SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid

TL;DR

This study shows that the MAS inhibitor AOA reduces rRNA transcription through KDM2A activity, while another inhibitor, NPM, does not, highlighting the role of SLC25A11 in this process.

Contribution

The study identifies SLC25A11 as a key player in KDM2A-dependent rRNA transcription reduction under MAS inhibition.

Findings

AOA induces KDM2A-dependent rRNA transcription reduction, while NPM does not.

SLC25A11 is associated with KDM2A activity under MAS inhibition.

Dimethyl αKG restores KDM2A activity inhibited by NPM pretreatment.

Abstract

What are the main findings?

Malate–aspartate shuttle (MAS) inhibitor AOA induces KDM2A-dependent reduction of rRNA transcription, whereas another MAS inhibitor, NPM, does not.

SLC25A11, the αKG/malate carrier in MAS, is associated with KDM2A activity under MAS inhibition.

What are the implications of the main findings?

The induction capacity of MAS inhibitor to induce KDM2A activity differs depending on the inhibition point.

SLC25A11 function has potential for modulation of epigenetic regulation.

The malate–aspartate shuttle (MAS) is an NADH shuttle that transports cytoplasmic reducing equivalents to the mitochondria for producing energy. We previously demonstrated that K-demethylase 2A (KDM2A), a jmjC-type histone demethylase, decreases ribosomal RNA (rRNA) transcription via demethylation of H3K36me2 in the rRNA gene promoter region in response to energy reduction in MCF-7 cells. However, whether MAS inhibition is involved in KDM2A activity has not been investigated. In this study, we demonstrate that aminooxyacetic acid (AOA), which inhibits aspartate transaminase (AST/GOT) in MAS, decreased intracellular ATP levels and reduced rRNA transcription via KDM2A-dependent reduction in H3K36me2 levels in the rRNA gene promoter in MCF-7 cells. On the other hand, N-phenylmaleimide (NPM), which inhibits the mitochondrial αKG/malate carrier SLC25A11 in MAS, also decreased intracellular ATP levels but did not induce KDM2A activity. Additionally, NPM pretreatment or knockdown of SLC25A11 inhibited AOA-induced KDM2A activity. Dimethyl αKG, a cell-permeable αKG, restored KDM2A activity inhibited by NPM-pretreatment in AOA-treated cells. These results demonstrate that AOA and NPM have different abilities to induce a decrease in rRNA transcription via KDM2A. Furthermore, the αKG/malate carrier SLC25A11 is associated with KDM2A-dependent reduction in rRNA transcription via demethylation under MAS inhibition.

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