The different axes of the mammalian mitochondrial unfolded protein response

Mitochondria are sensitive to numerous environmental stresses, which can lead to activation of mitochondrial stress responses (MSRs). Of particular recent interest has been the mitochondrial unfolded protein response (UPR(mt)), activated to restore protein homeostasis (proteostasis) upon mitochondrial protein misfolding. Several axes of the UPR(mt) have been described, creating some confusion as to the nature of the different responses. While distinct molecularly, these different axes are likely mutually beneficial and activated in parallel. This review aims at describing and distinguishing the different mammalian MSR/UPR(mt) axes to define key processes and members and to examine the involvement of protein misfolding.