Glycogen homeostasis and mitochondrial DNA expression require motor neuron to muscle TGF-β/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 development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, loss of Actβ reduces levels of nuclearly encoded genes required for mtDNA replication, transcription, and translation and mtDNA levels. Direct RNAi knockdown of nuclearly encoded mtDNA expression factors in muscle also results in decreased glycogen stores. Lastly, expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels in mutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis, and mtDNA expression factors.