Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis.
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 (UPR(mt)), 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 Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Kristen M
KM
Berendzen
The Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Jenni
J
Durieux
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Li-Wa
LW
Shao
The Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Ye
Y
Tian
The Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Hyun-Eui
HE
Kim
The Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Suzanne
S
Wolff
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Ying
Y
Liu
The Glenn Center for Aging Research, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dillin@berkeley.edu.
Andrew
A
Dillin
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002450:Cell Communication; D006706:Homeostasis; D008928:Mitochondria / Q000378:metabolism; D055099:Neuroendocrine Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D017510:Protein Folding; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D010455:Peptides; C107581:UNC-31 protein, C elegans; C097188:polyglutamine; D012701:Serotonin