Abstract
Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
Highlights
Mitochondria are unique cellular organelles in that they possess their own genome
These results provided initial evidence that Lsd1 in the liver may play an important role in regulating metabolism
Because of the critical roles of Lysine-specific demethylase-1 (LSD1) in regulating gene expression, we performed RNA sequencing (RNA-seq), followed by Gene Set Enrichment Analysis (GSEA), DAVID functional annotation, and Panther ontology analysis to identify gene sets and pathways that were regulated upon LSD1 KO in the liver
Summary
Mitochondria are unique cellular organelles in that they possess their own genome. the mitochondrial genome encodes only 13 proteins for oxidative phosphorylation (OXPHOS), as well as 2 rRNAs and 22 transfer RNAs (tRNAs) [1, 2]. Mitochondrial biogenesis and function are tightly controlled by more than 1000 proteins encoded by nuclear genes (nuclear DNA [nDNA]), forming a nuclear-to-mitochondrial anterograde regulatory system [1,2,3]. Nuclear respiratory factor-1 (NRF1), GA binding proteins (GABPα/β, known as NRF2), and estrogen-related receptor α (ERRα) are the key transcription factors controlling these nDNA-encoded mitochondrial genes. The transcription cofactor PGC-1α, which interacts with NRF1, ERRα, and GABPα/β, serves as a master regulator of mitochondrial biogenesis and function [5,6,7]. This transcriptional machinery is considered to be the major anterograde nucleus-to-mitochondria regulatory system to maintain mitochondrial homeostasis
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