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

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.

The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome

“…It is important to note, however, that increased mitochondrial membrane potential may result in increased ROS levels, and vice versa, high ROS levels can lead to the depolarization of the mitochondrial membrane potential (Korshunov et al 1997). Furthermore, under certain conditions mitochondrial membrane potential may be maintained at the expense of ATP production, by reversal of the activity of the ATP synthase (Duberley et al 2013). Similarly to the ROS results, we observed no changes in mitochondrial membrane potential in cells from both controls and all studied subjects, except fibroblasts from subject 3, in which we also observed increased mitochondrial volume, as discussed above.…”

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

“…Under normal conditions the process of respiration maintains the ΔΨ m but mitochondria can also hydrolyze the ATP forcing the ATPase to work in a reverse mode in order to maintain the ΔΨ m 37 . This has been thoroughly described in other neurodegenerative models in which an inhibition of respiration hampers the normal ΔΨ m maintenance forcing the reversal ATPase 38–40 .…”

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

“…The properties of I-ADMQ are not known but they may have antioxidant capacities and may also participate to mitochondrial respiration as demonstrated for the closely related molecule demethoxy-coenzyme Q (DMQ, 14 ; Wang and Hekimi, 2013b). Therefore, pABA may not be the most appropriate agent to induce CoQ 10 deficiency in cell lines and study the consequential physiological impacts (Gonzalez-Aragon et al, 2005; Duberley et al, 2013, 2014). Instead, 4-NB must be considered for such purposes since it does not form any prenylated products (Forsman et al, 2010; Quinzii et al, 2012).…”