Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS

Abstract

We report a 36-year-old man with MELAS in whom a 5-month course of high-dose oral idebenone, a derivative of coenzyme Q10, increased markedly cerebral metabolic ratio of oxygen and oxygen extraction fraction without increased cerebral blood flow with PET. The results indicate that idebenone improves mitochondrial oxidative metabolism in the brain and suggest a therapeutic potential of idebenone for MELAS.

Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Impaired Mitochondrial Complex I

“…To demonstrate this effect, previous studies used quinone concentrations, which were much higher than concentrations that can safely be achieved in vivo (high µM range) [8], [22]. Here, we describe for the first time that this mechanism can be observed in vitro at physiological concentrations, even in the low nanomolar range, which makes short-chain quinones an attractive option for the treatment of disorders associated with impaired mitochondrial complex I such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [16], [17] and Leber's hereditary optic neuropathy (LHON) [18], [19]. Although NQO1-dependent electron shuttling from the cytoplasm to the mitochondria by quinones has been described previously [6], [21], [22], it was unclear whether these reports could be seen as individual observations that are exclusively linked to certain cellular model systems.…”

“…Successful treatment of a patient with Leigh syndrome using idebenone, where high-dose CoQ 10 had no effect on respiratory function, is indicative of therapeutic levels of idebenone in the brain [15]. Thus, idebenone has been suggested for treating patients with mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [16], [17] and Leber's hereditary optic neuropathy (LHON) [18], [19].…”

Efficacy of idebenone for respiratory failure in a patient with Leigh syndrome: A long-term follow-up study

“…A recent study showed that idebenone is effective in improving the cardiac deficiency and cerebellar symptoms in patients with Friedreich's ataxia [12], which gene product is localized in the mitochondria. Idebenone has been given to three patients with MELAs [13][14][15] and reported to improve their clinical symptoms and cerebral functions, including electroencephalogram (EEG), IQ, and cerebral metabolic ratio of oxygen. However, its use in Leigh syndrome has not been reported previously.…”

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people

“…This compound was originally developed with a view to treating dementia but has been reported in numerous cases of MELAS 35. It functions as a free-radical scavenger and bypasses complex I.…”