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

Disorders of coenzyme Q₁₀ (CoQ₁₀) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ₁₀ deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ₁₀ deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ₁₀ deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ₁₀ biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ₁₀) decrease in neuronal CoQ₁₀ status (p < 0.01). Reduction of neuronal CoQ₁₀ 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 CoQ₁₀. Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ₁₀. A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ₁₀ with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ₁₀ deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ₁₀ deficiency.