TY  - JOUR
A1  - Wagner, Michael
A1  - Bertero, Edoardo
A1  - Nickel, Alexander
A1  - Kohlhaas, Michael
A1  - Gibson, Gary E.
A1  - Heggermont, Ward
A1  - Heymans, Stephane
A1  - Maack, Christoph
T1  - Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart
T2  - Basic Research in Cardiology
N2  - 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 H2O2 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, H2O2 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.
KW  - mitochondria
KW  - α-Ketoglutarate dehydrogenase
KW  - reactive oxygen species
KW  - nicotinamide nucleotide transhydrogenase
Y1  - 2020
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/23490
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-234907
SN  - 0300-8428
VL  - 115
ER  -