Current Drug Targets, 2010, 11, 111-121 111
1389-4501/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders
M. Mancuso*, D. Orsucci, L. Volpi, V. Calsolaro and G. Siciliano
Department of Neuroscience, Neurological Clinic, University of Pisa, Italy
Abstract: Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron
transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and
cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by
causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a
number of neuromuscular and neurodegenerative disorders.
Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical
awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor
(statins) treatment has been implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy.
CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular
disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson’s disease,
Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, and other conditions which have been linked to
This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10
supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative
disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.
Keywords: Coenzyme Q10, CoQ10 deficiency, idebenone, mitochondria, mitochondrial diseases, neurodegeneration, statins.
Coenzyme Q10 (CoQ10), or ubiquinone, is an endo-
genously synthesized lipid, which shuttles electrons from
complexes I (NDSH: Ubiquinone reductase) and II (succi-
nate: ubiquinone reductase) and from the oxidation of fatty
acids and branched-chain aminoacids (via flavin-linked
dehydrogenases) to complex III (ubiquinol cytochrome c
oxidase) of the mitochondrial respiratory chain (electron
transport chain, ETC)  (Fig. 1). The reduced form of
CoQ10 known as ubiquinol also has antioxidant properties,
protecting membrane lipids and proteins and mitochondrial
deoxyribonucleic acid (mtDNA) against oxidative damage
Intracellular synthesis is the major source of CoQ10,
although a small proportion is acquired through diet (i.e. oily
fish, organ meats such as liver, and whole grains). CoQ10
biosynthesis depends on the mevalonate pathway (Fig. 2), a
sequence of cellular reactions leading to farnesyl pyrophos-
phate, the common substrate for the synthesis of cholesterol,
dolichol, dolichyl posphate, CoQ10, and for protein prenyla-
tion (a post-translational modification necessary for the
targeting and function of many proteins) . Cells synthesize
CoQ10 de novo, starting with synthesis of the parahydroxy-
benzoate ring and the polyisoprenyl tail, which anchors
CoQ10 to membranes  (Fig. 3). The length of this tail
varies among different organisms. In humans, the side chain
is comprised of ten isoprenyls producing CoQ10 .
*Address correspondence to this author at the Department of Neuroscience,
Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy;
Tel: 0039-050-992440; Fax: 0039-050-554808;
been reported to improve subjective fatigue sensation and
physical performance during fatigue-inducing workload
CoQ10 has been widely used for the treatment of
mitochondrial disorders (MD) and other neurodegenerative
disorders, as well as its synthetic analogue, idebenone .
Potential treatment indications for the use of CoQ10 include
migraine [4, 5], chronic tinnitus aurium , hypertension ,
heart failure and atherosclerosis , although the role of
CoQ10 in such conditions is still an open question. CoQ10,
which may ameliorate endothelial dysfunction , is an
independent predictor of mortality in chronic heart failure,
and there is a rationale for controlled intervention studies
with CoQ10 in such condition [9, 10]. Although CoQ10 is
also used for the prevention and treatment of cancer, there is
as yet no convincing evidence of its efficacy treatment of
this order .
No absolute contraindications are known for CoQ10, and
adverse effects are rare . Mild dose-related gastrointes-
tinal discomfort is reported in <1% of patients . Potential
interactions with warfarin causing decreased international
normalized ratio (INR) have been suggested . Its various
formulations demonstrate variation in bioavailability and
dosage consistency, and there is a serious possibility that
patients may have been treated suboptimally . It is
important to use brands that have passed independent testing
for product purity and consistency . During CoQ10
supplementation plasma CoQ10 levels should be monitored
to ensure efficacy, given that there is variable bioavailability
between commercial formulations, and known inter-
individual variation in CoQ10 absorption . However,
plasma levels may not reflect that of the cell and other
In healthy individuals, oral administration of CoQ10 has
112 Current Drug Targets, 2010, Vol. 11, No. 1 Mancuso et al.
surrogates such as blood mononuclear cells may be more
Mitochondria are dynamic and pleomorphic organelles,
which evolved from the aerobic bacteria which about 1.5
billion years ago populated primordial eukaryotic cells, thus
endowing the host cells with oxidative metabolism (much
more efficient than anaerobic glycolysis) . Mitochondria
are composed of a smooth outer membrane surrounding an
inner membrane of significantly larger surface area that, in
turn, surrounds a protein-rich core, the matrix . They
contain two to ten molecules of mtDNA . In humans, the
mtDNA is transmitted through maternal lineage .
The most crucial task of the mitochondrion is the gene-
ration of energy as adenosine triphosphate (ATP), by means
of the ETC. The ETC is required for oxidative phos-
phorylation (which provides the cell with the most efficient
energetic outcome in terms of ATP production), and consists
of four multimeric protein complexes located in the inner
mitochondrial membrane . The ETC also requires the
mobile electron carriers, cytochrome c (cyt c) and CoQ10.
Electrons are transported along the complexes to molecular
oxygen (O2), finally producing water . At the same time,
protons are pumped across the mitochondrial inner mem-
brane, from the matrix to the intermembrane space, by comp-
lexes I, III, and IV. This process creates an electrochemical
proton gradient. ATP is produced by the influx of protons
back through the complex V, or ATP synthase (the “rotary
motor”) . This metabolic pathway is under control of
both nuclear (nDNA) and mitochondrial genomes . The
human mtDNA encodes information for mitochondrial
transfer RNAs (tRNAs), for ribosomal RNAs (rRNAs), and
for 13 subunits of the ETC . The remainder of the
mitochondrial proteins are encoded by nDNA .
Mitochondria also play a central role in apoptotic cell
death [see Fig. (1)] , and mitochondrial dysfunction
appears to have a certain impact on the pathogenesis of
several neurodegenerative diseases, such as amyotrophic
lateral sclerosis (ALS), Azheimer’s (AD) and Parkinson’s
disease (PD) . Oxidative stress is an earlier event
associated with mitochondrial dysfunction . The
transport of high-energy electrons through the mitochondrial
ETC is a necessary step for ATP production, but it is also
source of reactive oxygen species (ROS) production. The
Fig. (1). Mitochondrial metabolism. Schematic representation of mitochondrial biochemical pathways, representing relationship between
energy production (TCA and electron transport chain), reactive oxygen species production (superoxide O2˙?, hydroxyl radical OH˙),
apoptosis regulation. Electron transport chain complexes: I (NADH:ubiquinone reductase), II (succinate:ubiquinone reductase), III
(ubiquinone-cyt c oxidoreductase), IV (cytochrome c oxidase), F0V (ATP synthase). ADP, adenosine 5'-diphosphate; ATP, adenosine 5'-
triphosphate; AIF, apoptosis inducing factor; ANT, adenine nucleotide transporter; CAD, caspase-activated DNase; CytC, cytochrome c;
GPX, glutathione peroxidase; LDH, lactic dehydrogenase; MnSOD, manganese superoxide dismutase; NAD+/NADH, oxidized/reduced
nicotinamide adenine dinucleotide; OAA, oxalacetic acid; PDH, pyruvate dehydrogenase; Pi, inorganic phosphorus; TCA, tricarboxylic acid
cycle; VDAC, voltage-dependent anion channel. From MITOMAP: A Human Mitochondrial Genome Database, allowed reproduction
Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders Current Drug Targets, 2010, Vol. 11, No. 1 113
sites for ROS production in mitochondrial ETC are normally
ascribed to the activity of complexes I and III  [see Fig.
(1)]. At complexes I and III of the ETC, the high -energy
electrons can react with O2 to form superoxide (O2˙?) .
CoQ10 has also been reported to be a source of O2˙? radical
generation . Up to 4-5% of the O2 consumed by healthy
mitochondria is thought to be converted into O2˙?, and this
amount is higher in damaged and aged mitochondria .
When the respiratory system is inhibited, electrons
accumulate in the early stages of the ETC (complex I and
Fig. (2). A schematic representation of the mevalonate pathway, the sequence of cellular reactions that leads to farnesyl-PP. Farnesyl-
PP is the common substrate for the synthesis of cholesterol, dolichol, and Coenzyme Q10, as well as for prenylation of proteins. Coenzyme
Q10 contains also a benzoate ring originating from tyrosine. HMG-CoA reductase inhibitors, or statins, block production of mevalonate, a
critical intermediary in the cholesterol synthesis pathway. A hypothesized mechanism of statin myopathy involve mitochondrial dysfunction
caused by reduced intramuscular coenzyme Q10. HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; PP, pyrophosphate.
Fig. (3). Coenzyme Q10 biosynthesis. After 4-OH-benzoate and decaprenyl-PP [see Fig. (1)] are produced, at least seven enzymes (encoded
by COQ2-8 genes) catalyze condensation, methylation, decarboxylation, and hydroxylation reactions needed to synthesize Coenzyme Q10.
Abnormalities in any part of the metabolic cascade will cause primary CoQ10 deficiency. From Mancuso M. et al., Lett Drug Des Discov,
2006:3;378-82 (© 2006 Bentham Science Publishers Ltd.).
114 Current Drug Targets, 2010, Vol. 11, No. 1 Mancuso et al.
CoQ10), where they are donated directly to O2 to produce
O2˙?  [see Fig. (1)]. Conversely, the ETC is not univer-
sally accepted as the major site for mitochondrial ROS
generation . Studies have indicated that monoamine
oxidases and p66(Shc), may contribute to the preponderance of
mitochondrial ROS generation .
The accumulation of ROS can potentially damage bio-
molecules, including lipids, proteins and nucleic acids .
The accumulation of nDNA and mtDNA oxidative damage
is thought to be deleterious in post-mitotic cells such as
neurons, where DNA cannot be replaced through a cellu-lar
division mechanism . Indeed, oxidative base modifi-
cations to mtDNA could potentially cause bioenergetic dys-
functions resulting in cell death . The cells possess an
intricate network of defence mechanisms (mitochondrial
manganese superoxide dismutase, glutathione peroxidase
and other molecules) to neutralize excessive accumulation of
ROS and, under physiological conditions, are able to cope
with the flux of ROS . Oxidative stress describes a con-
dition in which cellular antioxidant defences are insufficient
to keep the levels of ROS below a toxic threshold .
The mtDNA is particularly sensitive to oxidative damage
because of its proximity to the inner mitochondrial mem-
brane, where oxidants are formed, and because it is not
protected by histones and is inefficiently repaired .
Because several of the mtDNA genes encode for subunits of
the mitochondrial ETC, oxidative mtDNA damage, if not
correctly repaired, could result in mutations and deletions in
these genes which may therefore result in defective ETC
complex enzymes being encoded. This may then result in
mitochondrial dysfunction, increased production of ROS,
and cellular death .
IN VITRO TESTS AND ANIMAL STUDIES
Several studies have investigated the role of CoQ10 as a
neuroprotective agent versus ROS damage and apoptotic cell
death. CoQ10 may act by stabilizing the mitochondrial mem-
brane when neuronal cells are subjected to oxidative stress
. Pre-treatment with water-soluble CoQ10 maintained
mitochondrial membrane potential during oxidative stress
and reduced the amount of mitochondrial ROS generation
. The evidence of mitochondrial involvement in neuro-
degenerative diseases  allowed the hypothesis that
CoQ10 may have a protective role in such diseases. Complex
I dysfunction has been implicated in the pathogenesis of PD
. Rotenone, an insecticide which is a specific inhibitor of
complex I, produced selective damage in the striatum and the
globus pallidus, but the substantia nigra was spared .
Winkler-Stuck and co-workers  observed that the activity
of ETC complexes, which were impaired in skin fibroblasts
from a subgroup of PD patients, was restored after culti-
vation in the presence of 5 ?M CoQ10. The neuroprotective
role of CoQ10 has been also studied in other cellular models
of PD, such as iron-induced apoptosis in cultured human
dopaminergic neurons . Iron-induced damage is media-
ted by ROS production and apoptosis activation; CoQ10
attenuated such iron-induced cellular damage . Recently,
CoQ10 has been found to be effective in a PD mouse model
of MPTP toxicity, reversing dopamine depletion, loss of
tyrosine hydroxylase neurons and induction of alpha-
synuclein inclusions in the substantia nigra pars compacta
. However, the positive effect of CoQ10 on PD patients
has not been clearly demonstrated in clinical trials (see
“Coenzyme Q10 and neurodegenerative disorders”).
Increasing evidence suggests that AD is associated with
oxidative damage and mitochondrial dysfunction [14, 24].
Exogenous CoQ10 was found to protect neuroblastoma cells
from ?-amyloid neurotoxic effect; dietary supplementation
of CoQ10 to AD mice suppressed brain protein carbonyl
levels, which are markers of oxidative damage . This
suggests that oral CoQ10 may be a viable antioxidant
strategy for neurodegenerative disease . The efficacy of
CoQ10 treatment against ?-amyloid induced mitochondrial
dysfunction has been evaluated also in brains of diabetic rats,
where CoQ10 treatment was found to attenuate the decrease
in oxidative phosphorylation and avoided the increase in
hydrogen peroxide production induced by the neurotoxic
peptide . An in vivo volume MRI study on mice with
mutation in the amyloid precursor protein showed that
CoQ10 significantly delayed hemispheric and hippocampal
atrophy . Furthermore, the efficacy of CoQ10 as a
neuroprotective factor against cognitive impairment has been
evaluated in mice with reduced cognitive performance .
In aged mice CoQ10, combined with alpha-tocopherol, could
have a role in improving learning .
In a mouse model of Huntington’s Disease (HD) in vivo
phosphorus magnetic resonance spectroscopy (31P-MRS)
has been used in order to evaluate the antioxidant effect of
CoQ10 and vitamin E on the activity of creatine kinase (CK),
a sensitive indicator of brain energy metabolism dysfunction
. The results showed that CoQ10 and vitamin E
prevented the increase of CK and the decrease of CoQ10
content in brain tissue, but were ineffective to prevent the
decline of ETC function . Smith and co-workers 
reported a dose dependent therapeutic benefit when CoQ10
was administered to the mouse model of HD, improving
motor performance, grip strength, reducing weight loss,
brain atrophy and huntingtin inclusions . Combined
minocycline (an antibiotic
neuroprotective properties ) and CoQ10 therapy in a
mouse model of HD ameliorated behavioral and neuropatho-
logical alterations, reduced gross brain atrophy, striatal
neuron atrophy, and huntingtin aggregation, and significantly
extended survival and improved motor performance to a
greater degree than either minocycline or CoQ10 alone .
The antioxidant function of CoQ10 has been also studied
in noise-induced hearing loss (NIHL) [33, 34]. The adminis-
tration of a water-soluble CoQ10 formulation to a guinea pig
model of acoustic trauma prevented apoptosis and improved
with anti-apoptotic and
COENZYME Q10 PRIMARY DEFICIENCY
There is a strong rationale for using CoQ10 supplemen-
tation to treat patients with primary CoQ10 deficiency [35,
Primary CoQ10 deficiency is an uncommon heteroge-
neous condition which has been associated with five major
known syndromes: (i) encephalomyopathy (with recurrent
Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders Current Drug Targets, 2010, Vol. 11, No. 1 115
myoglobinuria, brain involvement and ragged red fibers); (ii)
severe infantile multisystemic disease; (iii) cerebellar ataxia;
(iv) Leigh syndrome (growth retardation, ataxia and deaf-
ness); (v) isolated myopathy . Primary CoQ10 defi-
ciencies due to mutations in ubiquinone biosynthetic genes
(i.e. COQ2, PDSS1, PDSS2, CABC1) have been identified in
patients with the infantile multisystemic and cerebellar ataxic
phenotypes . In contrast, secondary CoQ10 deficiencies,
due to mutations in genes not directly related to ubiquinone
biosynthesis (i.e. APTX, ETFDH, BRAF) [36, 37], have been
identified in patients with cerebellar ataxia, pure myopathy,
and cardiofaciocutaneous syndrome .
The myopathic form of CoQ10 deficiency is potentially
treatable (see below). The only current available CoQ10
deficiency treatments is CoQ10 supplementation. Therefore,
a correct and timely diagnosis is crucial.
A 26-year-old man came to our attention for mildly
increased blood CK levels (ranging from 300 to 500 U/L
[normal <180]), exercise intolerance and two episodes of
myoglobinuria. There was no family history of neurological
or muscular disorders. Motor and intellectual milestones
were regular. At physical examination, there was not mus-
cular weakness. Blood lactate levels at rest and during
exercise were normal, as well as electromyography and
nerve conduction studies. 31P-MRS muscular metabolic
profile was similar to normal subjects. Muscular biopsy
showed mild myopathic signs. Cytochrome c oxidase (COX)
staining showed isolated hyporeactive fibers, with peripheral
rims, but not clear signs of mitochondrial dysfunction (COX-
deficient fibers). SDH (succinate dehydrogenase, ETC
complex II) and NADH staining were also present with rare
peripheral rims. Muscle immunohistochemistry for dystro-
phine, dysferlin, alfa-sarcoglycan, laminine and emerine was
normal. DNA analysis for dystrophin gene was negative. The
mitochondrial ETC activities in muscle were also normal.
CoQ10 concentration was determined in a skeletal muscle
specimen by a high-performance liquid chromatography
method with ultraviolet detection (275 nm), using the
Coenzyme Q10 Kit (Chromsystems) . On analysis the
patients skeletal muscle was found to have a CoQ10 level
54% of the reference mean value. Therefore, the patient
started substitutive therapy at an initial dose of 50 mg x
3/day, gradually increased up to 500 mg x 3/day, with a
dramatic improvement of the exercise intolerance. CK levels
remained mildly increased, but no further episodes of
myoglobinuria have so far been reported.
The myopathic form of CoQ10 deficiency is a rare
disease characterized by subacute (3-6 months) onset of
exercise intolerance and proximal limb weakness without
central nervous system involvement, increased serum lactate
and CK levels. Frequently it is associated with lipid droplets
with subtle signs of mitochondrial dysfunction at skeletal
muscle level, and reduced complexes I+III (NADH:
cytochrome c reductase) and II+III (Succinate: cytochrome c
reductase) activities (both complexes I+III and II+III rely on
endogenous CoQ10 for activity), and good clinical response
to CoQ10 supplementation [35, 38]. Our patient did not
present biochemical mitochondrial ETC defects, nor lipid
storage, but clinically improved after a period of oral CoQ10
intake. CoQ10 deficiency is an autosomal recessive mito-
chondrial disorder but a dominant effect cannot be discarded.
Infantile mitochondrial encephalomyopathy has been asso-
ciated to mutations in the first and second subunits of
decaprenyl diphosphate synthase (PDSS1 and PDSS2), in the
mevalonate pathway [39, 40]. Mutations in PDSS1 seem to
lead to a milder phenotype than mutations in PDSS2 in the
limited number of patients assessed. Patients with mutations
in para-hydroxybenzoate-polyprenyl transferase (COQ2), a
component of the CoQ10 biosynthesis complex that modifies
the ring, share early-onset nephrosis and encephalophaty [40,
41]. A myopathic form of CoQ10 deficiency has been
reported to occur as the result of a mutation in the electron-
transferring-flavoprotein dehydrogenase (ETFDH) gene .
ETFDH is also linked to another metabolic disorder, glutaric
aciduria type II (GAII) . Myopathic CoQ10 deficiency
with pathogenic ETFDH mutations and late-onset GAII
probably are the same disease . As CoQ10 is the direct
acceptor of electrons from the electron-transferring-flavo-
protein, the lack of the reducing enzyme may downregulate
the synthesis of CoQ10 . Alternatively, faulty binding of
the enzyme to CoQ10 could result in excessive degradation
of the acceptor molecule . Since CoQ10 deficiency/late-
onset GAII is treatable, the diagnosis should be considered
both in children and in adults with high-serum CK, proximal
myopathy (with or without hepatopathy or encephalopathy),
multiple acyl-CoA deficiency, lipid storage myopathy and
decreased activity of ETC complexes I, II + III and IV .
It has been suggested that patients should be treated with
both CoQ10 and riboflavin .
Interestingly, some cases of the ataxic variant of CoQ10
deficiency have been linked to a homozygous mutation in the
aprataxin (APTX) gene, which causes ataxia oculomotor
apraxia type 1 [42, 43]. The relationship beetween this
protein, involved in DNA repair, and CoQ10 homeostasis is
still unclear [42, 43]. CoQ10 deficiency with cerebellar
ataxia has been associated to mutation in CABC1/COQ8
gene  which encodes the Abc1 protein kinase ADCK3
. Very recently, a patient with primary CoQ10 deficiency
whose clinical history started with neonatal lactic acidosis
and who later developed multisytem disease including
intractable seizures, global developmental delay, hypertro-
phic cardiomyopathy, and renal tubular dysfunction was
reported to harbour a homozygous stop mutation affecting a
highly conserved residue of COQ9 gene, leading to the
truncation of 75 amino acids .
CoQ10 deficiency is a treatable condition, so a high
grade of “clinical suspicion” about this diagnosis is essential,
especially for paediatricians and infantile neurologists. An
early treatment with high-dose CoQ10 might radically
change the natural history of this group of diseases [35, 47,
48]. Patients with all forms of CoQ10 deficiency have shown
clinical improvement with oral CoQ10 supplementation, but
cerebral symptoms are only partially ameliorated (probably
because of irreversible structural brain damage before
treatment and because of poor penetration of CoQ10 across
the blood-brain barrier) . Patients were given various
doses of CoQ10 ranging from 90 to 2000 mg daily. The
small number of patients precluded any statistical analysis
but improvement was undoubtedly reported [35, 49]. In
several patients CoQ10 supplementation also ameliorated the
mitochondrial function (ETC activities, lactic acid values,
116 Current Drug Targets, 2010, Vol. 11, No. 1 Mancuso et al.
muscle CoQ10 content) . The beneficial effects of exo-
genous CoQ10 require high doses and long-term adminis-
tration. Also patients with ataxia oculomotor apraxia type 1
may benefit from this treatment .
ROLE OF COQ10 IN OTHER MITOCHONDRIAL
MD are commonly defined as a group of disorders
caused by impairment of the mitochondrial ETC , which
does not include other defects of mitochondrial metabolism
such as pyruvate dehydrogenase deficiency, carnitine
deficiency or fatty acid oxidation defects. The effects of
mutations which affect the ETC may be multisystemic, with
involvement of visual and auditory pathways, heart, central
nervous system, and skeletal muscle . The estimated
prevalence of MD is 1-2 in 10000 . MD are, therefore,
one of the commonest inherited neuromuscular disorders.
The genetic classification of MD distinguishes disorders
due to defects in mtDNA from those due to defects in nDNA
 (Table 1). The first ones are inherited according to the
rules of mitochondrial genetics (maternal inheritance,
heteroplasmy and the threshold effect, mitotic segregation)
. Each cell contains multiple copies of mtDNA
(polyplasmy), which in normal individuals are identical to
one another (homoplasmy) . Heteroplasmy refers to the
coexistence of two populations of mtDNA, normal and
mutated. Mutated mtDNA in a given tissue have to reach a
minimum critical number before oxidative metabolism is
impaired severely enough to cause dysfunction (threshold
effect) . Differences in mutational loads surpassing the
pathogenic threshold in some tissues but not in others may
contribute to the heterogeneity of phenotypes. Because of the
mitotic segregation, the mutation load can change from one
cell generation to the next and, with time, it can either
surpass or fall below the pathogenic threshold . Further,
the pathogenic threshold varies from tissue to tissue
according to the relative dependence of each tissue on
oxidative metabolism . For instance, central nervous
system, skeletal muscle, heart, endocrine glands, the retina,
the renal tubule and the auditory sensory cells are highly
dependent on oxidative metabolism for energy generation.
MD related to nDNA are caused by mutations in
structural components or ancillary proteins of the ETC, by
Table 1. Genetic Classification of Well Characterized Mitochondrial Diseases (MD). ETC, Electron Transport Chain; MELAS,
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes; MERRF, Myoclonic Epilepsy with
Ragged red Fibers; MNGIE, Mitochondrial Neurogastrointestinal Encephalomyopathy; MLASA, Mitochondrial Myopathy
and Sideroblastic Anemia; NARP, Neuropathy, Ataxia, Retinitis Pigmentosa; PEO, Progressive external Ophthalmoplegia
Disorders of mitochondrial genome MD caused by nuclear gene defects
Kearns-Sayre syndrome (KSS)
Diabetes and deafness
Sporadic point mutations
Maternal-inherited mtDNA point mutations
Genes encoding structural proteins
Leber hereditary optic neuropathy (LHON)
Maternal-inherited Leigh syndrome
Genes encoding tRNAs
Cardiomyopathy and myopathy (MIMyCa)
Diabetes and deafness
Sensorineural hearing loss
Genes encoding rRNAs
Defects of genes encoding for structural proteins of the complexes of
Cardiomyopathy hypertrophic, histiocitoide
Defects of genes encoding factors involved in the assembling complexes
of ETC (“Assembly genes”)
Defects of genes altering mtDNA stability and integrity (intergenomic
mtDNA depletion syndromes
Coenzyme Q10 deficiency
Cerebellar form coq2, coq8
Myopathic form etfdh
Infantile multisystemic disease pdss1, coq2
Leigh syndrome pdss2
Defects of the lipid milieu
Syndromes due to defects of mitochondrial ribonucleic acid
Defects of mitochondrial fission or fusion
Autosomal dominant optic atrophy (ADOA) Charcot-Marie-Tooth (CMT)
Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders Current Drug Targets, 2010, Vol. 11, No. 1 117
defects of the membrane lipid milieu, of CoQ10 biosynthetic
genes (see “Coenzyme Q10 primary deficiency”) and by
defects in intergenomic signalling (associated to mtDNA
depletion or multiple deletions) . Moreover, the occur-
rence of a single large-scale deletion, common cause of
progressive external ophthalmoplegia (PEO), is almost
In MD patient muscle homogenates, significantly posi-
tive correlation was observed between complexes I + III and
II + III activities with CoQ10 concentration . Recently,
CoQ10 content and ETC enzyme analysis were determined
in muscle biopsy specimens of 82 children with suspected
mitochondrial myopathy . Muscle total, oxidized, and
reduced CoQ10 concentrations were significantly decreased
in the probable defect group . Total muscle CoQ10 was
the best predictor of an ETC complex abnormality .
Determination of muscle CoQ10 deficiency in children with
suspected MD may facilitate diagnosis and encourage earlier
supplementation of this agent .
Therapy of MD is still inadequate, despite great progress
in the molecular understanding of these disorders . Apart
from symptomatic therapy, administration of metabolites and
cofactors, including CoQ10, as well as of ROS scavengers, is
the mainstay of real-life therapy. On the other hand, there is
currently no clear evidence supporting the use of any
intervention in MD , and further research is needed.
There have been very few randomised controlled clinical
trials for the treatment of MD. Those that have been
performed were short, and involved fewer than 20 study
participants with heterogeneous phenotypes .
The multitude of generally positive anecdotal data
together with the lack of negative side effects has contributed
to the widespread use of CoQ10 in MD [54, 55]. In studies
with eight to 44 patients CoQ10 seemed to demonstrate
positive trends in mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like syndrome (MELAS), Kearns-Sayre
syndrome (KSS), and myoclonus epilepsy with ragged red
fibers (MERRF) . Chen and co-workers  performed a
randomised, double-blind cross-over trial on eight MD
patients. Both subjective and objective measures showed a
trend towards improvement on treatment, but the global
Medical Research Council (MRC) index score of muscular
strength was the only measure reaching statistical signifi-
cance . However, there is a need for controlled trials in
large cohorts of patients .
Recently, Rodriguez and co-workers  studied the
effect of a combination therapy (creatine, CoQ10, and lipoic
acid) on several outcome variables using a randomized,
double-blind, placebo-controlled, crossover study design in
seventeen patients with various MD. Lipoic acid is found
naturally within the mitochondria and is an essential cofactor
for pyruvate dehydrogenase and ?-ketoglutarate dehydro-
genase, and is also a potent antioxidant . Such combi-
nation therapy resulted in lower resting plasma lactate and a
lowering of oxidative stress as reflected by a significant
reduction in urinary 8-isoprostanes and a directional trend in
8-hydroxy-2’-deoxyguanosine (8-OHdG) excretion .
Isoprostanes are prostaglandin-like compounds formed by
the peroxidation of arachadonic acid, and are considered one
of the most reliable markers to assess oxidative stress in vivo
. 8-OHdG is formed by the hydroxylation of guanosine
residues and is often used as a biomarker of oxidative
damage to DNA . Further, the combination therapy
attenuated the decrease in peak ankle dorsiflexion strength
that was observed following the placebo phase .
Two methodologies useful to detect the overall level of
oxidative damage in MD patients are micronucleus assay
followed by fluorescence in situ hybridisation (FISH), and
comet assay in cultured lymphocytes . An increased
frequency of micronucleated cells is considered a good
marker of genotoxic effects . The single cell gel electro-
phoresis (comet) assay in lymphocytes can estimate levels of
primary and oxidative DNA damage in the body . A
group of MD patients showed an increased level of
chromosome damage, expressed as frequency of micronuc-
leated lymphocytes, in comparison with healthy individuals
. Patients receiving a two week therapy with CoQ10
showed a statistically significant reduction in the frequency
of micronucleated cells after therapy . Therefore, the
DNA damage in MD patients was decreased by CoQ10,
which is also an efficient antioxidant .
Idebenone has been reported to improve brain and
skeletal muscle metabolism in isolated cases of MD, and
seemed to enhance the rate and degree of visual recovery in
Leber Hereditary Optic Neuropathy . Leber’s disease is a
maternally inherited condition characterized by acute or
subacute bilateral loss of vision, usually in young individuals
. Several point mutations in the mitochondrial genome
have been identified in patients with the condition .
Therapy for MD remains inadequate and mostly symp-
tomatic, but the rapidly increasing knowledge of their
molecular defects and pathogenic mechanisms allows for
some cautious optimism about the development of effective
treatments in the next future . One of the “cocktails” of
choice for the treatment of MD may be a combination of L-
carnitine (1,000 mg three times a day) and CoQ10 (at least
300 mg a day), with the rationale of restoring free carnitine
levels and exploiting the oxygen radical scavenger properties
of CoQ10 .
COENZYME Q10 AND STATINS
Statins are currently the most effective medications for
reducing low-density lipoprotein (LDL) cholesterol concen-
trations . Statins competitively inhibit HMG-CoA
reductase thereby decreasing synthesis of mevalonate, a
critical intermediary in the cholesterol synthesis pathway
[see Fig. (2)] . Although generally safe, they have been
associated with a variety of myopathic complaints. Their
most serious and frequent side effects are a variety of my-
opathic complaints ranging from mild myalgia to fatal
rhabdomyolysis . Statins via inhibition HMG-CoA
reductase cause a decrease in the synthesis of farnesyl pyro-
phosphate, an intermediate in the synthesis of CoQ10 .
The fact that statins block the mevalonate pathway has
prompted the idea that statin-induced CoQ10 deficiency may
be involved in the pathogenesis of statin myopathy (the
primary adverse effect limiting their use) . Thus, supple-
menting with CoQ10 may be recommended to prevent the
myopathic side effects associated with the statins. Evidences
for or against this hypothesis have been reviewed by Marcoff
118 Current Drug Targets, 2010, Vol. 11, No. 1 Mancuso et al.
and Thompson , but the question remains to be ans-
wered. A study performed on a sample of muscle biopsy of
patients with statin drug-related myopathy showed that the
decrease of CoQ10 concentration in muscle did not cause
histochemical or biochemical evidence of mitochondrial
myopathy or morphologic evidence of apoptosis in most
A study designed to assess the effect of high-dose statin
treatment has been performed on 48 patients with hypercho-
lesterolemia, randomly assigned to receive simvastatin,
atorvastatin, or placebo for 8 weeks . Muscle ubiquinone
concentration was reduced significantly in the simvastatin
group, but no reduction was observed in the atorvastatin or
placebo group . Also ETC and citrate synthase activities
were reduced in patients taking simvastatin .
The effect of simvastatin on CoQ10 plasmatic levels has
been compared with the effect of ezetimibe (a cholesterol
absorption inhibitor) and of the coadministration simvastatin/
ezetimibe . While simvastatin and the combination of
simvastatin and ezetimibe significantly decreased plasma
CoQ10 levels, ezetimibe monotherapy did not .
A randomized double-blind, placebo-controlled study
that examined the effects of CoQ10 and placebo in hyper-
cholesterolemic patients treated by atorvastatin showed a
similar decrease in LDL carriers in the two groups and an
high increase of CoQ10 levels in the CoQ10 group . In
particular, the placebo group showed a mean reductions of
plasma CoQ10 levels by 42%, whereas patients supple-
mented with CoQ10 showed a mean increase in plasma
CoQ10 by 127% . However, these changes in plasma
CoQ10 levels showed no relation to the changes in serum
transaminase and CK levels . Further studies are needed
in order to evaluate the role of CoQ10 supplementation
during statin therapy .
COENZYME Q10 AND NEURODEGENERATIVE
There is increasing evidence that impairment of mito-
chondrial function and oxidative damage are contributing
factors to the pathophysiology of Parkinson’s Disease (PD),
and a recent study reported a deficit in brain CoQ10 levels in
PD patients, which may be involved in the pathophysiology
of PD . In PD patients, CoQ10 was well tolerated at
doses as high as 1200 mg daily . A study on 130 PD
patients without motor fluctuations and a stable antipar-
kinsonian treatment reported that nanoparticular CoQ10 (300
mg daily) was safe and well tolerated, and led to plasma
levels similar to 1200 mg/day of standard formulations,
although did not result in symptomatic effects in midstage
PD . The efficacy of CoQ10 in PD remains an open
A very recent short-term, randomized, placebo-controlled
trial was performed in progressive supranuclear palsy (PSP).
PSP, the second most common cause of parkinsonism after
PD, is characterized by down gaze palsy with progressive
rigidity and imbalance leading to falls. Impairment of
mitochondrial ETC complex I activity has been reported in
PSP . CoQ10 improved cerebral energy metabolism on
magnetic resonance spectroscopy studies . Clinically,
PSP patients improved slightly, but statistically significantly,
upon CoQ10 treatment compared to placebo .
In HD, CoQ10 may slow the decline in total functional
capacity over 30 months . HD is a genetic disease
characterized by psychiatric disturbances, progressive
cognitive impairment, choreiform movements, and death 15
to 20 years after the onset of symptoms. Various lines of
evidence demonstrated the involvement of mitochondrial
dysfunction in the pathogenesis of HD, but the precise role
of mitochondria in the neurodegenerative cascade leading to
HD is still unclear. Kieburtz and co-workers  carried out
a trial in which 347 patients with early HD were randomized
to receive CoQ10 300 mg twice daily, remacemide hydro-
chloride 200 mg three times daily, both, or neither treatment,
and were followed every 4 to 5 months for a total of 30
months. Patients treated with CoQ10 showed a trend toward
slowing the decline in total functional capacity decline over
30 months, as well as beneficial trends in some secondary
measures . CoQ10 was well tolerated by HD patients.
Moreover, no reported side effects have been reported in
31 subjects with Amyotrophic Lateral Sclerosis (ALS)
treated with doses of CoQ10 as high as 3,000 mg/day for 8
months . ALS is a motor neuron disease, with selective
degeneration of the anterior horn cells of the spinal cord and
cortical motor neurons. Approximately 90% of cases are
sporadic, and 10% are familial. About 20% of familial cases
result from mutation in the gene encoding for the Cu/Zn-
superoxide dismutase (SOD1). The aetiology and patho-
genesis of the sporadic form of the disease are poorly
understood; mitochondrial dysfunction and oxidative stress
are involved . Mice expressing mutant SOD1 provide an
animal model of ALS. A significant increase in the oxidized
form of CoQ10 and in the ratio of oxidized form of CoQ10
to total CoQ10 have been reported in 20 sporadic ALS
patients . Moreover, the latter parameter significantly
correlated with the duration of disease, supporting systemic
oxidative stress in the pathogenesis of sporadic ALS .
However, a recent US randomized, controlled phase II trial
has demonstrated that CoQ10 administration in ALS patients
did not appear to slow the progression of this disease .
Most trials have demonstrated that idebenone (5 mg/kg
daily) reduced cardiac hypertrophy in Friedreich’s ataxia
[77, 78]. Friedreich’s ataxia is the most common hereditary
ataxia among white people, and it is caused by a trinuc-
leotide expansion in the X25 gene. In this disorder, the
genetic abnormality results in the deficiency of frataxin, a
protein targeted to the mitochondrion . Although the
exact physiological function of frataxin is not known, its
involvement in iron–sulphur cluster biogenesis has been
suggested . A possible manifestation of this disease is
cardiomyopathy. A recent pilot study investigated the
potential for high dose CoQ10/vitamin E therapy to modify
clinical progression in Friedreich’s ataxia . Fifty patients
were randomly divided into high or low dose CoQ10/vitamin
E groups . At baseline serum CoQ10 and vitamin E
levels were significantly decreased in patients . During
the trial CoQ10 and vitamin E levels significantly increased
in both groups . Serum CoQ10 levels have been reported
to be the best predictor of a positive clinical response to
CoQ10/vitamin E therapy  in this condition. Recently, a
randomised, placebo-controlled trial has been conducted on
Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders Current Drug Targets, 2010, Vol. 11, No. 1 119
48 patients with genetically confirmed Friedreich’s ataxia
. Treatment with higher doses of idebenone was gene-
rally well tolerated and associated with improvement also in
neurological function and activities of daily living in patients
with Friedreich’s ataxia . The degree of improvement
correlated with the dose of idebenone, suggesting that higher
doses may be necessary to have a beneficial effect on
neurological function .
The role of mitochondrial dysfunction and oxidative
stress in the pathogenesis of neurodegenerative diseases is
well documented . It will be important to develop a
better understanding of the role of oxidative stress and mito-
chondrial energy metabolism in neurodegeneration, since it
may lead to the development of more effective treatment
strategies for these devastating disorders.
In addition to primary CoQ10 deficiency, CoQ10
treatment has been reported to elicit some efficacy in the
treatment of MD and neurological disorders not directly
linked to a primary deficiency in this quinone. The reason for
this efficacy are uncertain but may be the ability of this
quinone to increase cellular antioxidant status or enhance
mitochondrial ETC function. CoQ10 therapy has been shown
to be relatively safe with few adverse effects being reported.
Additional studies on the potential usefulness of CoQ10
supplementation as an adjunct to conventional therapy in
neurological diseases, particularly neurodegenerative, are
still required before this quinine can be accepted as a
legitimate and universally accepted treatment for these
Phosphorus magnetic resonance
Amyotrophic lateral sclerosis
Electron transport chain
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Progressive supranuclear palsy
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Received: April 29, 2009 Revised: August 11, 2009 Accepted: September 1, 2009