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Human neuronal coenzyme Q 10 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
Author(s) -
Duberley Kate E. C.,
Abramov Andrey Y.,
Chalasani Annapurna,
Heales Simon J.,
Rahman Shamima,
Hargreaves Iain P.
Publication year - 2013
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9511-0
Subject(s) - coenzyme q10 , coenzyme q – cytochrome c reductase , mitochondrial respiratory chain , oligomycin , mitochondrion , oxidative stress , respiratory chain , oxidative phosphorylation , biology , mitochondrial disease , atp synthase , purkinje cell , biochemistry , endocrinology , enzyme , atpase , mitochondrial dna , cerebellum , cytochrome c , gene
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.