Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects

• DOI: 10.1016/j.celrep.2014.04.037
• Publication Date: 2014-05-22T12:21:46Z
• Authors: Andrew R. Mullen; Zeping Hu; Xiaolei Shi; Lei Jiang; Lindsey K. Boroughs; Zoltan Kovacs; Richard Boriack; Dinesh Rakheja; Lucas B. Sullivan; W. Marston Linehan; Navdeep S. Chandel; Ralph J. DeBerard...
• Keywords: Carboxylation; Alpha ketoglutarate; Tricarboxylic acid

Mammalian cells generate citrate by decarboxylating pyruvate in the mitochondria to supply tricarboxylic acid (TCA) cycle. In contrast, hypoxia and other impairments of mitochondrial function induce an alternative pathway that produces reductively carboxylating α-ketoglutarate (AKG) via NADPH-dependent isocitrate dehydrogenase (IDH). It is unknown how reducing equivalents necessary reductive carboxylation setting impairment. Here, we identified shared metabolic features using carboxylation. Paradoxically, was accompanied concomitant AKG oxidation TCA Inhibiting decreased equivalent availability suppressed Interrupting transfer from NADH NADPH nicotinamide nucleotide transhydrogenase increased abundance while suppressing The data demonstrate requires bidirectional metabolism along oxidative pathways, with producing used operate IDH reverse.