Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel

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176 Scopus citations


Rationale: Pyridine nucleotides regulate the cardiac Na current (INa) through generation of reactive oxygen species (ROS). Objective: We investigated the source of ROS induced by elevated NADH. Methods and Results: In human embryonic kidney (HEK) cells stably expressing the cardiac Na channel, the decrease of INa (52±9%; P<0.01) induced by cytosolic NADH application (100 μmol/L) was reversed by mitoTEMPO, rotenone, malonate, DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid), PK11195, and 4′-chlorodiazepam, a specific scavenger of mitochondrial superoxide and inhibitors of the mitochondrial complex I, complex II, voltage-dependent anion channels, and benzodiazepine receptor, respectively. Anti-mycin A (20 μmol/L), a complex III inhibitor known to generate ROS, decreased INa (51±4%, P<0.01). This effect was blocked by NAD, forskolin, or rotenone. Inhibitors of complex IV, nitric oxide synthase, the NAD(P)H oxidases, xanthine oxidases, the mitochondrial permeability transition pore, and the mitochondrial ATP-sensitive K channel did not change the NADH effect on INa. Analogous results were observed in cardiomyocytes. Rotenone, mitoTEMPO, and 4′-chlorodiazepam also blocked the mutant A280V GPD1-L (glycerol-3-phosphate dehydrogenase 1-like) effect on reducing INa, indicating a role for mitochondria in the Brugada syndrome caused by this mutation. Fluorescent microscopy confirmed mitochondrial ROS generation with elevated NADH and ROS inhibition by NAD. Conclusions: Altering the oxidized to reduced NAD(H) balance can activate mitochondrial ROS production, leading to reduced INa. This signaling cascade may help explain the link between altered metabolism, conduction block, and arrhythmic risk.

Original languageEnglish (US)
Pages (from-to)967-974
Number of pages8
JournalCirculation research
Issue number8
StatePublished - Oct 15 2010


  • arrhythmia
  • metabolism
  • pyridine nucleotides
  • sudden death


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