A tale of two pathways: Regulation of proteostasis by UPRmt and MDPs. (February 2023)

• Record Type: Journal Article
• Authors: Johns, Angela; Higuchi-Sanabria, Ryo; Thorwald, Max A.; Vilchez, David
• Is Part Of: Current opinion in neurobiology. Volume 78(2023)
• Publication Date: 2023-02
• Subjects: Neurobiology -- Periodicals; 573.8
• DOI: 10.1016/j.conb.2022.102673
• Languages: English
• ISSNs: 0959-4388

Abstract

Abstract: 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. Highlights: Mitochondria-derived peptides (MDPs) impact proteostasis and neuronal health. Identification of novel MDPs can reveal new therapies for age-related diseases. Mitochondrial permeability transition pore promotes aging. Neuronal UPR mt promotes whole organism health through non-autonomous signaling. Germline mitochondrial proteostasis prevents protein aggregation in distal tissues.