ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q₁₀ (CoQ₁₀) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ₁₀ levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ₁₀ biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ₁₀ addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ₁₀ treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ₁₀ biosynthesis may be treatable with CoQ₁₀.     

A novel COQ8A missense variant associated with a mild form of primary coenzyme Q10 deficiency type 4

BackgroundPrimary coenzyme Q10 deficiency refers to a group of diseases characterised by reduced levels of coenzyme Q10 in related tissues or cultured cells associated with the 9 genes involved in the biosynthesis of coenzyme Q10. A biallelic pathogenic variant of COQ8A gene causes the occurrence of the primary coenzyme Q10 deficiency type 4. The objective of this study was to investigate the genetic cause of muscle weakness in a proband who had a negative DMD gene test for Becker muscular dystrophy.MethodsThe DNA of the proband was sequenced using whole exome sequencing. With the help of the Human Phenotype Ontology (HPO), the range of related candidate pathogenic genes has been reduced to a certain extent based on “muscle weakness” (HP:0001324). In addition, family linkage analysis, phenotypic-genotype check and protein structure modeling were used to explore the genetic cause of the proband.ResultsThe compound heterozygous variant c.836A > C (p.Gln279Pro) and c.1228C > T (p.Arg410Ter) in the COQ8A gene was identified in the proband. According to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, the novel variant c.836A > C could be classified as “likely pathogenic” for the proband.ConclusionThe p.Gln279Pro was detected in the KxGQ motif and the QKE triplet of the COQ8A protein, whose structures were crucial for the structure and function of the COQ8A protein associated with the biosynthesis of coenzyme Q10 and the proband's clinical symptoms were relatively milder than those previously reported.     

Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders

Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and Deltacoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.     

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.     

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

BACKGROUND: As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans. MATERIAL AND METHODS: We assessed the effect of simvastatin on left ventricular function and coenzyme Q10 levels in 21 (11 male, 10 female) hypercholesterolaemic subjects (mean age = 56 years) with normal LVF, over a period of 6 months. Subjects were re-tested after a 1-month wash-out period (7 months). Echocardiography was performed on all subjects before commencement of simvastatin (20 mg day(-1)), and at 1, 3, 6 and 7 months after initiation of treatment. Fasting blood samples were also collected at these intervals to assess lipids, apoproteins, vitamin E and coenzyme Q10. RESULTS: Serum lipids showed the expected reductions. Plasma vitamin E and coenzyme Q10 levels were reduced by 17 +/- 4% (P < 0.01) and 12 +/- 4% (P < 0.03) at 6 months. However, the coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio increased significantly. Left ventricular ejection fraction (EF) decreased transiently after 1 month, while no significant change was observed at 3 and 6 months. Other markers of left ventricular function did not change significantly at any time point. CONCLUSION: Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.     

Therapeutic role of coenzyme Q(10) in Parkinson's disease

Mitochondrial dysfunction has been well established to occur in Parkinson's disease (PD) and appears to play a role in the pathogenesis of the disorder. A key component of the mitochondrial electron transport chain (ETC) is coenzyme Q(10), which not only serves as the electron acceptor for complexes I and II of the ETC but is also an antioxidant. In addition to being crucial to the bioenergetics of the cell, mitochondria play a central role in apoptotic cell death through a number of mechanisms, and coenzyme Q(10) can affect certain of these processes. Levels of coenzyme Q(10) have been reported to be decreased in blood and platelet mitochondria from PD patients. A number of preclinical studies in in vitro and in vivo models of PD have demonstrated that coenzyme Q(10) can protect the nigrostriatal dopaminergic system. A phase II trial of coenzyme Q(10) in patients with early, untreated PD demonstrated a positive trend for coenzyme Q(10) to slow progressive disability that occurs in PD.     

Plasma coenzyme Q10 reference intervals,but not redox status,are affected by gender and race in self-reported healthy adults

BACKGROUND: Abnormal concentrations of coenzyme Q(10) have been reported in many patient groups, including certain cardiovascular, neurological, hematological, neoplastic, renal, and metabolic diseases. However, controls in these studies are often limited in number, poorly screened, and inadequately evaluated statistically. The purpose of this study is to determine the reference intervals of plasma concentrations of ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) for self-reported healthy adults. METHODS: Adults (n=148), who were participants in the Princeton Prevalence Follow-up Study, were identified as healthy by questionnaire. Lipid profiles, ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) concentrations were measured in plasma. The method used to determine the reference intervals is a procedure incorporating outlier detection followed by robust point estimates of the appropriate quantiles. RESULTS: Significant differences between males and females were present for ubiquinol-10 and total coenzyme Q(10). Blacks had significantly higher Q(10) measures than whites in all cases except for the ubiquinol-10/total Q(10) fraction. CONCLUSIONS: The fraction of ubiquinol-10/total coenzyme Q(10) is a tightly regulated measure in self-reported healthy adults, and is independent of sex and racial differences. Different reference intervals for certain coenzyme Q(10) measures may need to be established based upon sex and racial characteristics.     

Open label trial of coenzyme Q10 as a migraine preventive

The objective was to assess the efficacy of coenzyme Q10 as a preventive treatment for migraine headaches. Thirty-two patients (26 women, 6 men) with a history of episodic migraine with or without aura were treated with coenzyme Q10 at a dose of 150 mg per day. Thirty-one of 32 patients completed the study; 61.3% of patients had a greater than 50% reduction in number of days with migraine headache. The average number of days with migraine during the baseline period was 7.34 and this decreased to 2.95 after 3 months of therapy, which was a statistically significant response (P < 0.0001). Mean reduction in migraine frequency after 1 month of treatment was 13.1% and this increased to 55.3% by the end of 3 months. Mean migraine attack frequency was 4.85 during the baseline period and this decreased to 2.81 attacks by the end of the study period, which was a statistically significant response (P < 0.001). There were no side-effects noted with coenzyme Q10. From this open label investigation coenzyme Q10 appears to be a good migraine preventive. Placebo-controlled trials are now necessary to determine the true efficacy of coenzyme Q10 in migraine prevention.     

Plasma coenzyme Q(10) in children and adolescents undergoing doxorubicin therapy

The objective of this study was to test the hypothesis that doxorubicin treatment for cancer in childhood and adolescence causes a dose-related decrease in the concentration of plasma coenzyme Q(10). The concentration of plasma coenzyme Q(10) was measured before and after administration of doxorubicin in six patients, and before and after chemotherapy in six patients undergoing treatments that did not include doxorubicin. There was a significant increase in the concentration of plasma coenzyme Q(10) in post-treatment samples compared to pre-treatment samples in patients treated with doxorubicin (P=0.008; n=32), whereas there were no significant changes in plasma coenzyme Q(10) concentrations in patients treated with chemotherapy that did not include doxorubicin. (P=0.770; n=30). We hypothesise that the increase in plasma coenzyme Q(10) that was observed in patients undergoing doxorubicin treatment is due to release of coenzyme Q(10) from apoptotic or necrotic cardiac tissue. We conclude that the cardiotoxicity due to doxorubicin therapy does not involve acute myocardial depletion of coenzyme Q(10).     

Coenzyme Q10 and cardiovascular disease: a review

This article provides a comprehensive review of 30 years of research on the use of coenzyme Q10 in prevention and treatment of cardiovascular disease. This endogenous antioxidant has potential for use in prevention and treatment of cardiovascular disease, particularly hypertension, hyperlipidemia, coronary artery disease, and heart failure. It appears that levels of coenzyme Q10 are decreased during therapy with HMG-CoA reductase inhibitors, gemfibrozil, Adriamycin, and certain beta blockers. Further clinical trials are warranted, but because of its low toxicity it may be appropriate to recommend coenzyme Q10 to select patients as an adjunct to conventional treatment.     

Steroid-sensitive mechanism of soluble immune response suppressor production in steroid-responsive nephrotic syndrome.

Soluble immune response suppressor (SIRS), a lymphokine that suppresses antibody production and delayed type hypersensitivity in vivo, has been detected in urine and serum from certain patients with nephrotic syndrome. In the present paper, the relationship between SIRS production and nephrotic syndrome is further characterized. A striking correlation was found between detection of SIRS and the presence of steroid-responsive nephrotic syndrome (SRNS). A potential mechanism of SIRS production in SRNS patients was identified, in that lymphocytes from patients produced SIRS without requiring activation by exogenous agents, and incubation of normal lymphocytes with serum from patients activated the cells to secrete SIRS in culture. Although SIRS disappears rapidly from urine or serum after initiation of corticosteroid therapy, hydrocortisone (10(-6)-10(-7) M) did not block secretion of SIRS by activated suppressor cells. It did, however, inhibit in vitro activation of lymphocytes to produce SIRS by concanavalin A, interferon, or SRNS patient serum. The association of suppressor cell activation with SRNS and the sensitivity of both to steroids suggest that the pathogeneses of albuminuria and SIRS production are related.     

Coenzyme Q10

Coenzyme Q10 is a vitamin-like substance used in the treatment of a variety of disorders primarily related to suboptimal cellular energy metabolism and oxidative injury. Studies supporting the efficacy of coenzyme Q10 appear most promising for neurodegenerative disorders such as Parkinson's disease and certain encephalomyopathies for which coenzyme Q10 has gained orphan drug status. Results in other areas of research, induding treatment of congestive heart failure and diabetes, appear to be contradictory or need further clarification before proceeding with recommendations. Coenzyme Q10 appears to be a safe supplement with minimal side effects and low drug interaction potential.     

ADCK4 “reenergizes” nephrotic syndrome

Steroid-resistant nephrotic syndrome has a poor prognosis and often leads to end-stage renal disease development. In this issue of the JCI, Ashraf and colleagues used exome sequencing to identify mutations in the aarF domain containing kinase 4 (ADCK4) gene that cause steroid-resistant nephrotic syndrome. Patients with ADCK4 mutations had lower coenzyme Q₁₀ levels, and coenzyme Q₁₀ supplementation ameliorated renal disease in a patient with this particular mutation, suggesting a potential therapy for patients with steroid-resistant nephrotic syndrome with ADCK4 mutations.     

Reduced prosaposin levels in HepG2 cells with long-term coenzyme Q10 deficiency

Glycosphingolipids are involved in intercellular signaling, adhe­sion, proliferation, and differentiation. Saposins A, B, C, and D are cofactors required for glycosphingolipid hydrolysis. Saposins A–D are present in series in a common precursor protein, prosaposin. Thus, glycosphingolipids amounts depend on prosaposin cellular levels. We previously reported that prosaposin and saposin B bind coenzyme Q10 in human cells. Coenzyme Q10 is an essential lipid of the mitochondrial electron transport system, and its reduced form is an important antioxidant. Coenzyme Q10 level decrease in aging and in various progressive diseases. Therefore, it is interesting to understand the cellular response to long-term coenzyme Q10 deficiency. We established a long-term coenzyme Q10 deficient cell model by using the coenzyme Q10 biosynthesis inhibitor, 4-nitrobenzoate. The levels of coenzyme Q10 were reduced by 4-nitrobenzoate in HepG2 cells. Administration of 4-nitrobenzoate also decreased prosaposin protein and mRNA levels. The cellular levels of coenzyme Q10 and prosaposin were recovered by treatment with 4-hydroxybenzoquinone, a substrate for coenzyme Q10 synthesis that counteracts the effect of 4-nitrobenzoate. Furthermore, the ganglioside levels were altered in 4-nitrobenzoate treated cells. These results imply that long-term coenzyme Q10 deficiency reduces cellular prosaposin levels and disturbs glycosphingolipid metabolism.     

Crumbs homolog 2 mutation in two siblings with steroid-resistant nephrotic syndrome: Two case reports

BACKGROUND Crumbs homolog 2 (CRB2) is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes; mutations can directly lead to steroid-resistant nephrotic syndrome (SRNS). However, the characteristics of nephrotic syndrome (NS) caused by CRB2 mutations have not been described.CASE SUMMARYWe report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS. The two siblings had edema, proteinuria, hypoproteinemia and hyperlipidemia. Both their father and mother had normal phenotypes (no history of NS). Whole exon sequencing (WES) of the family showed a novel compound heterozygous mutation, c.2290 (exon 8) C > T and c.3613 (exon 12) G > A. Glucocorticoid therapy (methylprednisolone pulse therapy or oral prednisone) and immunosuppressive agents (tacrolimus) had no effect. During a 3-year follow-up after genetic diagnosis by WES, proteinuria persisted, but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7, 10, and 12. Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.     

Measurement and stability of plasma reduced, oxidized and total coenzyme Q10 in humans

There are findings indicating that a decreased ratio of plasma coenzyme Q10 (Q10) to LDL cholesterol could be associated with an increased risk of atherosclerosis. Furthermore, the proportion of plasma Q10H2 (reduced Q10, ubiquinol) of total Q10 has been shown to be attenuated in major diseases, such as hyperlipidemia and coronary artery disease. These observations suggest that measurement of plasma total Q10 and the proportion of plasma Q10H2 of total Q10 would be of clinical significance. However, epidemiological studies addressing this issue require large numbers of subjects, and measurements from unfrozen samples are unfeasible. For this reason, we evaluated the stability of Q10 samples during sample storage and processing. We also compared solid phase and hexane pre-treatments prior to high-performance liquid chromatographic determination of Q10. Our results indicate that samples for plasma total Q10 measurement can be pre-treated in normal laboratory lighting conditions, thawed and frozen several times, and stored deep frozen for a couple of years without changes in measured Q10 values. If purification of the samples by silica and C18 is needed, the best reproducibility tends to be achieved with powder treatment (not with cartridges). However, to measure successfully the proportion of plasma ubiquinol of total Q10, samples must be thawed, extracted, and analysed one at a time and quickly to ensure minimal ubiquinol oxidation during the measurement process.     

辅酶Q10、黄芪、舒血宁治疗急性病毒性心肌炎82例疗效观察

目的：探讨辅酶Q10、黄芪、舒血宁治疗急性病毒性心肌炎(VMC)的临床效果。方法：回顾性分析在常规治疗的基础上加辅酶Q10、黄芪、舒血宁治疗VMC82例的临床资料。结果：治疗组总有效率为92％，对照组为85％，两组疗效有显著性差异。结论：辅酶Q10、黄芪、舒血宁联合治疗急性病毒性心肌炎具有确切效果，可作为中西医结合治疗VMC的方法之一。     

肾病综合征外周血单个核细胞凋亡与P-糖蛋白170表达

目的 检测原发性肾病综合征(PNS)患儿外周血单个核细胞(PBMC)细胞凋亡、P-糖蛋白170(P-gp170)的表达情况,分析二者关系,探讨其在糖皮质激素(GC)耐药中的作用.方法 对28例PNS患儿分别于GC(强的松)治疗前和治疗4周时采血,流式细胞仪(FCM)检测PBMC细胞凋亡、P-gp170表达情况,并进行相关性分析.依据对GC的反应分为激素敏感组(SSNS组,16例)、激素耐药组(SRNS组,12例),另设10例健康体检儿童作为对照组.结果 (1)GC治疗前PBMC在SSNS组、SRNS组及对照组均有凋亡,凋亡率分别为(6.14±1.85)％、(6.44±1.83)％和(5.56±1.53)％,3组间差异无统计学意义(P＞0.05);与治疗前比较,治疗4周后SSNS组凋亡率增高为(11.48 ±6.25)％(P＜0.01),SRNS组无明显变化[(6.94±1.87)％,P＞0.05].(2)GC治疗前P-gp170在SSNS、SRNS、对照组表达率分别为(4.54±3.10)％、(11.78±4.52)％和(2.30±2.07)％,3组间差异有统计学意义(P＜0.01),SRNS组高于其他2组,SSNS组高于对照组;治疗后P-gp170在SSNS、SRNS组的表达率较治疗前增高为(7.29±2.69)％、(15.36±4.36)％,差异有统计学意义(P均＜0.01),且SRNS组高于SSNS组(P＜0.01).(3)PBMC细胞凋亡与P-gp170表达未见线性相关(r=-0.174,P＞0.05).结论 (1)PBMC的凋亡延迟可能参与PNS患儿GC耐药.(2)外周血P-gp170表达增高可能与PNS患儿GC耐药有关.(3)PBMC细胞凋亡率及P-gp170表达情况可作为判断PNS患儿预后的指标.     

Measurement of reduced and oxidized coenzyme Q9 and coenzyme Q10 levels in mouse tissues by HPLC with coulometric detection

BACKGROUND: Ubiquinone-responsive multiple respiratory chain dysfunction due to coenzyme Q(10) (CoQ(10)) deficiency has been previously identified in muscle biopsies. However, previous methods are unreliable for estimating CoQ(10) redox status in tissue. We developed an accurate method for measuring tissue concentrations of reduced and oxidized coenzyme Q (CoQ). METHODS: Mouse tissues were weighed in the frozen state and homogenized with cold 1-propanol on ice. After solvent extraction, centrifugation and filtration, the filtrate was subsequently analyzed by reversed-phase HPLC with coulometric detection. RESULTS: Reference calibration curves were used to determine reduced and oxidized coenzyme Q(9) (CoQ(9)) and CoQ(10) concentrations in tissues. The method is sensitive ( approximately 15 microg/l), reproducible (6% CV) for CoQ(9) and CoQ(10), and linear up to 20 mg/l for CoQ(9) and CoQ(10). Analytical recoveries were 90-104%. In mouse tissues the amounts of total CoQ (TQ) ranged from 261 to 1737 nmol/g of protein. Total CoQ(9) levels are comparable with the values of those previously reported. CoQ is found to be mostly in the reduced form in mouse liver ( approximately 87%), heart ( approximately 60%), and muscle tissues ( approximately 58%); in the brain, most of the CoQ is in the oxidized state ( approximately 65%). CONCLUSION: This procedure provides a precise, sensitive, and direct assay method for the determination of reduced and oxidized CoQ(9) and CoQ(10) in mouse hindleg muscle, heart, brain, and liver tissues.     

Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients

OBJECTIVES: An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. Oxygen derived radicals are able to cause damage to membranes, mitochondria, and macromolecules including proteins, lipids and DNA. Accumulation of DNA damages has been suggested to contribute to carcinogenesis. It would, therefore, be advantageous to pinpoint the effects of oxygen derived radicals in cancer development. DESIGN AND METHODS: In the present study, we investigated the relationship between oxidative stress and breast cancer development in tissue level. Breast cancer is the most common malignant disease in Western women. Twenty-one breast cancer patients, who underwent radical mastectomy and diagnosed with infiltrative ductal carcinoma, were used in the study. We determined coenzyme Q10 (Q) concentrations, antioxidant enzyme activities (mitochondrial and total superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase), and malondialdehyde (MDA) levels in tumor and surrounding tumor-free tissues. RESULTS: Q concentrations in tumor tissues significantly decreased as compared to the surrounding normal tissues (p < 0.001). Higher MDA levels were observed in tumor tissues than noncancerous tissues (p < 0.001). The activities of MnSOD, total SOD, GSH-Px and catalase in tumor tissues significantly increased (p < 0.001) compared to the controls. CONCLUSIONS: These findings may support that reactive oxygen species increased in malignant cells, and may cause overexpression of antioxidant enzymes and the consumption of coenzyme Q10. Increased antioxidant enzyme activities may be related with the susceptibility of cells to carcinogenic agents and the response of tumor cells to the chemotherapeutic agents. Administration of coenzyme Q10 by nutrition may induce the protective effect of coenzyme Q10 on breast tissue.