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In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H 2 O 2  by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H 2 O 2  elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in  skeletal  muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H 2 O 2  emission in  cardiac  mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H 2 O 2  emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H 2 O 2  emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H 2 O 2 -eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H 2 O 2  emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H 2 O 2 -eliminating capacity increases H 2 O 2  emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H 2 O 2  emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H 2 O 2  elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.   Electronic supplementary material  The online version of this article (10.1007/s00395-020-0815-1) contains supplementary material, which is available to authorized users.

basic research in cardiology

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