Glycogen homeostasis and mtDNA expression require motorneuron to muscle TGFβ/Activin Signaling in Drosophila

Abstract

Maintaining metabolic homeostasis requires coordinated nutrient utilization between intracellular organelles and across multiple organ systems. Many organs rely heavily on mitochondria to generate (ATP) from glucose, or stored glycogen. Proteins required for ATP generation are encoded in both nuclear and mitochondrial DNA (mtDNA). We show that motoneuron to muscle signaling by the TGF{beta}/Activin family member Act{beta} positively regulates glycogen levels during Drosophila development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, Act{beta} loss reduces levels of mtDNA and nuclearly encoded genes required for mtDNA replication, transcription and translation. Direct RNAi mediated knockdown of these same nuclearly encoded mtDNA expression factors also results in decreased glycogen stores. Lastly, we find that expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels in act{beta} mutants, thereby confirming a direct link between Act{beta} signaling, glycogen homeostasis and mtDNA expression. Key PointsO_LIThe Drosophila TGF{beta} family member Act{beta} signals from motor neuron to muscle positively regulating glycogen levels C_LIO_LIAct{beta} positively regulates nuclearly encoded factors required for mtDNA expression C_LIO_LIGenes involved in mtDNA expression directly regulate glycogen stores C_LIO_LIExpressing an activated receptor in muscle restores glycogen and mtDNA in act{beta} mutants C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/600699v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1bafafaorg.highwire.dtl.DTLVardef@b34255org.highwire.dtl.DTLVardef@c80b05org.highwire.dtl.DTLVardef@14b9b9e_HPS_FORMAT_FIGEXP M_FIG C_FIG