Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart

We investigated how impaired α-ketoglutarate dehydrogenase activity affects the C­ a2+-dependent regeneration of NAD(P)H when mitochondria are integrated in their physiological context of intact cardiac myocytes

Michael Wagner; Edoardo Bertero; Alexander Nickel; Michael Kohlhaas; Gary E. Gibson; Ward Heggermont; Stephane Heymans; Christoph Maack

2020

Scholarcy highlights

  • Mitochondria are the major source of cellular adenosine triphosphate, and reactive oxygen species
  • The Krebs cycle enzyme α-ketoglutarate dehydrogenase is a major source of NADH within mitochondria, but its contribution to nicotinamide adenine dinucleotide phosphate regeneration and thereby, the maintenance of mitochondrial antioxidative capacity is not known
  • NADPH produced by the Krebs cycle dehydrogenases and the nicotinamide nucleotide transhydrogenase reaction is pivotal to regenerating mitochondrial antioxidative capacity in the heart, and studies evaluating α-KGDH-dependent ROS production were performed in skeletal muscle and brain mitochondria, where NNT activity is negligible compared to the heart
  • Significance was calculated using two-way ANOVA with Bonferroni’s post-hoc test strains. These results suggest that NADH derived from the α-KGDH reaction is preferentially used for NADPH regeneration via the NNT, which represents the dominant source of NADPH in the presence of α-KG alone
  • Our results indicate that in cardiac mitochondria, the α-KGDH is a sink rather than a source of ROS, since NADH produced from α-KGDH is preferentially shuttled towards the NNT rather than to complex I
  • We re-grouped WT and Dlst+/− myocytes into those with low, intermediate, and high α-KGDH activity depending on whether the α-KGDH in the respective tissue was below 60%, between 60 and 80% or above 80%, respectively, compared to the one of WT myocytes with the highest α-KGDH activity
  • We showed previously that in contrast to cardiac mitochondria, these have negligible NNT activity, thereby preventing the antioxidative “safety valve escape” of NADH shuttling to NADPH under reducing conditions
  • Downregulation of α-ketoglutarate dehydrogenase by microRNA-146a during cardiac hypertrophy and failure may contribute to redox imbalance during situations of elevated cardiac workload

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