Disruption of Mitochondrial Dynamics Increases Stress Resistance Through Activation of Multiple Stress Response Pathways

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2020 May 10

PMID 32385951

Citations 20

Authors

Emily Machiela

Thomas Liontis

Dylan J Dues

Paige D Rudich

Annika Traa

Leslie Wyman

Corah Kaufman

Jason F Cooper

Leira Lew

Saravanapriah Nadarajan

Megan M Senchuk

Jeremy M Van Raamsdonk

Affiliations

Soon will be listed here.

Abstract

Mitochondria are dynamic organelles that can change shape and size depending on the needs of the cell through the processes of mitochondrial fission and fusion. In this work, we investigated the role of mitochondrial dynamics in organismal stress response. By using C. elegans as a genetic model, we could visualize mitochondrial morphology in a live organism with well-established stress assays and well-characterized stress response pathways. We found that disrupting mitochondrial fission (DRP1/drp-1) or fusion (OPA1/eat-3, MFN/fzo-1) genes caused alterations in mitochondrial morphology that impacted both mitochondrial function and physiologic rates. While both mitochondrial fission and mitochondrial fusion mutants showed increased sensitivity to osmotic stress and anoxia, surprisingly we found that the mitochondrial fusion mutants eat-3 and fzo-1 are more resistant to both heat stress and oxidative stress. In exploring the mechanism of increased stress resistance, we found that disruption of mitochondrial fusion genes resulted in the upregulation of multiple stress response pathways. Overall, this work demonstrates that disrupting mitochondrial dynamics can have opposite effects on resistance to different types of stress. Our results suggest that disruption of mitochondrial fusion activates multiple stress response pathways that enhance resistance to specific stresses.

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References

Maycotte P, Marin-Hernandez A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortes-Hernandez P . Mitochondrial dynamics and cancer. Tumour Biol. 2017; 39(5):1010428317698391. DOI: 10.1177/1010428317698391. View

Byrne J, Soh M, Chandhok G, Vijayaraghavan T, Teoh J, Crawford S . Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans. Cell Mol Life Sci. 2019; 76(10):1967-1985. PMC: 6478650. DOI: 10.1007/s00018-019-03024-5. View

Machiela E, Dues D, Senchuk M, Van Raamsdonk J . Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes. Neurobiol Dis. 2016; 96:1-11. DOI: 10.1016/j.nbd.2016.08.008. View

Toyama E, Herzig S, Courchet J, Lewis Jr T, Loson O, Hellberg K . Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science. 2016; 351(6270):275-281. PMC: 4852862. DOI: 10.1126/science.aab4138. View

Wang S, Xiao W, Shan S, Jiang C, Chen M, Zhang Y . Multi-patterned dynamics of mitochondrial fission and fusion in a living cell. PLoS One. 2012; 7(5):e19879. PMC: 3359327. DOI: 10.1371/journal.pone.0019879. View

Rea S, Wu D, Cypser J, Vaupel J, Johnson T . A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nat Genet. 2005; 37(8):894-8. PMC: 1479894. DOI: 10.1038/ng1608. View

Archer S . Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N Engl J Med. 2013; 369(23):2236-51. DOI: 10.1056/NEJMra1215233. View

Luz A, Rooney J, Kubik L, Gonzalez C, Song D, Meyer J . Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes. PLoS One. 2015; 10(6):e0130940. PMC: 4480853. DOI: 10.1371/journal.pone.0130940. View

Link C, Johnson C . Reporter transgenes for study of oxidant stress in Caenorhabditis elegans. Methods Enzymol. 2002; 353:497-505. DOI: 10.1016/s0076-6879(02)53072-x. View

10.

Yang W, Hekimi S . Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell. 2010; 9(3):433-47. DOI: 10.1111/j.1474-9726.2010.00571.x. View

11.

Dues D, Andrews E, Senchuk M, Van Raamsdonk J . Resistance to Stress Can Be Experimentally Dissociated From Longevity. J Gerontol A Biol Sci Med Sci. 2018; 74(8):1206-1214. PMC: 6625593. DOI: 10.1093/gerona/gly213. View

12.

Burte F, Carelli V, Chinnery P, Yu-Wai-Man P . Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol. 2014; 11(1):11-24. DOI: 10.1038/nrneurol.2014.228. View

13.

Van Raamsdonk J, Meng Y, Camp D, Yang W, Jia X, Benard C . Decreased energy metabolism extends life span in Caenorhabditis elegans without reducing oxidative damage. Genetics. 2010; 185(2):559-71. PMC: 2881137. DOI: 10.1534/genetics.110.115378. View

14.

Link C, Cypser J, Johnson C, Johnson T . Direct observation of stress response in Caenorhabditis elegans using a reporter transgene. Cell Stress Chaperones. 1999; 4(4):235-42. PMC: 312938. DOI: 10.1379/1466-1268(1999)004<0235:doosri>2.3.co;2. View

15.

Dues D, Schaar C, Johnson B, Bowman M, Winn M, Senchuk M . Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans. Free Radic Biol Med. 2017; 108:362-373. PMC: 5493208. DOI: 10.1016/j.freeradbiomed.2017.04.004. View

16.

van Horssen J, van Schaik P, Witte M . Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?. Neurosci Lett. 2017; 710:132931. DOI: 10.1016/j.neulet.2017.06.050. View

17.

de Castro E, Hegi de Castro S, Johnson T . Isolation of long-lived mutants in Caenorhabditis elegans using selection for resistance to juglone. Free Radic Biol Med. 2004; 37(2):139-45. DOI: 10.1016/j.freeradbiomed.2004.04.021. View

18.

Frank S, Gaume B, Bergmann-Leitner E, Leitner W, Robert E, Catez F . The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001; 1(4):515-25. DOI: 10.1016/s1534-5807(01)00055-7. View

19.

Liesa M, Palacin M, Zorzano A . Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009; 89(3):799-845. DOI: 10.1152/physrev.00030.2008. View

20.

Redpath C, Bou Khalil M, Drozdzal G, Radisic M, McBride H . Mitochondrial hyperfusion during oxidative stress is coupled to a dysregulation in calcium handling within a C2C12 cell model. PLoS One. 2013; 8(7):e69165. PMC: 3704522. DOI: 10.1371/journal.pone.0069165. View