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1.  Mutation in an mtDNA Protein-Coding Gene: Prenatal Diagnosis Aided by Fetal Muscle Biopsy 
Journal of child neurology  2012;28(2):264-268.
Prenatal diagnosis of disorders due to mitochondrial DNA (mtDNA) tRNA gene mutations is problematic. Experience in families harboring the protein-coding ATPase 6 m.8993T>G mutation suggests that the mutant load is homogeneous in different tissues, thus allowing prenatal diagnosis. We have encountered a novel protein-coding gene mutation, m.10198C>T in MT-ND3. A baby girl homoplasmic for this mutation died at 3 months after severe psychomotor regression and respiratory arrest. The mother had no detectable mutation in accessible tissues. The product of a second pregnancy showed only wild-type mt genomes in amniocytes, chorionic villi, and biopsied fetal muscle. This second girl is now 18 months old and healthy. Our observations support the concept that the pathogenic mutation in this patient appeared de novo and that fetal muscle biopsy is a useful aide in prenatal diagnosis.
doi:10.1177/0883073812441067
PMCID: PMC3959766  PMID: 22532554
mtDNA; complex I deficiency; prenatal diagnosis; mitochondria
2.  MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions 
Archives of neurology  2012;69(12):1648-1651.
Objective
To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA).
Design
Case report.
Setting
University hospitals.
Patient
A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility.
Results
Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase–deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions.
Conclusions
In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions.
doi:10.1001/archneurol.2012.405
PMCID: PMC3894685  PMID: 22964873
3.  Slowly Progressive Encephalopathy with Hearing Loss Due to a Mutation in the mtDNA tRNALeu(CUN) Gene 
Pathogenic mutations in the tRNALeu(UCN) gene of mitochondrial DNA (mtDNA) have been invariably accompanied by skeletal myopathy with or without chronic progressive external ophthalmoplegia (CPEO). We report a young woman with a heteroplasmic m.12276G>A mutation in tRNALeu(UCN), who had childhood-onset and slowly progressive encephalopathy with ataxia, cognitive impairment, and hearing loss. Sequencing of the 22 tRNA mitochondrial genes is indicated in all unusual neurological syndromes, even in the absence of maternal inheritance.
doi:10.1016/j.jns.2009.12.001
PMCID: PMC3891822  PMID: 20022607
4.  MITOCHONDRIAL DNA DEPLETION SYNDROME DUE TO MUTATIONS IN THE RRM2B GENE 
Neuromuscular disorders : NMD  2008;18(6):453-459.
Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in The RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in 7 infants from 4 families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age.
We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at three months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months.
All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exon 6, 8 and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.
doi:10.1016/j.nmd.2008.04.006
PMCID: PMC3891825  PMID: 18504129
5.  Effect of Coenzyme Q10 on Doxorubicin Cytotoxicity in Breast Cancer Cell Cultures 
Integrative cancer therapies  2012;11(3):10.1177/1534735412439749.
Background/hypotheses
Doxorubicin is a standard adjuvant therapy for early-stage breast cancer and it significantly improves disease-free and overall survival. However, 3-20% of breast cancer patients develop chronic cardiomyopathic changes and congestive heart failure due to doxorubicin therapy. Doxorubicin-induced cardiotoxicity is thought to be due to increased generation of reactive oxygen species (ROS) within cardiac myocyte mitochondria. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant that may protect against mitochondrial ROS, and thus prevent doxorubicin-induced cardiotoxicity. Despite the potential benefits of CoQ10 in preventing cardiotoxicity, it is unknown if CoQ10 diminishes the antineoplastic effects of doxorubicin therapy.
Study design
In vitro cell culture experiments.
Methods
Breast cancer cell lines (MDA-MB-468 and BT549) were tested for their ability to uptake exogenous CoQ10 using high performance liquid chromatography (HPLC). Breast cancer cell lines were then treated with doxorubicin and a range of CoQ10 concentrations to determine the effect of CoQ10 on doxorubicin’s cytotoxicity.
Results
This study demonstrated that intracellular and mitochondrial CoQ10 concentrations increased substantially as higher exogenous concentrations are administered to breast cancer cells. CoQ10 had no effect on the ability of doxorubicin to induce apoptosis or inhibit growth or colony formation in both cell lines tested when CoQ10 was applied over a wide dose range, which encompassed typical basal plasma levels as well as plasma levels above those typically achieved by supplemented patients.
Conclusion
The clinical testing of CoQ10 as supplement to prevent doxorubicin induced cardiotoxicity requires confidence that it does not decrease chemotherapy efficacy. These results support the hypothesis that CoQ10 does not alter the antineoplastic properties of doxorubicin. Further in vivo studies, as well as combination chemotherapy studies, would be reassuring before large scale clinical testing of CoQ10 as a cardioprotective drug.
doi:10.1177/1534735412439749
PMCID: PMC3840161  PMID: 22544232
Doxorubicin; Adriamycin; Coenzyme Q10; cytotoxicity; breast cancer; in vitro
6.  A novel POLG gene mutation in a patient with SANDO 
Journal of experimental and integrative medicine  2012;2(2):10.5455/jeim.200312.cr.001.
The human mitochondrial genome is replicated by DNA polymerase γ, which is encoded by polymerase γ gene (POLG1) on chromosome 15q25. Patients with POLG1 mutations usually present as Alpers’ syndrome or progressive external ophthalmoplegia. Our patient was a 48-year old woman with sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. Sequence analysis revealed that she has two heterozygous missense mutations in the POLG1, a c.1774C>T substitution in exon 10, which results in a p.L591F amino acid change; and a c.3286C>T substitution in exon 21, which results in a p.R1096C amino acid change. The 1774C>T substitution is a novel mutation.
Previously described adult patients with one mutation in exon 10 and the other in exon 21 of POLG1 had presented with progressive external ophthalmoplegia. We now describe a patient with mutations in the same exons but suffering from the more complex clinical syndrome of sensory ataxic neuropathy, dysarthria, ophthalmoplegia.
doi:10.5455/jeim.200312.cr.001
PMCID: PMC3832984  PMID: 24265579
Novel mutation; PEO; POLG1; SANDO
7.  A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes 
Archives of neurology  2010;67(2):10.1001/archneurol.2009.332.
Objective
To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children.
Design
Genotype-phenotype correlation.
Setting
Tertiary care universities.
Patients
Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure.
Interventions
Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene.
Main Outcome Measures
Definition of clinical variability.
Results
All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation.
Conclusions
The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.
doi:10.1001/archneurol.2009.332
PMCID: PMC3826985  PMID: 20142534
8.  Conventional Frequency Ultrasonic Biomarkers of Cancer Treatment Response In Vivo12 
Translational Oncology  2013;6(3):234-243.
BACKGROUND: Conventional frequency quantitative ultrasound in conjunction with textural analysis techniques was investigated to monitor noninvasively the effects of cancer therapies in an in vivo preclinical model. METHODS: Conventional low-frequency (∼7 MHz) and high-frequency (∼20 MHz) ultrasound was used with spectral analysis, coupled with textural analysis on spectral parametric maps, obtained from xenograft tumor-bearing animals (n = 20) treated with chemotherapy to extract noninvasive biomarkers of treatment response. RESULTS: Results indicated statistically significant differences in quantitative ultrasound-based biomarkers in both low- and high-frequency ranges between untreated and treated tumors 12 to 24 hours after treatment. Results of regression analysis indicated a high level of correlation between quantitative ultrasound-based biomarkers and tumor cell death estimates from histologic analysis. Applying textural characterization to the spectral parametric maps resulted in an even stronger correlation (r2 = 0.97). CONCLUSION: The results obtained in this research demonstrate that quantitative ultrasound at a clinically relevant frequency can monitor tissue changes in vivo in response to cancer treatment administration. Using higher order textural information extracted from quantitative ultrasound spectral parametric maps provides more information at a high sensitivity related to tumor cell death.
PMCID: PMC3678128  PMID: 23761215
9.  Coenzyme Q10 levels are low and associated with increased mortality in post-cardiac arrest patients☆ 
Resuscitation  2012;83(8):991-995.
Aim
Survival after cardiac arrest (CA) is limited by the profound neurologic insult from ischemia–reperfusion injury. Therapeutic options are limited. Previous data suggest a benefit of coenzyme Q10 (CoQ10) in post-arrest patients. We hypothesized that plasma CoQ10 levels would be low after CA and associated with poorer outcomes.
Methods
Prospective observational study of post-arrest patients presenting to a tertiary care center. CoQ10 levels were drawn 24 h after return of spontaneous circulation (ROSC) and compared to healthy controls. Levels of inflammatory cytokines and biomarkers were analyzed. Primary endpoints were survival to discharge and neurologic status at time of discharge.
Results
23 CA subjects and 16 healthy controls were enrolled. CoQ10 levels in CA patients (0.28 µmol L−1, inter-quartile range (IQR): 0.22–0.39) were significantly lower than in controls (0.75 µmol L−1, IQR: 0.61–1.08, p < 0.0001). The mean CoQ10 level in CA patients who died was significantly lower than in those who survived (0.27 vs 0.47 µmol L−1, p = 0.007). There was a significant difference in median CoQ10 level between patients with a good vs poor neurological outcome (0.49 µmol L−1, IQR: 0.30–0.67 vs 0.27 µmol L−1, IQR: 0.21–0.30, p = 0.02). CoQ10 was a statistically significant predictor of poor neurologic outcome (adjusted p = 0.02) and in-hospital mortality (adjusted p = 0.026).
Conclusion
CoQ10 levels are low in human subjects with ROSC after cardiac arrest as compared to healthy controls. CoQ10 levels were lower in those who died, as well as in those with a poor neurologic outcome.
doi:10.1016/j.resuscitation.2012.03.023
PMCID: PMC3658101  PMID: 22465806
Cardiac arrest; Coenzyme Q10; Cytokines; Biomarkers; Inflammatory cascade
10.  Evaluation of Neoadjuvant Chemotherapy Response in Women with Locally Advanced Breast Cancer Using Ultrasound Elastography1 
Translational Oncology  2013;6(1):17-24.
PURPOSE: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. METHODS: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. RESULTS: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. CONCLUSIONS: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.
PMCID: PMC3573650  PMID: 23418613
11.  Diffuse Optical Spectroscopy Evaluation of Treatment Response in Women with Locally Advanced Breast Cancer Receiving Neoadjuvant Chemotherapy1 
Translational Oncology  2012;5(4):238-246.
The aim of this study was to investigate the potential of diffuse optical spectroscopy for monitoring of patients with locally advanced breast cancer (LABC) undergoing neoadjuvant chemotherapy. Fifteen women receiving treatment for LABC had the affected breast scanned before; 1 week, 4 weeks, and 8 weeks after treatment initiation; and before surgery. Optical properties related to tissue microstructure and biochemical composition were obtained. Clinical and pathologic tumor response was evaluated using whole-mount pathology after mastectomy. Patients who responded to treatment demonstrated an initial increase followed by a drop in optical parameters measured in the whole breast, whereas nonresponding patients demonstrated only a drop in the same parameters 1 week after treatment initiation. Responding patients demonstrated a significant increase of 17% ± 7%, 8% ± 8%, 10% ± 7%, 11% ± 11%, and 16% ± 15% in deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin concentrations, water percentage, and tissue optical index, 1 week after treatment initiation, respectively. In contrast, nonresponding patients had a decrease of 14% ± 9%, 18% ± 7%, 17% ± 7%, 29% ± 7%, and 32% ± 9% in their corresponding optical parameters. Deoxygenated hemoglobin concentration (with 100% sensitivity, 83% specificity) and water percentage (with 75% sensitivity, 100% specificity) were found to be the best predictors of treatment response at 1 week after starting treatment. The results of this study suggest that optical parameters can be potentially used to predict and monitor patients' responses to neoadjuvant chemotherapy and can form a basis for the customization of treatments in which inefficacious treatments can be switched to more efficacious therapies.
PMCID: PMC3431033  PMID: 22937175
12.  Short Communication: Transplacental Nucleoside Analogue Exposure and Mitochondrial Parameters in HIV-Uninfected Children 
Abstract
Transplacental nucleoside analogue exposure can affect infant mitochondrial DNA (mtDNA). We evaluated mitochondria in peripheral blood mononuclear cells of children with and without clinical signs of mitochondrial dysfunction (MD) and antiretroviral (ARV) exposure. We previously identified 20 children with signs of MD (cases) among 1037 HIV-uninfected children born to HIV-infected women. We measured mtDNA copies/cell and oxidative phosphorylation (OXPHOS) NADH dehydrogenase (complex I) and cytochrome c oxidase (complex IV) protein levels and enzyme activities, determined mtDNA haplogroups and deletions in 18 of 20 cases with stored samples and in sex- and age-matched HIV-uninfected children, both ARV exposed and unexposed, (1) within 18 months of birth and (2) at the time of presentation of signs of MD. In specimens drawn within 18 months of birth, mtDNA levels were higher and OXPHOS protein levels and enzyme activities lower in cases than controls. In contrast, at the time of MD presentation, cases and ARV-exposed controls had lower mtDNA levels, 214 and 215 copies/cell, respectively, than ARV-unexposed controls, 254 copies/cell. OXPHOS protein levels and enzyme activities were lower in cases than exposed controls, and higher in cases than unexposed controls, except for complex IV activity, which was higher in cases. Haplotype H was less frequent among cases (6%) than controls (31%). No deletions were found. The long-term significance of these small but potentially important alterations should continue to be studied as these children enter adolescence and adulthood.
doi:10.1089/aid.2010.0204
PMCID: PMC3159117  PMID: 21142587
13.  Effects of Inhibiting CoQ10 Biosynthesis with 4-nitrobenzoate in Human Fibroblasts 
PLoS ONE  2012;7(2):e30606.
Coenzyme Q10 (CoQ10) is a potent lipophilic antioxidant in cell membranes and a carrier of electrons in the mitochondrial respiratory chain. We previously characterized the effects of varying severities of CoQ10 deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ10 biosynthesis. We observed a unimodal distribution of ROS production with CoQ10 deficiency: cells with <20% of CoQ10 and 50–70% of CoQ10 did not generate excess ROS while cells with 30–45% of CoQ10 showed increased ROS production and lipid peroxidation. Because our previous studies were limited to a small number of mutant cell lines with heterogeneous molecular defects, here, we treated 5 control and 2 mildly CoQ10 deficient fibroblasts with varying doses of 4-nitrobenzoate (4-NB), an analog of 4-hydroxybenzoate (4-HB) and inhibitor of 4-para-hydroxybenzoate:polyprenyl transferase (COQ2) to induce a range of CoQ10 deficiencies. Our results support the concept that the degree of CoQ10 deficiency in cells dictates the extent of ATP synthesis defects and ROS production and that 40–50% residual CoQ10 produces maximal oxidative stress and cell death.
doi:10.1371/journal.pone.0030606
PMCID: PMC3281033  PMID: 22359546
14.  Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock 
Critical Care  2011;15(4):R189.
Introduction
Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo.
Methods
We conducted a post hoc analysis of a prospective, randomized trial of simvastatin versus placebo in patients with septic shock (ClinicalTrials.gov ID: NCT00676897). Adult patients with suspected or confirmed infection and the need for vasopressor support were included in the initial trial. For the current analysis, blood specimens were analyzed for plasma CoQ10 and low-density lipoprotein (LDL) levels. The relationship between CoQ10 levels and inflammatory and vascular endothelial biomarkers was assessed using either the Pearson or Spearman correlation coefficient.
Results
We analyzed 28 samples from 14 patients. CoQ10 levels were low, with a median of 0.49 (interquartile range 0.26 to 0.62) compared to levels in healthy control patients (CoQ10 = 0.95 μmol/L ± 0.29; P < 0.0001). Statin therapy had no effect on plasma CoQ10 levels over time (P = 0.13). There was a statistically significant relationship between plasma CoQ10 levels and levels of vascular cell adhesion molecule (VCAM) (r2 = 0.2; P = 0.008), TNF-α (r2 = 0.28; P = 0.004), IL-8 (r2 = 0.21; P = 0.015), IL-10 (r2 = 0.18; P = 0.025), E-selectin (r2 = 0.17; P = -0.03), IL-1ra (r2 = 0.21; P = 0.014), IL-6 (r2 = 0.17; P = 0.029) and IL-2 (r2 = 0.23; P = 0.009). After adjusting for LDL levels, there was a statistically significant inverse relationship between plasma CoQ10 levels and levels of VCAM (r2 = 0.24; P = 0.01) (Figure 3) and IL-10 (r2 = 0.24; P = 0.02).
Conclusions
CoQ10 levels are significantly lower in septic shock patients than in healthy controls. CoQ10 is negatively associated with vascular endothelial markers and inflammatory molecules, though this association diminishes after adjusting for LDL levels.
doi:10.1186/cc10343
PMCID: PMC3271709  PMID: 21827677
15.  Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects 
PLoS ONE  2010;5(7):e11897.
Background
Coenzyme Q10 (CoQ10) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress.
Methodology/Principal Findings
To test these concepts, we have evaluated the effects of CoQ10, coenzyme Q2 (CoQ2), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ10 deficiency. A final concentration of 5 µM of each compound was chosen to approximate the plasma concentration of CoQ10 of patients treated with oral ubiquinone. CoQ10 supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ10 deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements.
Conclusions/Significance
These results indicate that: 1) pharmacokinetics of CoQ10 in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ10 in the mitochondrial respiratory chain under conditions of CoQ10 deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ10 deficiencies should be treated with CoQ10 supplementation but not with short-tail ubiquinone analogs, such as idebenone or CoQ2. Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.
doi:10.1371/journal.pone.0011897
PMCID: PMC2912846  PMID: 20689595
16.  Longitudinal Changes of mtDNA A3243G Mutation Load and Level of Functioning in MELAS 
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common mitochondrial multisystemic diseases, is most commonly associated with an A-to-G transition at nucleotide position 3243 (A3243G) in mitochondrial DNA. We studied 34 individuals harboring the A3243G mutation for up to 7 years; 17 had the full MELAS phenotype and 17 who were classified as “carrier relatives” because they were either asymptomatic or had some symptoms suggestive of mitochondrial disease but no seizures or strokes. Using the sensitive real-time polymerase chain reaction to quantify the A3234G mutation, we confirmed that the percent mutation decreases progressively in DNA isolated from blood: the average percent decrease was 0.5% per year for fully symptomatic patients and 0.2% per year for oligosymptomatic carrier relatives. We also correlated mutant loads with functional status estimated by the Karnofsky score: even though the mutation load decreases, the level of functioning worsens in fully symptomatic patients, whereas the level of functioning of carrier relatives remains largely unchanged. This study suggests that A3243G mutant load in DNA isolated from blood is neither useful for prognosis nor for functional assessment.
doi:10.1002/ajmg.a.32703
PMCID: PMC2663596  PMID: 19253345
mitochondrial DNA mutation; MELAS; A3243G; heteroplasmy; mutant load
17.  Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency 
Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Last year, we reported the first mutations in CoQ10 biosynthetic genes, COQ2, which encodes 4-parahydroxybenzoate: polyprenyl transferase; and PDSS2, which encodes subunit 2 of decaprenyl diphosphate synthase. However, the pathogenic mechanisms of primary CoQ10 deficiency have not been well characterized. In this study, we investigated the consequence of severe CoQ10 deficiency on bioenergetics, oxidative stress, and antioxidant defenses in cultured skin fibroblasts harboring COQ2 and PDSS2 mutations. Defects in the first two committed steps of the CoQ10 biosynthetic pathway produce different biochemical alterations. PDSS2 mutant fibroblasts have 12% CoQ10 relative to control cells and markedly reduced ATP synthesis, but do not show increased reactive oxygen species (ROS) production, signs of oxidative stress, or increased antioxidant defense markers. In contrast, COQ2 mutant fibroblasts have 30% CoQ10 with partial defect in ATP synthesis, as well as significantly increased ROS production and oxidation of lipids and proteins. On the basis of a small number of cell lines, our results suggest that primary CoQ10 deficiencies cause variable defects of ATP synthesis and oxidative stress, which may explain the different clinical features and may lead to more rational therapeutic strategies.—Quinzii, C. M., López, L. C., Von-Moltke, J., Naini, A., Krishna, S., Schuelke, M., Salviati, L., Navas, P., DiMauro, S., Hirano, M. Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency.
doi:10.1096/fj.07-100149
PMCID: PMC2731482  PMID: 18230681
mitochondria; reactive oxygen species; COQ2; PDSS2
18.  D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease 
Journal of Clinical Investigation  2003;112(6):892-901.
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body D-β-hydroxybutyrate (DβHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II–dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DβHB may be a novel neuroprotective therapy for PD.
doi:10.1172/JCI200318797
PMCID: PMC193668  PMID: 12975474

Results 1-18 (18)