoxia differentially regulates contractile and metabolic components of muscle oxidative phenotype in a HIF-1α-dependent manner.     

Nitric oxide synthase-1 is enriched in fast-twitch oxidative myofibers

Nitric oxide synthase-1 (NOS-1) is found in high concentrations in skeletal muscles, where its synthesis product nitric oxide (NO) is reported to be involved in a number of processes, including the modulation of the oxidative metabolism of myofibers. Performing immunoblot analysis and quantification of formazan produced by its specific NADPH diaphorase activity, we found NOS-1 to be enriched in rat skeletal muscles with a high proportion of fast-twitch myofibers. Since these myofibers represent a metabolically heterogeneous subpopulation, we extended our investigation to the level of individual myofibers. Using serial sections we combined myosin heavy chain-based fiber-typing with quantitative succinate dehydrogenase histochemistry to determine three groups of fiber-types, comprising fast-oxidative, fast-glycolytic and slow-oxidative myofibers. Image analysis showed that NOS-1 diaphorase activity is significantly enriched in fast-oxidative myofibers compared with fast-glycolytic and slow-oxidative ones. In order to characterize potential biological effects of the fiber-type-specific enrichment of NOS-1, we performed cytochrome oxidase histochemistry in the presence of the NO donors NOC-9 and SNAP. Both NO donors reduced cytochrome oxidase activity in all myofibers investigated with almost identical semi-maximal inhibition rates, although fast-oxidative and slow-oxidative myofibers contained twice as much basal catalytic activity than fast-glycolytic ones. In summary, we suggest that the NOS-1/NO system of skeletal muscles exerts its biological role especially in fast-oxidative myofibers, since these myofibers express more NOS-1 than fast-glycolytic or slow-oxidative ones and also contain the highest concentrations of cytochrome oxidases as potential target molecules of NO.     

Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes

Coenzyme Q10(CoQ10) is a known anti-adipogenic factor. However, the mechanism by which CoQ10 acts is unclear. In this study, we found that CoQ10 increased the phosphorylation of AMP-activated protein kinase (AMPK) in 3T3-L1preadipocytes. CoQ10 induced an increase in cytoplasmic calcium concentrations, which is reflected by increased Fluo-3 intensity under confocal microscopy recording. Either inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) or knock-down CaMKK blocked CoQ10-induced AMPK phosphorylation, suggesting the involvement of calcium in CoQ10-mediated AMPK signaling. CoQ10 also increased the expression of peroxisome proliferator-activated receptor alpha (PPARα) at both the mRNA and protein levels. Knock down of AMPK with siRNA or inhibition of AMPK using an AMPK inhibitor compound C blocked CoQ10-induced expression of PPARα, indicating that AMPK plays a critical role in PPARα induction. In addition, CoQ10 increased fatty acid oxidation in 3T3-L1preadipocytes. The promoter activity of PPARα was increased by CoQ10 in an AMPK-dependent fashion. Moreover, the induction of acyl-CoA oxidase (ACO), a target gene of PPARα, was blocked under the PPARα knock down condition. Furthermore, treatment with CoQ10 blocked differentiation-induced adipogenesis. This blockade was not observed under the PPARα knock-down condition. Collectively, these results demonstrate that CoQ10 induces PPARα expression via the calcium-mediated AMPK signal pathway and suppresses differentiation-induced adipogenesis.     

Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes

Statins, the widely prescribed cholesterol-lowering drugs for the treatment of cardiovascular disease, cause adverse skeletal muscle side effects ranging from fatigue to fatal rhabdomyolysis. The purpose of this study was to determine the effects of simvastatin on mitochondrial respiration, oxidative stress, and cell death in differentiated primary human skeletal muscle cells (i.e., myotubes). Simvastatin induced a dose-dependent decrease in viability of proliferating and differentiating primary human muscle precursor cells, and a similar dose-dependent effect was noted in differentiated myoblasts and myotubes. Additionally, there were decreases in myotube number and size following 48 h of simvastatin treatment (5 μM). In permeabilized myotubes, maximal ADP-stimulated oxygen consumption, supported by palmitoylcarnitine+malate (PCM, complex I and II substrates) and glutamate+malate (GM, complex I substrates), was 32-37% lower (P<0.05) in simvastatin-treated (5 μM) vs control myotubes, providing evidence of impaired respiration at complex I. Mitochondrial superoxide and hydrogen peroxide generation were significantly greater in the simvastatin-treated human skeletal myotube cultures compared to control. In addition, simvastatin markedly increased protein levels of Bax (proapoptotic, +53%) and Bcl-2 (antiapoptotic, +100%, P<0.05), mitochondrial PTP opening (+44%, P<0.05), and TUNEL-positive nuclei in human skeletal myotubes, demonstrating up-regulation of mitochondrial-mediated myonuclear apoptotic mechanisms. These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis in primary human skeletal myotubes, suggesting that mitochondrial dysfunction may underlie human statin-induced myopathy.     

Antioxidant and prooxidant properties of mitochondrial Coenzyme Q

Coenzyme Q is both an essential electron carrier and an important antioxidant in the mitochondrial inner membrane. The reduced form, ubiquinol, decreases lipid peroxidation directly by acting as a chain breaking antioxidant and indirectly by recycling Vitamin E. The ubiquinone formed in preventing oxidative damage is reduced back to ubiquinol by the respiratory chain. As well as preventing lipid peroxidation, Coenzyme Q reacts with other reactive oxygen species, contributing to its effectiveness as an antioxidant. There is growing interest in using Coenzyme Q and related compounds therapeutically because mitochondrial oxidative damage contributes to degenerative diseases. Paradoxically, Coenzyme Q is also involved in superoxide production by the respiratory chain. To help understand how Coenzyme Q contributes to both mitochondrial oxidative damage and antioxidant defences, we have reviewed its antioxidant and prooxidant properties.     

Effects of coenzyme Q10 on the heart ultrastructure and nitric oxide synthase during hyperthyroidism

Coenzyme Q10 is an important component of mitochondrial electron transport chain and antioxidant. Hyperthyroidism manifests hyperdynamic circulation with increased cardiac output, increased heart rate and decreased peripheral resistance. The heart is also under the oxidative stress in the hyperthyroidism. The aim of this study was to examine both how the coenzyme Q10 can affect heart ultrastructure in the hyperthyroidism and how the relationship between nitric oxide synthase (NOS) and heart damage and coenzyme Q10. Swiss Black C57 mice received 5 mg/kg L-thyroxine. Coenzyme Q10 (1.5 mg/kg) and L-thyroxine together was given to second group mice. Coenzyme Q10 and serum physiologic were applied to another two groups, respectively. All treatments were performed daily for 15 days by gavage. Free triiodothyronine and thyroxine were increased in two groups given L-thyroxine; thyroid-stimulating hormone level did not change. Hyperthyroid heart showed an increased endothelial NOS (eNOS) and inducible NOS (iNOS) immunoreactivity in the tissue. Coenzyme Q10 administration decreased these NOS immunoreactivities in the hyperthyroid animals. Cardiomyocytes of the hyperthyroid animals was characterized by abnormal shape and invaginated nuclei, and degenerative giant mitochondria. Desmosome plaques reduced in density. In hyperthyroid mice given coenzyme Q10, the structural disorganization and mitochondrial damage regressed. However, hearts of healthy mice given coenzyme Q10 displayed normal ultrastructure, except for increased mitochondria and some of them were partially damaged. Coenzyme Q10 increased the glycogen in the cardiomyocytes. In conclusion, coenzyme Q10 administration can prevent the ultrastructural disorganization and decrease the iNOS and eNOS increment in the hyperthyroid heart.     

The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder for which available treatments provide symptom relief but do not stop disease progression. Mitochondria, and in particular mitochondrial dynamics, have been postulated as plausible pharmacological targets. Mitochondria-targeted antioxidants have been developed to prevent mitochondrial oxidative damage, and to alter the involvement of reactive oxygen species (ROS) in signaling pathways. In this study, we have dissected the effect of MitoQ, which is produced by covalent attachment of ubiquinone to a triphenylphosphonium lipophilic cation by a ten carbon alkyl chain. MitoQ was tested in an in vitro PD model which involves addition of 6-hydroxydopamine (6-OHDA) to SH-SY5Y cell cultures. At sublethal concentrations of 50 μM, 6-OHDA did not induce increases in protein carbonyl, mitochondrial lipid peroxidation or mitochondrial DNA damage. However, after 3 h of treatment, 6-OHDA disrupts the mitochondrial morphology and activates the machinery of mitochondrial fission, but not fusion. Addition of 6-OHDA did not increase the levels of fission 1, mitofusins 1 and 2 or optic atrophy 1 proteins, but does lead to the translocation of dynamin related protein 1 from the cytosol to the mitochondria. Pre-treatment with MitoQ (50 nM, 30 min) results in the inhibition of the mitochondrial translocation of Drp1. Furthermore, MitoQ also inhibited the translocation of the pro-apoptotic protein Bax to the mitochondria. These findings provide mechanistic evidence for a role for redox events contributing to mitochondrial fission and suggest the potential of mitochondria-targeted therapeutics in diseases that involve mitochondrial fragmentation due to oxidative stress.     

The origin of secondary myotubes in mammalian skeletal muscles: ultrastructural studies

The distribution of secondary myotubes and undifferentiated mononucleated cells (presumed to be myoblasts) within foetal IVth lumbrical muscles of the rat was analyzed with serial section electron microscopy. In all myotube clusters for which the innervation zone was located, every secondary myotube overlapped the end-plate region of the primary myotube. No secondary myotubes were ever demonstrated to occur at a distance from the primary myotube innervation zone. This indicates that new secondary myotubes begin to form only in the innervation zone of the muscle. Some young secondary myotubes made direct contact with a nerve terminal, but we cannot say if this is true for all developing secondary myotubes. Myoblasts were not clustered near the innervation zone, but were uniformly distributed throughout the muscle. Myoblasts were frequently interposed between a primary and a secondary myotube, in equally close proximity to both cell membranes. We conclude that specificity in myoblast-myotube fusion does not depend on restrictions in the physical distribution of myoblasts within the muscle, and therefore must reflect more subtle mechanisms for intercellular recognition.     

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.     

Micronutrient special issue: Coenzyme Q(10) requirements for DNA damage prevention

Coenzyme Q(10) (CoQ(10)) is an essential component for electron transport in the mitochondrial respiratory chain and serves as cofactor in several biological processes. The reduced form of CoQ(10) (ubiquinol, Q(10)H(2)) is an effective antioxidant in biological membranes. During the last years, particular interest has been grown on molecular effects of CoQ(10) supplementation on mechanisms related to DNA damage prevention. This review describes recent advances in our understanding about the impact of CoQ(10) on genomic stability in cells, animals and humans. With regard to several in vitro and in vivo studies, CoQ(10) provides protective effects on several markers of oxidative DNA damage and genomic stability. In comparison to the number of studies reporting preventive effects of CoQ(10) on oxidative stress biomarkers, CoQ(10) intervention studies in humans with a direct focus on markers of DNA damage are limited. Thus, more well-designed studies in healthy and disease populations with long-term follow up results are needed to substantiate the reported beneficial effects of CoQ(10) on prevention of DNA damage.     

Regulation of specific developmental fates of larval- and adult-type muscles during metamorphosis of the frog Xenopus

During anuran metamorphosis, larval-type myotubes in both trunk and tail are removed by apoptosis, and only trunk muscles are replaced by newly formed adult-type myotubes. In the present study, we clarified the regulatory mechanisms for specific developmental fates of adult and larval muscles. Two distinct (adult and larval) types of myoblasts were found to exist in the trunk, but no or very few adult myoblasts were found in the tail. Each type of myoblast responded differently to metamorphic trigger, 3,3',5-triiodo-L-thyronine (T(3)) in vitro. T(3)-induced cell death was observed in larval myoblasts but not in adult myoblasts. These results suggest that the fates (life or death) of trunk and tail muscles are determined primarily by the differential distribution of adult myoblasts within the muscles. However, a transplantation study clarified that each larval and adult myoblast was not committed to fuse into particular myotube types, and they could form heterokaryon myotubes in vivo. Cell culture experiments suggested that the following two mechanisms are involved in the specification of myotube fate: (1) Heterokaryon myotubes could escape T(3)-induced death only when the proportion of adult nuclei number was higher than 70% in the myotubes. Apoptosis was not observed in any larval nuclei within the surviving heterokaryon myotubes, suggesting the conversion of larval nuclei fate. (2) Differentiation of adult myoblasts was promoted by the factor(s) released from larval myoblasts in a cell type-specific manner. Taken together, the developmental fate of myotubes is determined by the ratio of nuclei types, and the formation of adult nuclei-rich myotubes was specifically enhanced by larval myoblast factor(s).     

The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice

A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants.     

Mitochondrial mass is inversely correlated to complete lipid oxidation in human myotubes

Exercise increases while physical inactivity decrease mitochondrial content and oxidative capacity of skeletal muscles in vivo. It is unknown whether mitochondrial mass and substrate oxidation are related in non-contracting skeletal muscle. Mitochondrial mass, ATP, ADP, AMP, glucose and lipid oxidation (complete and incomplete) were determined in non-contracting myotubes established from 10 lean, 10 obese and 10 subjects with type 2 diabetes precultured under normophysiological conditions. ATP, ADP, AMP, mitochondrial mass and energy charge were not different between groups. In diabetic myotubes, basal glucose oxidation and incomplete lipid oxidation were significantly increased while complete lipid oxidation was lower. Mitochondrial mass was not correlated to glucose oxidation or incomplete lipid oxidation in human myotubes but inversely correlated to complete lipid oxidation. Thus within a stable energetic background, an increased mitochondrial mass in human myotubes was not positive correlated to an increased substrate oxidation as expected from skeletal muscles in vivo but surprisingly with a reduced complete lipid oxidation.     

Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools

Antioxidants, such as ubiquinones, are widely used in mitochondrial studies as both potential therapies and useful research tools. However, the effects of exogenous ubiquinones can be difficult to interpret because they can also be pro-oxidants or electron carriers that facilitate respiration. Recently we developed a mitochondria-targeted ubiquinone (MitoQ10) that accumulates within mitochondria. MitoQ10 has been used to prevent mitochondrial oxidative damage and to infer the involvement of mitochondrial reactive oxygen species in signaling pathways. However, uncertainties remain about the mitochondrial reduction of MitoQ10, its oxidation by the respiratory chain, and its pro-oxidant potential. Therefore, we compared MitoQ analogs of varying alkyl chain lengths (MitoQn, n = 3-15) with untargeted exogenous ubiquinones. We found that MitoQ10 could not restore respiration in ubiquinone-deficient mitochondria because oxidation of MitoQ analogs by complex III was minimal. Complex II and glycerol 3-phosphate dehydrogenase reduced MitoQ analogs, and the rate depended on chain length. Because of its rapid reduction and negligible oxidation, MitoQ10 is a more effective antioxidant against lipid peroxidation, peroxynitrite and superoxide. Paradoxically, exogenous ubiquinols also autoxidize to generate superoxide, but this requires their deprotonation in the aqueous phase. Consequently, in the presence of phospholipid bilayers, the rate of autoxidation is proportional to ubiquinol hydrophilicity. Superoxide production by MitoQ10 was insufficient to damage aconitase but did lead to hydrogen peroxide production and nitric oxide consumption, both of which may affect cell signaling pathways. Our results comprehensively describe the interaction of exogenous ubiquinones with mitochondria and have implications for their rational design and use as therapies and as research tools to probe mitochondrial function.     

Inhibition of complex I of the electron transport chain causes O2-. -mediated mitochondrial outgrowth

Recent evidence indicates that oxidative stress is central to the pathogenesis of a wide variety of degenerative diseases, aging, and cancer. Oxidative stress occurs when the delicate balance between production and detoxification of reactive oxygen species is disturbed. Mammalian cells respond to this condition in several ways, among which is a change in mitochondrial morphology. In the present study, we have used rotenone, an inhibitor of complex I of the respiratory chain, which is thought to increase mitochondrial O(2)(-)* production, and mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to investigate the relationship between mitochondrial O(2)(-)* production and morphology in human skin fibroblasts. Video-rate confocal microscopy of cells pulse loaded with the mitochondria-specific cation rhodamine 123, followed by automated analysis of mitochondrial morphology, revealed that chronic rotenone treatment (100 nM, 72 h) significantly increased mitochondrial length and branching without changing the number of mitochondria per cell. In addition, this treatment caused a twofold increase in lipid peroxidation as determined with C11-BODIPY(581/591). Finally, digital imaging microscopy of cells loaded with hydroethidine, which is oxidized by O(2)(-)* to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a twofold increase in the rate of O(2)(-)* production. MitoQ (10 nM, 72 h) did not interfere with rotenone-induced ethidium formation but abolished rotenone-induced outgrowth and lipid peroxidation. These findings show that increased mitochondrial O(2)(-)* production as a consequence of, for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this O(2)(-)* to prevent alterations in mitochondrial morphology.     

Changes of plasma coenzyme Q10 levels in early infancy

Rapid perfusion of oxygen in infants at birth may increase oxidative stress which has been incriminated in serious diseases including neonatal respiratory distress syndrome, chronic lung disease, and retinopathy of prematurity. Elucidating the antioxidant defense systems of neonates in clinical practice is important. Coenzyme Q(10) is a widely distributed, redox-active quinoid compound originally discovered as an essential part of the mitochondrial respiratory chain in mammals. Although coenzyme Q(10) is a powerful lipid antioxidant in vivo, few data pertain to plasma CoQ(10) levels in infants. This is the first paper to report plasma coenzyme Q(10) levels in preterm infants.     

Neural determination of muscle fibre numbers in embryonic rat lumbrical muscles

The generation and development of muscle cells in the IVth hindlimb lumbrical muscle of the rat was studied following total or partial denervation. Denervation was carried out by injection of beta-bungarotoxin (beta-BTX), a neurotoxin which binds to and destroys peripheral nerves. Primary myotubes were generated in denervated muscles and reached their normal stable number on embryonic day 17 (E17). This number was not maintained and denervated muscles examined on E19 or E21 contained many degenerating primary myotubes. Embryos injected with beta-bungarotoxin (beta-BTX) on E12 or E13 suffered a partial loss of motoneurones, resulting in a reduced number of axons in the L4 ventral root (the IVth lumbrical muscle is supplied by axons in L4, L5 and L6 ventral roots) and reduced numbers of nerve terminals in the intrinsic muscles of the hindfoot. Twitch tension measurements showed that all myotubes in partly innervated muscles examined on E21 contracted in response to nerve stimulation. Primary myotubes were formed and maintained at normal numbers in muscles with innervation reduced throughout development, but a diminished number of secondary myotubes formed by E21. The latter was correlated with a reduction in number of mononucleate cells within the muscles. If beta-BTX was injected on E18 to denervate muscles after primary myotube formation was complete, E21 embryo muscles contained degenerating primary myotubes. After injection to denervate muscles on E19, the day secondary myotubes begin to form, E21 muscles possessed normal numbers of primary myotubes. In both cases, secondary myotube formation had stopped about 1 day after the injection and the number of mononucleate cells was greatly reduced, indicating that cessation of secondary myotube generation was most probably due to exhaustion of the supply of competent myoblasts. We conclude that nerve terminals regulate the number of secondary myotubes by stimulating mitosis in a nerve-dependent population of myoblasts and that activation of these myoblasts requires the physical presence of nerve terminals as well as activation of contraction in primary myotubes.     

The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.