Uncoupling protein-4 (UCP4) increases neuronal ATP production via respiratory Complex-II activation - a bioenergetic study

Abstract

Mitochondrial uncoupling protein-4 (UCP4) can protect neurons against 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced toxicity but how UCP4 can affect mitochondrial function is unclear. We investigated how UCP4 overexpression can affect mitochondrial bioenergetics in SH-SY5Y neuronal cells. UCP4 overexpression did not alter mitochondrial mass and morphology insitu. UCP4-overexpressing cells had higher oxygen consumption (10.1±0.36%, p < 0.01) under normal culture conditions with 20% greater mitochondrial proton leak than controls (p < 0.01). Increased cellular energy supply was reflected by higher total ATP levels in UCP4-overexpressing cells than controls (p < 0.05). Although classical State-4/State-3 mitochondrial respiration rates were similar between UCP4-overexpressing and control cells, mitochondrial Complex-II REDOX activity in UCP4-overexpressing cells was 30% higher (p < 0.05), but not for Complex-I and -IV. Increased Complex-II activity was associated with 20% higher ADP/O ratio (p < 0.05), but unchanged for Complex-I. These indicate that increased ATP in UCP4-overexpressing cells was produced via Complex-II. ADP/ATP exchange rate reflecting mitochondrial ATP export was not affected by UCP4 overexpression as shown by similar ADP uptake via adenine nucleotide translocase (ANT) with controls. Our findings demonstrate how UCP4 overexpression could increase the efficiency of oxidative phosphorylation and ATP synthesis via Complex-II, suggesting how UCP4 can protect neurons against MPTP-induced ATP deficiency and cell death where Complex-I is inhibited.