Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness

Abstract

Conditions resulting from loss of cellular homeostasis, including oxidative stress, inflammation, protein aggregation, endoplasmic reticulum stress, metabolic stress, and perturbation of mitochondrial function, are common to many pathological disorders and contribute to aging. Cells face these stress situations by engaging quality control mechanisms aimed to restore cellular homeostasis and preserve cell viability. Among them, the autophagy-lysosomal pathway mediates the specific degradation of damaged proteins and organelles, and its proper function is related to cellular protection and increased life span in many model organisms. Besides autophagy, increasing evidence underscores a role for exosomes in the selective secretion of harmful/damaged proteins and RNAs and thus in the maintenance of cellular fitness. In this perspective article, we discuss the emerging function of exosomes as a means of alleviating intracellular stress conditions, and how secretion of harmful or unwanted material in exosomes, in coordination with the autophagy-lysosomal pathway, is essential to preserve intracellular protein and RNA homeostasis. Finally, we provide an overview about the consequences of the spreading of the exosome content in physiological and pathological situations, and suggest putative therapeutic strategies for these exosome-mediated alterations.

Keywords: aging; autophagy; endosome; exosomes; lysosome; multivesicular bodies; neurodegeneration; proteostasis; spreading.

Figure 1

Crosstalk between exosome secretion and autophagy in maintenance of cellular homeostasis. Exosome secretion is an alternative way to alleviate stress when recycling pathways are compromised, with an impact in neighboring cells. Recycling mechanisms relay on endosome/autophagy and lysosomal function. Recycling pathways include: macroautophagy where whole cytosolic regions are sequestered inside autophagosomes that fuse either with MVBs or lysosomes, chaperone-mediated autophagy (CMA) where LAMP-2A acts as a receptor for hsc70 on the lysosome to deliver unfolded proteins into the lysosomal lumen, and microautophagy that involves engulfment of small cytoplasmic components by inward invagination of the lysosomal or endosomal membrane.