Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbα

Abstract

Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erba tightly controls the level of its own ligand. Heme binding to Rev-erba recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1a, a potent inducer of heme synthesis. Depletion of Rev-erba derepresses PGC-1a, resulting in increased heme levels. Conversely, increased Rev-erba reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erba dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erba modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.[Keywords: Rev-erba; PGC-1a; heme homeostasis; mitochondria; energy] Supplemental material is available at http://www.genesdev.org.

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase

“…The final step of heme biosynthesis occurs in the mitochondria (6). Because free heme is toxic to cells as a result of its potential to generate reactive oxygen species that can cause damage to DNA, proteins, and lipids (3), cells keep intracellularfree heme levels to the minimum (6)(7)(8) and heme homeostasis is one of the most highly regulated processes in mammals (9). Heme insertion into apo-proteins is a key posttranslational event that must take place within this context.…”

Negative feedback confers mutational robustness in yeast transcription factor regulation

“…Additionally, negative regulatory feedback, in which a biomolecule represses its own abundance, can buffer variation in gene expression (11,12), and negative feedback loops have been shown to underlie robustness to variable environmental conditions and stochastic intracellular change (13-15). Negative feedback may also confer network stability against the effects of mutations (3, 16), but evidence for negative feedback as a driver of mutational robustness in vivo has been at a premium (17); the relevance of this principle to natural genetic variation remains largely unknown.In this work, we focused on negative feedback in yeast hypoxia regulation motivated by the extensive evidence for feedback in oxygen response pathways across biology (18,19). We characterized the feedback loop at the yeast hypoxia regulator ROX1 in molecular detail, and we harnessed this system as a test bed to study how feedback confers stability against naturally occurring mutations.…”

“…In this work, we focused on negative feedback in yeast hypoxia regulation motivated by the extensive evidence for feedback in oxygen response pathways across biology (18,19). We characterized the feedback loop at the yeast hypoxia regulator ROX1 in molecular detail, and we harnessed this system as a test bed to study how feedback confers stability against naturally occurring mutations.…”

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

“…These add to the biological importance of the HO-1 and HO-2 enzyme system. Protection against obesity and oxidative stress-related diseases: HO-1 expression levels exhibit circadian (daynight) cycles (Yin et al 2007;Wu et al 2009). HO-1 expression is regulated by the transcription factor network, including CLOCK, Bmal and Per, that works in concert to generate day-night cyclic expression of the genes involved in energy metabolism (Bass and Takahashi 2010;Huang et al 2011;Dang 2012).…”

“…Li and co-workers (2012) postulate that increased heme catabolism via HO-1 up-regulation blunts the rate of glycolysis in liver. Because heme is known to have inhibitory effects on glucose production (gluconeogenesis) (Wu et al 2009;Yin et al 2007), up-regulation of HO-1 is a logical response as it can lower intracellular heme concentrations in order to take liver glucose production for its own use and to release it into the circulation to maintain blood glucose levels. Dampening of glycolysis is required to prevent a futile cycle.…”