The
2-oxoglutarate dehydrogenase complex (OGDHc) is a key
enzyme in the
tricarboxylic acid (TCA) cycle and represents one of the major regulators of mitochondrial metabolism through
NADH and
reactive oxygen species levels. The OGDHc impacts cell metabolic and cell signaling pathways through the coupling of
2-oxoglutarate metabolism to gene transcription related to
tumor cell proliferation and aging. DHTKD1 is a gene encoding 2-oxoadipate
dehydrogenase (E1a), which functions in the
L-lysine degradation pathway. The potentially damaging variants in DHTKD1 have been associated to the (neuro) pathogenesis of several diseases. Evidence was obtained for the formation of a hybrid complex between the OGDHc and E1a, suggesting a potential cross talk between the two metabolic pathways and raising fundamental questions about their assembly. Here we reviewed the recent findings and advances in understanding of
protein-
protein interactions in OGDHc and 2-oxoadipate
dehydrogenase complex (OADHc), an understanding that will create a scaffold to help design approaches to mitigate the effects of diseases associated with dysfunction of the TCA cycle or
lysine degradation. A combination of biochemical, biophysical and structural approaches such as chemical cross-linking MS and cryo-EM appears particularly promising to provide vital information for the assembly of 2-oxoacid
dehydrogenase complexes, their function and regulation.