UPR^mt scales mitochondrial biomass with protein synthesis via mitochondrial import flux

Individual cells acquire mitochondrial biomass to fulfill physiologic requirements. However, it remains unknown how mitochondrial biomass is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPR^mt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). We demonstrate that ATFS-1 mediates an adaptable mitochondrial biogenesis program that is active throughout development. ATFS-1 possesses a relatively inefficient MTS, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPR^mt activity due to increased accumulation within mitochondria. The insulin signaling-TORC1 and Integrated Stress Response pathways affect UPR^mt activation in a manner that correlated with protein synthesis. Manipulation of either pathway to increase protein synthesis caused UPR^mtactivation, which required the inefficient MTS. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial import of ATFS-1. We propose that mitochondrial biomass expansion is an emergent property of the translation of highly expressed mitochondrial proteins with strong MTSs that outcompete ATFS-1 at the import channels, causing UPR^mt activation. Mitochondrial biomass expansion is attenuated once mitochondrial import is resolved.