A tale of two pathways: Regulation of proteostasis by UPR^mt and MDPs

Mitochondrial fitness is critical to organismal health and its impairment is associated with aging and age-related diseases. As such, numerous quality control mechanisms exist to preserve mitochondrial stability, including the unfolded protein response of the mitochondria (UPR^mt). The UPR^mt is a conserved mechanism that drives the transcriptional activation of mitochondrial chaperones, proteases, autophagy (mitophagy), and metabolism to promote restoration of mitochondrial function under stress conditions. UPR^mt has direct ramifications in aging, and its activation is often ascribed to improve health whereas its dysfunction tends to correlate with disease. This review pairs a description of the most recent findings within the field of UPR^mt with a more poorly understood field: mitochondria-derived peptides (MDPs). Similar to UPR^mt, MDPs are microproteins derived from the mitochondria that can impact organismal health and longevity. We then highlight a tantalizing interconnection between UPR^mt and MDPs wherein both mechanisms may be efficiently coordinated to maintain organismal health.