Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

Abstract

Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis through unclear means. Here we demonstrate that, unlike the canonical iron-induced alterations to transcript stability, loss of iron dampens the transcription of genes encoding mitochondrial proteins with no change to transcript half-life. Using mass spectrometry, we demonstrate that these transcriptional changes are accompanied by dynamic alterations to histone acetylation and methylation levels that are largely reversible upon readministration of iron. Moreover, histone deacetylase inhibition abrogates the decreased histone acetylation observed upon iron deprivation and restores normal transcript levels at genes encoding mitochondrial proteins. Collectively, we demonstrate that deprivation of an essential nutrient induces transcriptional repression of organellar biogenesis involving epigenetic alterations.

The presence of anaemia negatively influences survival in patients with POLG disease

“…In a study using matched quantitative genomic and proteomic analysis in mouse muscle cells, iron deprivation resulted in a rapid, dose-dependent decrease of mitochondrial proteins and oxidative capacity that was fully reversed when iron was reintroduced (Rensvold et al 2013). Subsequent studies showed that the transcriptional changes were accompanied by alterations to histone acetylation and methylation levels that were largely reversible by reintroduction of iron (Rensvold et al 2016).…”

Molecular regulation of cellular iron balance

“…However, to adapt to iron deprivation, the cell also adopts other molecular mechanisms operating at the transcriptional and post‐translational level. On the one hand, the cells save iron by epigenetically repressing the transcription of genes coding for mitochondrial proteins , possibly because the demethylating enzymes of the Jumonji C family involved in histone modifications require ferrous iron . On the other hand, iron conservation mechanisms involving preferential expression of essential iron‐dependent proteins are also active during iron starvation, a condition in which the biosynthesis of proteins involved in nonessential functions is downregulated by TTP .…”

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

“…While the role of α-KG levels in regulation of JmjC family histone demethylases has not yet been shown, both oxygen and iron availability mediate the activity of these enzymes. Hypoxia has been reported to increase histone methylation and modulate downstream gene expression in a number of settings and cell types via inhibition of JmjC demethylases (119–121), and pharmacologic iron chelation in mouse myoblast cells results in increased histone methylation at JmjC target sites (122). Notably, although the direct role of α-KG as a regulator of JmjC family members remains to be elucidated, its structural analog 2-hydroxyglutarate (2-HG), which is produced by cancer-associated IDH1 and IDH2 mutants, is a competitive inhibitor of these enzymes, resulting in aberrant histone methylation that contributes to the cancer phenotype (123,124).…”