Mitochondrial-derived compartments facilitate cellular adaptation to amino acid stress

• Published in: Molecular cell 2021-09, Vol.81 (18), p.3786-3802.e13
• Main Authors: Schuler, Max-Hinderk, English, Alyssa M., Xiao, Tianyao, Campbell, Thane J., Shaw, Janet M., Hughes, Adam L.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; amino acid; Amino Acids - metabolism; Amino Acids - toxicity; Carrier Proteins - metabolism; Homeostasis; lysosome; MDC; Membrane Transport Proteins - metabolism; mitochondria; Mitochondria - metabolism; Mitochondria - physiology; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins - metabolism; Multivesicular Bodies - metabolism; nutrient carrier; Organic Anion Transporters - metabolism; Protein Transport; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Stress, Physiological - physiology; Tom70; vacuole; Vacuoles - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.08.021

Amino acids are essential building blocks of life. However, increasing evidence suggests that elevated amino acids cause cellular toxicity associated with numerous metabolic disorders. How cells cope with elevated amino acids remains poorly understood. Here, we show that a previously identified cellular structure, the mitochondrial-derived compartment (MDC), functions to protect cells from amino acid stress. In response to amino acid elevation, MDCs are generated from mitochondria, where they selectively sequester and deplete SLC25A nutrient carriers and their associated import receptor Tom70 from the organelle. Generation of MDCs promotes amino acid catabolism, and their formation occurs simultaneously with transporter removal at the plasma membrane via the multivesicular body (MVB) pathway. The combined loss of vacuolar amino acid storage, MVBs, and MDCs renders cells sensitive to high amino acid stress. Thus, we propose that MDCs operate as part of a coordinated cell network that facilitates amino acid homeostasis through post-translational nutrient transporter remodeling. [Display omitted] •Mitochondrial-derived compartments (MDCs) are micron-sized organelle subdomains•Formation of MDCs occurs in response to elevated amino acid levels•MDCs sequester the mitochondrial protein import receptor Tom70 and SLC25A carriers•MDC formation promotes cellular adaptation to amino acid excess Mitochondrial-derived compartments (MDCs) are enigmatic mitochondrial subdomains that have been observed in aged yeast cells experiencing lysosome dysfunction. Schuler et al. show that MDCs are generated in response to acute elevation in cellular amino acids and that these domains facilitate cellular adaptation to amino acid overabundance.