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

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 TGFβ/Activin family member Actβ positively regulates glycogen levels during Drosophila development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, Actβ 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 actβ mutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis and mtDNA expression.

Key Points

• The Drosophila TGFβ family member Actβ signals from motor neuron to muscle positively regulating glycogen levels

• Actβ positively regulates nuclearly encoded factors required for mtDNA expression

• Genes involved in mtDNA expression directly regulate glycogen stores

• Expressing an activated receptor in muscle restores glycogen and mtDNA in actβ mutants

Abstract Figure