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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H2O2 by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H2O2 elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, alpha-ketoglutarate dehydrogenase (alpha-KGDH) is a major source of superoxide inskeletalmuscle mitochondria with low NNT activity. Here, we analyzed how alpha-KGDH and NNT control H2O2 emission incardiacmitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H2O2 emission is equally low with pyruvate/malate (P/M) or alpha-ketoglutarate (alpha-KG) as substrates. Complex I inhibition with rotenone increases H2O2 emission from P/M, but not alpha-KG respiring mitochondria, which is potentiated by depleting H2O2-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H2O2 emission is higher with alpha-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H2O2-eliminating capacity increases H(2)O(2)emission from P/M, but not alpha-KG respiring mitochondria. In cardiac myocytes, downregulation of alpha-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H2O2 emission. In conclusion, NADH from alpha-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, alpha-KGDH plays a key role for H2O2 elimination, but is not a relevant source of superoxide in heart. In heart failure, alpha-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of alpha-KGDH may, therefore, predispose to oxidative stress in heart failure.

Original languageEnglish
Article number53
Number of pages16
JournalBasic Research in Cardiology
Issue number5
Publication statusPublished - 3 Aug 2020


  • Mitochondria
  • alpha-Ketoglutarate dehydrogenase
  • Reactive oxygen species
  • Nicotinamide nucleotide transhydrogenase

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