Abstract
Structures of cellular organelles are intertwined with their functions that undergo alterations once the organelles are stressed. Since organelle functions are dependent on each other, an organelle-specific stress possibly influences the structure and function of its associated organelles. In this perspective, our study demonstrated that endoplasmic reticulum (ER)-specific stress induced by tunicamycin in primary astroglial culture is associated with altered mitochondrial dynamics and matched with the changes as observed in the aging rat brain. However, the exogenous addition of biotin, a highly lipogenic and mitochondrial vitamin, ameliorates ER stress even though its direct targets are not known within ER. Alternatively, the increased biotinylation of mitochondrial carboxylases preserves its basal respiratory capacity by upregulating mitofusin 2 (Mfn2) and, possibly, its associated role on mitochondrial fusion. Furthermore, the Mfn2 increase by biotin augments physical interaction between ER and functional mitochondria to exchange biomolecules as a part of ER stress resolution. This suggests an increased demand for micronutrient biotin under ER stress resolves the same by undergoing appropriate structural and metabolic contacts between ER and mitochondria. These findings provide a paradigm to resolve stress in one organelle by sustaining the metabolic commitments of another interdependent organelle. The findings also highlight a novel role of biotin in inducing Mfn2 expression and localization under ER stress in addition to its known role as a co-enzyme.
Similar content being viewed by others
Data availability
All data files associated with this manuscript are available upon request from the corresponding author.
References
Austin S, St-Pierre J (2012) PGC1α and mitochondrial metabolism–emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 125:4963–4971. https://doi.org/10.1242/jcs.113662
Bramwell ME (1987) Characterization of biotinylated proteins in mammalian cells using 125I-streptavidin. J Biochem Biophys Methods 15:125–132. https://doi.org/10.1016/0165-022x(87)90111-4
Castro JP, Wardelmann K, Grune T, Kleinridders A (2018) Mitochondrial chaperones in the brain: safeguarding brain health and metabolism? Front Endocrinol (Lausanne) 9:196. https://doi.org/10.3389/fendo.2018.00196
Chandler CS, Ballard FJ (1988) Regulation of the breakdown rates of biotin-containing proteins in Swiss 3T3-L1 cells. Biochem J 251:749–755. https://doi.org/10.1042/bj2510749
Csordás G, Weaver D, Hajnóczky G (2018) Endoplasmic reticulum–mitochondrial contactology: structure and signaling functions. Trends Cell Biol 28:523–540. https://doi.org/10.1016/j.tcb.2018.02.009
De Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. https://doi.org/10.1038/nature07534
Du F, Yu Q, Chen A et al (2018) Astrocytes attenuate mitochondrial dysfunctions in human dopaminergic neurons derived from iPSC. Stem cell reports 10:366–374. https://doi.org/10.1016/j.stemcr.2017.12.021
Frakes AE, Metcalf MG, Tronnes SU, Bar-Ziv R, Durieux J, Gildea HK, Kandahari N, Monshietehadi S, Dillin A (2020) Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans. Science 367:436–440. https://doi.org/10.1126/science.aaz6896
Ganesan D, Santhaseela Ramaian A, Rajasekaran S, et al (2020) Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA-mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain. J Neurochem e14979. https://doi.org/10.1111/jnc.14979
Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol 5:a013169. https://doi.org/10.1101/cshperspect.a013169
Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ (2014) Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 112:24–49. https://doi.org/10.1016/j.pneurobio.2013.10.004
Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 143:418–431. https://doi.org/10.1111/jnc.14037
Kowald A, Kirkwood TBL (2011) Evolution of the mitochondrial fusion–fission cycle and its role in aging. Proc Natl Acad Sci 108:10237–10242. https://doi.org/10.1073/pnas.1101604108
Landenberger A, Kabil H, Harshman LG, Zempleni J (2004) Biotin deficiency decreases life span and fertility but increases stress resistance in Drosophila melanogaster. J Nutr Biochem 15:591–600. https://doi.org/10.1016/j.jnutbio.2004.04.006
Lin W, Popko B (2009) Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci 12:379–385. https://doi.org/10.1038/nn.2273
Murao N, Nishitoh H (2017) Role of the unfolded protein response in the development of central nervous system. J Biochem 162:155–162. https://doi.org/10.1093/jb/mvx047
Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158. https://doi.org/10.1083/jcb.201007152
Pacheco-Alvarez D, Solorzano-Vargas RS, Gravel RA et al (2004) Paradoxical regulation of biotin utilization in brain and liver and implications for inherited multiple carboxylase deficiency. J Biol Chem 279:52312–52318. https://doi.org/10.1074/jbc.M407056200
Reddy PH (2014) Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis 40:245–256. https://doi.org/10.3233/JAD-132060
Rieusset J (2018) The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update. Cell Death Dis 9:1–12. https://doi.org/10.1038/s41419-018-0416-1
Schuck S, Prinz WA, Thorn KS, Voss C, Walter P (2009) Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol 187:525–536. https://doi.org/10.1083/jcb.200907074
Sharma A, Smith HJ, Yao P, Mair WB (2019) Causal roles of mitochondrial dynamics in longevity and healthy aging. EMBO Rep 20: e48395. https://doi.org/10.15252/embr.201948395
Tong L (2013) Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 70:863–891. https://doi.org/10.1007/s00018-012-1096-0
Wai T, Langer T (2016) Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 27:105–117. https://doi.org/10.1016/j.tem.2015.12.001
Yao C-H, Wang R, Wang Y, Kung CP, Weber JD, Patti GJ (2019) Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation. Elife 8:e41351. https://doi.org/10.7554/eLife.41351
Acknowledgments
We thank the Department of Science and Technology, Govt. of India (DST)-FIST, DST-PURSE programs and Department of Biotechnology, Govt. of India (DBT)-BUILDER [BT/PR12153/INF/22/200/2014] program for extracellular flux analyzer, confocal microscope, and chemiluminescence instrumentation support. We thank the ICMR, Government of India for research fellowship awarded to A.R.S [IRIS-ID: 2015-25060] and S.R [IRIS-ID: 2017-3862/CMB-BMS]. We also thank UGC-RGNF, Government of India for Research Fellowship awarded to D.G (Award no.: F1-17.1/2014-15/RGNF-2014-15-SC-TAM-57123/(SAIII/Website)).
Funding
This study was supported in part by grants-in-aid for research from Department of Biotechnology, Govt. of India (BT/PR15162/GBD/27/348/2011) and University Grants Commission, Govt. of India (41-1272/2012 (SR)).
Author information
Authors and Affiliations
Contributions
Anand Ramaian Santhaseela and Dhasarathan Ganesan contributed to conception, study design, data collection, analysis, and drafting of the article. Sudarshana Rajasekaran contributed to data collection and analysis. Tamilselvan Jayavelu contributed to conception, study design, data analysis and drafting of the article. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
All procedures were conducted in compliance with the institutional animal ethics committee guidelines (CBT/AU/IAEC/11/2012)
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Anand, R.S., Ganesan, D., Rajasekaran, S. et al. Astrocytes resolve ER stress through mitochondrial fusion facilitated by biotin availability. Cell Stress and Chaperones 25, 945–953 (2020). https://doi.org/10.1007/s12192-020-01129-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-020-01129-6