Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response

Mitochondria are organelles that make ATP by generating a proton gradient across the inner membrane through the action of the electron transport chain (ETC). The gradient is composed of a membrane potential (Δψm) and a concentration gradient (ΔpH). In addition to energy production, mitochondria are recognized as signaling organelles (Chandel 2015), and Δψm powers diverse signaling outputs that mitochondria coordinate. One such signaling response is the mitochondrial unfolded protein response (UPRmt). Some ETC complex components are encoded by mitochondrial or nuclear genes and require coordination between the genomes for proper stoichiometry (Shpilka and Haynes 2018). The UPRmt is a protein homeostasis response that is activated when nuclear and mitochondrial gene expression are not correctly coordinated (Melber and Haynes 2018). When the expression of mitochondrial and nuclear encoded proteins is mismatched, the UPRmt is activated. In C. elegans, the UPRmt is controlled by the transcription factor ATFS-1, which is normally trafficked to mitochondria and degraded. When nuclear:mitochondrial gene expression is perturbed, ATFS-1 is blocked from entering mitochondria and is instead trafficked to the nucleus where a host of chaperones and stress-response genes are activated and transcribed.