Luís PB et al (2013) Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases. J Inherit Metab Dis. 2013 Oct 24. [Epub ahead of print]
Luis et al propose a new mechanism for valproic acid-induced mitochondrial dysfunction, particularly in patients with deficiencies of the mtDNA replication machinery.
Succinate:CoA ligase (SUCL), also known as succinyl-CoA synthetase, is a mitochondrial enzyme that participates in the Krebs cycle by converting succinyl-CoA into succinate and coenzyme A. Its deficiency is known to cause a mitochondrial DNA depletion syndrome with mild methylmalonic aciduria. Although the mechanism of mitochondrial DNA depletion in primary SUCL deficiency has not been entirely elucidated, it has been proposed that SUCL is tightly associated with NDPK (nucleoside diphosphate kinase), which is a crucial component of the mitochondrial dNTP salvage pathway. A deficiency of SUCL may therefore affect the function of NDPK and cause a nucleotide imbalance in mitochondria, leading to mitochondrial DNA depletion (Elpeleg et al 2005).
In this study, the authors show that valproyl-CoA (but not valproic acid per se) inhibits SUCL in healthy human fibroblasts, at least when enzyme activity is measured in the reverse direction (i.e. the formation of succinyl-CoA). The inhibition is incomplete (to 45-55% of control activity at valproic acid levels corresponding to therapeutic plasma concentrations) possibly explaining the absence of the specific biochemical abnormalities associated with SUCL deficiency in patients on valproic acid. The authors suggest, however, that this partial inhibition may be sufficient to impair the cellular energy status by interfering with the Krebs cycle, but also to perturb NDPK function and thereby cause mitochondrial DNA depletion; patients with underlying primary deficiencies in the mtDNA replication machinery (e.g. with POLG deficiency) would be particularly vulnerable to this effect.
References: Elpeleg O et al (2005). Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 76:1081-1086.
Posted by: Alina Levtova, MD