Heme Interaction with the Pyruvate Dehydrogenase Complex: A Novel Strategy to Promote Hypoxic Survival

Heme is an important regulator of biological processes, but an unresolved question remains, can heme regulate the switch between glycolysis and mitochondrial oxidation in mammalian cells? Here we show that ABCB6, a member of the ATP‐binding cassette (ABC) family and an activator of heme synthesis facilitates a heme dependent metabolic transition between mitochondrial oxidative phosphorylation and glycolytic metabolism. ABCB6 is upregulated by the Hif‐1α pathway and mimicking this, overexpression of ABCB6 primarily increased mitochondrial heme, reduced pyruvate‐fueled mitochondrial oxygen consumption and increased hypoxic survival. Suppression of heme synthesis abolished this hypoxic survival advantage. Deletion of ABCB6 increased mitochondrial oxygen consumption in the inherently hypoxic double‐negative thymocytes. We hypothesized that pyruvate dehydrogenase (PDH) activity was suppressed by heme and directly demonstrated that heme potently inhibited PDH activity. Hemin‐agarose affinity chromatography revealed that only one subunit of the multimeric PDH complex, PDHA1, is bound to heme. Mutagenesis of PDHA1 suggested that the heme binding site was distinct from the substrate binding site, a finding consistent with heme inhibiting PDH non‐competitively. Heme binding to PDHA1 resulted in its dissociation from the PDH complex. PDHA1 dissociation was reversible, as dilution of heme containing PDH promoted reformation of the complex, which paralleled restoration of PDH activity. These findings reveal a new relationship between heme production and the ability to metabolically switch from pyruvate oxidation in the mitochondria to its glycolytic conversion to lactate. Support or Funding Information This work was supported by NIH and by the ALSAC. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .