Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
Schroder, M. & Kaufman, R. J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789 (2005).
Hsu, A. L., Murphy, C. T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003).
Westerheide, S. D., Anckar, J., Stevens, S. M. Jr, Sistonen, L. & Morimoto, R. I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063–1066 (2009).
Dabsan, S., Twito, G., Biadsy, S. & Igbaria, A. Less is better: various means to reduce protein load in the endoplasmic reticulum. FEBS J. 292, 976–989 (2025).
Bernales, S., Papa, F. R. & Walter, P. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508 (2006).
Matai, L. et al. Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. Proc. Natl. Acad. Sci. USA 116, 17383–17392 (2019).
Sadighi Akha, A. A. et al. Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity. J. Biol. Chem. 286, 30344–30351 (2011).
Goodall, E. F. et al. Age-associated mRNA and miRNA expression changes in the blood-brain barrier. Int. J. Mol. Sci. 20, 3097 (2019).
Berchtold, N. C. et al. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc. Natl. Acad. Sci. USA 105, 15605–15610 (2008).
Hartmann, E. et al. Evolutionary conservation of components of the protein translocation complex. Nature 367, 654–657 (1994).
Romisch, K. A case for Sec61 channel involvement in ERAD. Trends Biochem. Sci. 42, 171–179 (2017).
Wei, X. et al. Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nat. Commun. 15, 659 (2024).
Chen, Y. G. & Hur, S. Cellular origins of dsRNA, their recognition and consequences. Nat. Rev. Mol. Cell Biol. 23, 286–301 (2022).
Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018).
Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y. & Sfeir, A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature 591, 477–481 (2021).
Bonekamp, N. A. et al. Small-molecule inhibitors of human mitochondrial DNA transcription. Nature 588, 712–716 (2020).
López-Polo, V. et al. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells. Nat. Commun. 15, 7378 (2024).
Wang, G. et al. PNPASE regulates RNA import into mitochondria. Cell 142, 456–467 (2010).
Wang, P. C. et al. ANT2 functions as a translocon for mitochondrial cross-membrane translocation of RNAs. Cell Res. 34, 504–521 (2024).
Khawaja, A. et al. Distinct pre-initiation steps in human mitochondrial translation. Nat. Commun. 11, 2932 (2020).
Singh, V. et al. Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome. Nat. Struct. Mol. Biol. 31, 1838–1847 (2024).
Obara, C. J. et al. Motion of VAPB molecules reveals ER-mitochondria contact site subdomains. Nature 626, 169–176 (2024).
Ito, N. et al. MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51. J. Biochem. 171, 529–541 (2022).
Qin, J. et al. ER-mitochondria contacts promote mtDNA nucleoids active transportation via mitochondrial dynamic tubulation. Nat. Commun. 11, 4471 (2020).
Lewis, S. C., Uchiyama, L. F. & Nunnari, J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, aaf5549 (2016).
Erdmann, F. et al. Interaction of calmodulin with Sec61alpha limits Ca2+ leakage from the endoplasmic reticulum. EMBO J. 30, 17–31 (2011).
de Juan-Sanz, J. et al. Axonal endoplasmic reticulum Ca(2+) content controls release probability in CNS nerve terminals. Neuron 93, 867–881.e6 (2017).
Zhu, X. et al. Cold-inducible RNA binding protein alleviates iron overload-induced neural ferroptosis under perinatal hypoxia insult. Cell Death Differ. 31, 524–539 (2024).
Becher, B., Spath, S. & Goverman, J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol. 17, 49–59 (2017).
Patel, H. et al. Transcriptomic analysis of probable asymptomatic and symptomatic alzheimer brains. Brain Behav. Immun. 80, 644–656 (2019).
Xu, L., Wang, X. & Tong, C. Endoplasmic reticulum-mitochondria contact sites and neurodegeneration. Front. Cell Dev. Biol. 8, 428 (2020).
Hedskog, L. et al. Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc. Natl. Acad. Sci. USA 110, 7916–7921 (2013).
Kraushar, M. L. et al. Protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit. Mol. Cell 81, 304–322.e16 (2021).
Singh, R., Kaur, N., Choubey, V., Dhingra, N. & Kaur, T. Endoplasmic reticulum stress and its role in various neurodegenerative diseases. Brain Res. 1826, 148742 (2024).
Elia, F., Yadhanapudi, L., Tretter, T. & Römisch, K. The N-terminus of Sec61p plays key roles in ER protein import and ERAD. PloS One 14, e0215950 (2019).
Area-Gomez, E. et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106–4123 (2012).
Paillusson, S. et al. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca homeostasis and mitochondrial ATP production. Acta Neuropathol. 134, 129–149 (2017).
Guardia-Laguarta, C. et al. α-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249–259 (2014).
Anagnostou, G. et al. Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord. Neurobiol. Aging 31, 969–985 (2010).
Stoica, R. et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 5, 3996 (2014).
Schaum, N. et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 583, 596–602 (2020).
Zhang, W., Sun, H. S., Wang, X., Dumont, A. S. & Liu, Q. Cellular senescence, DNA damage, and neuroinflammation in the aging brain. Trends Neurosci. 47, 461–474 (2024).
Gulen, M. F. et al. cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature 620, 374–380 (2023).
Kim, J. et al. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366, 1531–1536 (2019).
Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).
De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).
Liu, X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 186, 287–304.e26 (2023).
Miller, K. N. et al. Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell 184, 5506–5526 (2021).
Hooftman, A. et al. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature 615, 490–498 (2023).
Kim, S. et al. Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development. Cell Rep. 40, 111178 (2022).
Yoon, J. et al. Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjögren’s syndrome. Mol. Ther. Nucleic Acids 30, 257–269 (2022).
Csordas, G., Weaver, D. & Hajnoczky, G. Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions. Trends Cell Biol. 28, 523–540 (2018).
Basu, U., Bostwick, A. M., Das, K., Dittenhafer-Reed, K. E. & Patel, S. S. Structure, mechanism, and regulation of mitochondrial DNA transcription initiation. J. Biol. Chem. 295, 18406–18425 (2020).
Fernandez-Silva, P., Enriquez, J. A. & Montoya, J. Replication and transcription of mammalian mitochondrial DNA. Exp. Physiol. 88, 41–56 (2003).
Ben-Zvi, A., Miller, E. A. & Morimoto, R. I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl. Acad. Sci. USA 106, 14914–14919 (2009).
Schumacher, B., Pothof, J., Vijg, J. & Hoeijmakers, J. H. J. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021).
Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).
Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563.e19 (2018).
Dieterich, D. C. et al. Labeling, detection and identification of newly synthesized proteomes with bioorthogonal non-canonical amino-acid tagging. Nat. Protoc. 2, 532–540 (2007).
Huang, J., Liu, P. & Wang, G. Regulation of mitochondrion-associated cytosolic ribosomes by mammalian mitochondrial ribonuclease T2 (RNASET2). J. Biol. Chem. 293, 19633–19644 (2018).
Williamson, C. D., Wong, D. S., Bozidis, P., Zhang, A. & Colberg-Poley, A. M. Isolation of endoplasmic reticulum, mitochondria, and mitochondria-associated membrane and detergent resistant membrane fractions from transfected cells and from human cytomegalovirus-infected primary fibroblasts. Curr. Protoc. Cell Biol. 68, 3.27.21–23.27.33 (2015).
Li, M. et al. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine. Cell Res. 34, 683–706 (2024).
Ly, K., Reid, S. J. & Snell, R. G. Rapid RNA analysis of individual Caenorhabditis elegans. MethodsX 2, 59–63 (2015).
Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).
Miller, K. G. et al. A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc. Natl. Acad. Sci. USA 93, 12593–12598 (1996).