Coenzyme Q10 (CoQ10) is a lipophillic molecule composed of a benzoquinone ring and a hydrophobic decaprenyl tail. In the mitochondrial respiratory chain, CoQ10 transports electrons from complexes I and II to complex III. It is also an antioxidant, co-factor for pyrimidine biosynthesis, and modulator of apoptosis. Human CoQ10 deficiency is a genetically and clinically heterogeneous disease. Response to therapy is variable. Our studies of cultured fibroblasts from patients carrying mutations in PDSS2, COQ2, ADCK3, and COQ9, have revealed correlations between level of CoQ10 and oxidative stress;<15% and >60% residual CoQ10 are not associated with oxidative stress, whereas 30-50% residual CoQ10 is associated with oxidative stress, mitochondrial hyperpolarization followed by depolarization and cell death. In cell lines with primary CoQ10 deficiency, incubation of CoQ10 deficient fibroblasts for 1 week with 5mM CoQ10 (but not short-tail ubiquinone analogs) improved bioenergetics indicating pharmacokinetic constraints and dose of CoQ10 may limit efficacy in CoQ10 deficient patients. Based on our studies, we hypothesize that: 1) genotypic heterogenity contributes to the phenotypic variability of CoQ10-deficiency;2) levels of oxidative stress, respiratory chain deficiency, and apoptosis differ depending on the severity CoQ10 deficiency, and 3) CoQ10 and its analogs have variable efficacy in CoQ10 deficiencies. To test these hypotheses, we propose the following two specific aims:
Aim 1) To test genetic and pharmacologic therapies for CoQ10 deficiency in vitro by assessing ADCK3 overexpression and analogs of 4- hydroxybenzoic acid, as approaches to rescue endogenous CoQ10 biosynthesis defects;
Aim 2) To test therapies in two mouse model of CoQ10 deficiency by comparing efficacies of oral and intratechal administration of CoQ10 and idebenone in preventing or delaying the onset of the disease in the Pdss2 kd/kd and Coq9X/X mutant mice.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD080642-01
Application #
8741708
Study Section
Developmental Biology Subcommittee (CHHD)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Joseph, Leroy C; Barca, Emanuele; Subramanyam, Prakash et al. (2016) Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes. PLoS One 11:e0145750
Barca, E; Musumeci, O; Montagnese, F et al. (2016) Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. Clin Genet 90:156-60
Torres-Torronteras, Javier; Cabrera-Pérez, Raquel; Barba, Ignasi et al. (2016) Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Hum Gene Ther 27:656-67
Fryer, Robert H; Bain, Jennifer M; De Vivo, Darryl C (2016) Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatr Neurol 56:59-61
Dalla Rosa, Ilaria; Cámara, Yolanda; Durigon, Romina et al. (2016) MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. PLoS Genet 12:e1005779
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Engelstad, Kristin; Sklerov, Miriam; Kriger, Joshua et al. (2016) Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum Reprod 31:1058-65
Barca, Emanuele; Tang, Maoxue; Kleiner, Giulio et al. (2016) CoQ10 Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome. JIMD Rep 29:47-52
Sadat, Roa; Barca, Emanuele; Masand, Ruchi et al. (2016) Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency. Mol Genet Metab 118:28-34
Varma, Hemant; Faust, Phyllis L; Iglesias, Alejandro D et al. (2016) Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet 59:540-5

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