Mitochondrial unfolded protein response (UPRmt)

The Mitochondrial Unfolded Protein Response (UPRmt) is a highly conserved adaptive signaling pathway that maintains mitochondrial proteostasis by responding to proteotoxic stress within the organelle [1,2]. When misfolded proteins accumulate or mitochondrial function is compromised, a retrograde signal is sent to the nucleus to trigger the upregulation of protective genes, including nuclear-encoded mitochondrial chaperones (e.g., HSP60) and proteases (e.g., ClpP) [1,3]. This pathway is essential for mitochondrial quality control and has been linked to longevity and metabolic health in various model organisms [4]. In human health, the UPRmt plays a dual role: its activation can be neuroprotective in diseases like Alzheimer's and Parkinson's by improving mitochondrial health, but its chronic induction in cancer cells often facilitates survival under harsh tumor microenvironments and promotes resistance to chemotherapy [5,6]. Therapeutic strategies targeting the UPRmt involve both activators and inhibitors. Small molecules such as NAD+ precursors (e.g., nicotinamide riboside) and certain antibiotics (e.g., doxycycline) have been shown to induce the UPRmt, providing mitohormetic benefits that enhance cellular resistance to aging and metabolic stress [3,7]. Conversely, inhibitors targeting specific UPRmt components, like the protease ClpP or the chaperone TRAP1 (Hsp90L), are being explored as anti-cancer agents to disrupt the mitochondrial stability that tumor cells rely upon [8]. Monitoring the pathway often involves measuring the expression levels of ATF5, HSP60, or systemic stress markers like GDF15 [2,9].

Other names

Mitochondrial stress responseUPRmt pathwayMitochondrial proteostasis responseMitochondrial-to-nuclear retrograde signaling

The UPRmt is activated through mitochondrial-to-nuclear retrograde signaling triggered by proteotoxic stress or mitochondrial dysfunction. In mammals, this involves the stabilization and nuclear translocation of transcription factors like ATF5, which then promote the transcription of mitochondrial chaperones (e.g., HSP60, HSP10) and proteases (e.g., ClpP) to restore mitochondrial protein folding and degradation balance. Small molecules can modulate this pathway by inducing mild mitochondrial stress (mitohormesis) or by increasing NAD+ levels to activate sirtuin-mediated signaling.