Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

Abstract

SUMMARY During neurodegenerative disease, the toxic accumulation of aggregates and misfolded proteins is often accompanied with widespread changes in peripheral metabolism, even in cells in which the aggregating protein is not present. The mechanism by which the central nervous system elicits a distal reaction to proteotoxic stress remains unknown. We hypothesized that the endocrine communication of neuronal stress plays a causative role in the changes in mitochondrial homeostasis associated with proteotoxic disease states. We find that an aggregation-prone protein expressed in the neurons of C. elegans binds to mitochondria, eliciting a global induction of a mitochondrial-specific unfolded protein response (UPRmt), affecting whole-animal physiology. Importantly, dense core vesicle release and secretion of the neurotransmitter serotonin is required for the signal’s propagation. Collectively, these data suggest the commandeering of a nutrient sensing network to allow for cell-to-cell communication between mitochondria in response to protein folding stress in the nervous system.

The mitochondrial unfolded protein response: Signaling from the powerhouse

“…Two recent advancements have been made into the identity of the mitokines that regulate the cell non-autonomous control of the UPR mt . In the first study, the bioamine neurotransmitter serotonin was found to be required for activation of the UPR mt in the intestine as a consequence of mitochondrial protein aggregate accumulation in neurons (26). In a parallel study, interneuron secretion of the neuropeptide FLP-2 was necessary and sufficient for UPR mt activation in the intestine (27).…”

Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

“…Mitochondrial unfolded protein response (UPR mt ) is an evolutionarily conserved system that confers resistance to mitochondrial stresses by upregulating mitochondrion-specific chaperones, such as heat shock protein 6 (HSP-6) or HSP-60 (16,34). To investigate whether loss of asymmetric arginine dimethylation on mitochondrial proteins causes stress in mitochondria, we employed a highly sensitive reporter strain, the zcIS13[Phsp6::gfp] strain, that induces hsp-6 promoter-driven green fluorescent protein (GFP) expression specifically responding to mitochondrial stresses (16,35). As shown in Fig.…”

The mitokine quest(ion)

“…While the relationship between FLP-2 and serotonin has not been examined, it is safe to assume that a number of interesting signaling events occur downstream of both molecules to affect the regulation of intestinal ATFS-1. Both studies indicate that ATFS-1 is essential in both the sensing neurons as well as in the intestinal cells for non-autonomous UPR mt activa-tion [3,5]. In neurons where mitochondria are perturbed directly, ATFS-1 activation is likely achieved by impaired mitochondrial protein import effi ciency.…”

“…activation likely promotes coordination of mitochondrial function or metabolic adaptations across tissues, which may contribute to the metabolic abnormalities found in distal tissues in neurodegenerative diseases such as Huntington's disease and Parkinson's disease [3]. Because neurons do not innervate the worm intestine, non-automonous UPR mt signaling has been hypothesized to be mediated by a "mitokine" [4], however, the mode of signal transduction has remained unclear, as have the functional ramifications.…”

“…Thus, FLP-2 likely functions elsewhere. Similarly, a recent study demonstrated a requirement for the neuronal release of serotonin in activation of the non-autonomous UPR mt , but how serotonin effects intestinal cells remains to be determined [3]. While the relationship between FLP-2 and serotonin has not been examined, it is safe to assume that a number of interesting signaling events occur downstream of both molecules to affect the regulation of intestinal ATFS-1.…”