Abstract
Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation-induced necrosis, but its function and substrates remain unclear. Herein, we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.
Highlights
The α-ketoglutarate (α-KG) dioxygenases are a diverse enzyme superfamily, whose primary biochemical function is the addition of hydroxyl (–OH) to protein or nucleic acid substrates.[1]
As such, agreeing with the observed cardioprotection in the Alkbh7-/- mouse originating via hormetic signaling, we found that protection against IR injury was lost in aged male Alkbh7-/- mice (Fig. S6)
Summarizing the current findings, a comprehensive analysis of the Alkbh7-/- mouse heart suggests Alkb homolog 7 (ALKBH7) is not a functional prolyl-hydroxylase that regulates mitochondrial activity, and that its role in necrosis involves rewiring of MGO metabolism
Summary
The α-ketoglutarate (α-KG) dioxygenases are a diverse enzyme superfamily, whose primary biochemical function is the addition of hydroxyl (–OH) to protein or nucleic acid substrates.[1]. In parallel with analysis of P-OH, the TMT proteomic experiment yielded relative abundance values for 3,737 proteins in Alkbh7-/- and WT hearts, with a volcano plot (Fig. 2A) revealing several differences which may underlie the metabolic phenotype of the knockout animals.A The lipid droplet protein perilipin-5, which signals via Sirt1/PPAR-α to drive mitochondrial biogenesis and fat oxidation,[22] was 25% lower in Alkbh7-/- vs WT.
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