Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response.
Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimer's, Parkinson's, and Huntington's. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small-molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Hyun-Eui
HE
Kim
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Ana Rodrigues
AR
Grant
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Milos S
MS
Simic
Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Rebecca A
RA
Kohnz
Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
Daniel K
DK
Nomura
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Jenni
J
Durieux
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Celine E
CE
Riera
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Melissa
M
Sanchez
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Erik
E
Kapernick
Glenn Center for Research on Aging, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Suzanne
S
Wolff
Glenn Center for Research on Aging, 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 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics; D018869:Heat-Shock Response / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis*; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics; D017510:Protein Folding; D056811:Unfolded Protein Response / Q000502:physiology*
D006360:Heat-Shock Proteins; D008055:Lipids; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones