The mitochondrial unfolded protein response: Signaling from the powerhouse

Abstract

Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPR^mt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR^mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.

Keywords: Mitochondrial dysfunction; cell metabolism; cell signaling; cellular regulation; mitochondria; mitochondrial quality control; mitochondrial stress signaling; mitochondrial unfolded protein response; stress response.

Figure 1.

Regulation of the UPR^mt in C. elegans and mammals. A, in C. elegans, the UPR^mt is principally regulated by the bZIP transcription factor ATFS-1 that contains both mitochondrial and nuclear sorting sequences. In the absence of mitochondrial stress, ATFS-1 localizes to mitochondria and is degraded by the protease Lon. Perturbation to mitochondrial function reduces mitochondrial import efficiency causing an accumulation of cytosolic ATFS-1 and subsequent nuclear import. ATFS-1 regulates a diverse transcriptional program to recover mitochondrial function, including the attenuation of OXPHOS gene expression in both the nucleus and mitochondria. Multiple regulators of the UPR^mt have been identified, including the protease ClpP and the ABC transporter HAF-1 that control UPR^mt activity through an unidentified mechanism involving peptide efflux. B, mammalian UPR^mt is regulated by the transcription factors CHOP and ATF5 that transcriptionally regulate genes to restore mitochondrial homeostasis. CHOP is transcriptionally activated by transcription factor c-Jun during mitochondrial stress. ATF5 contains mitochondrial and nuclear localization sequences similar to ATFS-1 that regulate UPR^mt activity based on the efficiency of mitochondrial import.

Figure 2.

Cell non-autonomous regulation of the UPR^mt. Mitochondrial dysfunction in neurons activates the UPR^mt in distal tissues such as the intestine through diffusible “mitokine” signals, including the neurotransmitter serotonin and the neuropeptide FLP-2. stress^mt, mitochondrial stress.

Figure 3.

Biological roles of the UPR^mt. The UPR^mt supports a variety of organismal functions, including the regulation of innate immunity during pathogen infection (A); the control of deleterious mitochondrial genome numbers (B); mediating metabolic adaptations during mitochondrial stress (C); and promoting stem cell maintenance (D). stress^mt, mitochondrial stress.