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Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment.
J Inherit Metab Dis. 2013 Jan; 36(1):63-73.JI

Abstract

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

Authors+Show Affiliations

Department of Molecular Neuroscience, UCL Institute of Neurology and Neurometabolic Unit, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK. skgtked@ucl.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22767283

Citation

Duberley, Kate E C., et al. "Human Neuronal Coenzyme Q10 Deficiency Results in Global Loss of Mitochondrial Respiratory Chain Activity, Increased Mitochondrial Oxidative Stress and Reversal of ATP Synthase Activity: Implications for Pathogenesis and Treatment." Journal of Inherited Metabolic Disease, vol. 36, no. 1, 2013, pp. 63-73.
Duberley KE, Abramov AY, Chalasani A, et al. Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. J Inherit Metab Dis. 2013;36(1):63-73.
Duberley, K. E., Abramov, A. Y., Chalasani, A., Heales, S. J., Rahman, S., & Hargreaves, I. P. (2013). Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. Journal of Inherited Metabolic Disease, 36(1), 63-73. https://doi.org/10.1007/s10545-012-9511-0
Duberley KE, et al. Human Neuronal Coenzyme Q10 Deficiency Results in Global Loss of Mitochondrial Respiratory Chain Activity, Increased Mitochondrial Oxidative Stress and Reversal of ATP Synthase Activity: Implications for Pathogenesis and Treatment. J Inherit Metab Dis. 2013;36(1):63-73. PubMed PMID: 22767283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. AU - Duberley,Kate E C, AU - Abramov,Andrey Y, AU - Chalasani,Annapurna, AU - Heales,Simon J, AU - Rahman,Shamima, AU - Hargreaves,Iain P, Y1 - 2012/07/06/ PY - 2012/03/21/received PY - 2012/06/14/accepted PY - 2012/06/11/revised PY - 2012/7/7/entrez PY - 2012/7/7/pubmed PY - 2013/9/26/medline SP - 63 EP - 73 JF - Journal of inherited metabolic disease JO - J Inherit Metab Dis VL - 36 IS - 1 N2 - Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency. SN - 1573-2665 UR - https://www.unboundmedicine.com/medline/citation/22767283/Human_neuronal_coenzyme_Q10_deficiency_results_in_global_loss_of_mitochondrial_respiratory_chain_activity_increased_mitochondrial_oxidative_stress_and_reversal_of_ATP_synthase_activity:_implications_for_pathogenesis_and_treatment_ L2 - https://doi.org/10.1007/s10545-012-9511-0 DB - PRIME DP - Unbound Medicine ER -