AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Nano Research Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Research Article

Super-resolution quantification of nanoscale damage to mitochondria in live cells

Xintian Shao1,2,3,§, Qixin Chen4,§, Lianting Hu5,§, Zhiqi Tian2, Liuyi Liu6, Fei Liu1,3, Fengshan Wang3, Peixue Ling1,3( ), Zong-Wan Mao6( ), Jiajie Diao2( )
Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250062, China
School of Information Management, Wuhan University, Wuhan 430072, China
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China

§ Xintian Shao, Qixin Chen, and Lianting Hu contributed equally to this work.

Show Author Information

Graphical Abstract

Abstract

Mitochondrial damage, characterized by altered morphological distribution and the damage of cristae, is closely associated with mitochondrial disease. However, imaging methods for capturing mitochondrial morphology at the nanoscale level in live samples remain unavailable, which seriously hinders the accurate evaluation and diagnosis of mitochondrial-related diseases. In response, we propose a super-resolution quantification strategy based on structured illumination microscopy (SIM) for the rapid, accurate evaluation of mitochondrial morphology. Using the strategy, we accurately captured the morphological distribution of mitochondria at the nanoscale level in a way generally applicable to checking various cell processes and identifying patients with mitochondrial disease who exhibit the SLC25A46 mutation. We also used algorithm-assisted super-resolution imaging to quantitatively analyze damage to mitochondrial cristae, which supports a novel drug screening strategy—high-resolution drug screening—for investigating drugs’ pharmacodynamics on organelles in living cells. In short, our strategy improves the accurate examination of changes in mitochondrial morphology in living cells and indicates new ways in which SIM-imaging can assist in diagnosing mitochondrial disease at the single-cell level.

Keywords

mitochondriastructured illumination microscopyquantification analyzemorphologycristae

Electronic Supplementary Material

Download File(s)
12274_2020_2822_MOESM1_ESM.pdf (2.1 MB)

References

[1]
Schapira, A. H. Mitochondrial disease. Lancet 2006, 368, 70-82.
Google Scholar
[2]
Senyilmaz, D.; Virtue, S.; Xu, X. J.; Tan, C. Y.; Griffin, J. L.; Miller, A. K.; Vidal-Puig, A.; Teleman, A. A. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature 2015, 525, 124-128.
Google Scholar
[3]
Guarani, V.; McNeill, E. M.; Paulo, J. A.; Huttlin, E. L.; Fröhlich, F.; Gygi, S. P.; Van Vactor, D.; Harper, J. W. QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. eLife 2015, 4, e06265.
Google Scholar
[4]
Blanco, F. J.; Rego, I.; Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 2011, 7, 161-169.
Google Scholar
[5]
Yu, T. Z.; Robotham, J. L.; Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA 2006, 103, 2653-2658.
Google Scholar
[6]
Alirol, E.; Martinou, J. C. Mitochondria and cancer: Is there a morphological connection? Oncogene 2006, 25, 4706-4716.
Google Scholar
[7]
Chen, Q. X.; Shao, X. T.; Tian, Z. Q.; Chen, Y.; Mondal, P.; Liu, F.; Wang, F. S.; Ling, P. X.; He, W. J.; Zhang, K. et al. Nanoscale monitoring of mitochondria and lysosome interactions for drug screening and discovery. Nano Res. 2019, 12, 1009-1015.
Google Scholar
[8]
Hell, S. W.; Wichmann, J. Breaking the diffraction resolution limit by stimulated emission: Stimulated-emission-depletion fluorescence microscopy. Opt. Lett. 1994, 19, 780-782.
Google Scholar
[9]
Gustafsson, M. G. L. Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy. J. Microsc. 2000, 198, 82-87.
Google Scholar
[10]
Huang, X. S.; Fan, J. C.; Li, L. J.; Liu, H. S.; Wu, R. L.; Wu, Y.; Wei, L. S.; Mao, H.; Lal, A.; Xi, P. et al. Fast, long-term, super-resolution imaging with Hessian structured illumination microscopy. Nat. Biotechnol. 2018, 36, 451-459.
Google Scholar
[11]
Rust, M. J.; Bates, M.; Zhuang, X. W. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat. Meth. 2006, 3, 793-796.
Google Scholar
[12]
Betzig, E.; Patterson, G. H.; Sougrat, R.; Lindwasser, O. W.; Olenych, S.; Bonifacino, J. S.; Davidson, M. W.; Lippincott-Schwartz, J.; Hess, H. F. Imaging intracellular fluorescent proteins at nanometer resolution. Science 2006, 313, 1642-1645.
Google Scholar
[13]
Chen, Q. X.; Jin, C. Z.; Shao, X. T.; Guan, R. L.; Tian, Z. Q.; Wang, C. R.; Liu, F.; Ling, P. X.; Guan, J. L.; Ji, L. N. et al. Super-resolution tracking of mitochondrial dynamics with an iridium(III) luminophore. Small 2018, 14, 1802166.
Google Scholar
[14]
Challa, S.; Kanikannan, M. A.; Murthy, J. M.; Bhoompally, V. R.; Surath, M. Diagnosis of mitochondrial diseases: Clinical and histological study of sixty patients with ragged red fibers. Neurol. India 2004, 52, 353-358.
Google Scholar
[15]
Parikh, S.; Goldstein, A.; Koenig, M. K.; Scaglia, F.; Enns, G. M.; Saneto, R.; Anselm, I.; Cohen, B. H.; Falk, M. J.; Greene, C. et al. Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society. Genet. Med. 2015, 17, 689-701.
Google Scholar
[16]
Hao, L.; Li, Z. W.; Zhang, D. Y.; He, L.; Liu, W. T.; Yang, J.; Tan, C. P.; Ji, L. N.; Mao, Z. W. Monitoring mitochondrial viscosity with anticancer phosphorescent Ir(III) complexes via two-photon lifetime imaging. Chem. Sci. 2019, 10, 1285-1293.
Google Scholar
[17]
Mo, R.; Sun, Q.; Xue, J. W.; Li, N.; Li, W. Y.; Zhang, C.; Ping, Q. N. Multistage pH-responsive liposomes for mitochondrial-targeted anticancer drug delivery. Adv. Mater. 2012, 24, 3659-3665.
Google Scholar
[18]
Cao, X.; Wang, H. Q.; Wang, Z.; Wang, Q. Y.; Zhang, S.; Deng, Y. P.; Fang, Y. S. In vivo imaging reveals mitophagy independence in the maintenance of axonal mitochondria during normal aging. Aging Cell 2017, 16, 1180-1190.
Google Scholar
[19]
Berman, S. B.; Pineda, F. J.; Hardwick, J. M. Mitochondrial fission and fusion dynamics: The long and short of it. Cell Death Differ. 2008, 15, 1147-1152.
Google Scholar
[20]
Wai, T.; Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 2016, 27, 105-117.
Google Scholar
[21]
Yaffe, M. P. Dynamic mitochondria. Nat. Cell Biol. 1999, 1, E149-E150.
Google Scholar
[22]
Arnoult, D. Mitochondrial fragmentation in apoptosis. Trends Cell Biol. 2007, 17, 6-12.
Google Scholar
[23]
Youle, R. J.; Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 2011, 12, 9-14.
Google Scholar
[24]
Wolvetang, E. J.; Johnson, K. L.; Krauer, K.; Ralph, S. J.; Linnane, A. W. Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett. 1994, 339, 40-44.
Google Scholar
[25]
Karbowski, M.; Youle, R. J. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 2003, 10, 870-880.
Google Scholar
[26]
Suen, D. F.; Norris, K. L.; Youle, R. J. Mitochondrial dynamics and apoptosis. Genes Dev. 2008, 22, 1577-1590.
Google Scholar
[27]
Dixon, S. J.; Lemberg, K. M.; Lamprecht, M. R.; Skouta, R.; Zaitsev, E. M.; Gleason, C. E.; Patel, D. N.; Bauer, A. J.; Cantley, A. M.; Yang, W. S. et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012, 149, 1060-1072.
Google Scholar
[28]
Xie, Y.; Hou, W.; Song, X.; Yu, Y.; Huang, J.; Sun, X.; Kang, R.; Tang, D. Ferroptosis: Process and function. Cell Death Differ. 2016, 23, 369-379.
Google Scholar
[29]
Stockwell, B. R.; Angeli, J. P. F.; Bayir, H.; Bush, A. I.; Conrad, M.; Dixon, S. J.; Fulda, S.; Gascón, S.; Hatzios, S. K.; Kagan, V. E. et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017, 171, 273-285.
Google Scholar
[30]
Angeli, J. P. F.; Schneider, M.; Proneth, B.; Tyurina, Y. Y.; Tyurin, V. A.; Hammond, V. J.; Herbach, N.; Aichler, M.; Walch, A.; Eggenhofer, E. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 2014, 16, 1180-1191.
Google Scholar
[31]
Tian, Z. Q.; Gong, J. H.; Crowe, M.; Lei, M.; Li, D.C. ; Ji, B. H.; Diao, J. J. Biochemical studies of membrane fusion at the single-particle level. Prog. Lipid Res. 2019, 73, 92-100.
Google Scholar
[32]
Chen, Q. X.; Shao, X. T.; Hao, M. G.; Fang, H. B.; Guan, R. L.; Tian, Z. Q.; Li, M. L.; Wang, C. R.; Ji, L. N.; Chao, H. et al. Quantitative analysis of interactive behavior of mitochondria and lysosomes using structured illumination microscopy. Biomaterials 2020, 250, 120059.
Google Scholar
[33]
Hwang, J. M.; Cho, J. S.; Kim, T. H.; Lee, Y. I. Ellagic acid protects hepatocytes from damage by inhibiting mitochondrial production of reactive oxygen species. Biomed. Pharmacother. 2010, 64, 264-270.
Google Scholar
[34]
Li, Z.; Slone, J.; Wu, L. Q.; Huang, T. S. Neurodegenerative diseases associated with mutations in SLC25A46. In Recent Advances in Neurodegeneration; Borreca, A., Ed.; IntechOpen, 2018.
[35]
Steffen, J.; Vashisht, A. A.; Wan, J. J.; Jen, J. C.; Claypool, S. M.; Wohlschlegel, J. A.; Koehler, C. M.; Fox, T. D. Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria. Mol. Biol. Cell 2017, 28, 600-612.
Google Scholar
[36]
Yoshii, S. R.; Kishi, C.; Ishihara, N.; Mizushima, N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J. Biol. Chem. 2011, 286, 19630-19640.
Google Scholar
[37]
Spinazzola, A.; Viscomi, C.; Fernandez-Vizarra, E.; Carrara, F.; D’Adamo, P.; Calvo, S.; Marsano, R. M.; Donnini, C.; Weiher, H.; Strisciuglio, P. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat. Genet. 2006, 38, 570-575.
Google Scholar
[38]
Strauss, M.; Hofhaus, G.; Schröder, R. R.; Kühlbrandt, W. Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J. 2008, 27, 1154-1160.
Google Scholar
[39]
Fang, H. B.; Yao, S. K.; Chen, Q. X.; Liu, C. Y.; Cai, Y. Q.; Geng, S. S.; Bai, Y.; Tian, Z. Q.; Zacharias, A. L.; Takebe, T. et al. De novo-designed near-infrared nanoaggregates for super-resolution monitoring of lysosomes in cells, in whole organoids and in vivo. ACS Nano 2019, 13, 14426-14436.
Google Scholar
Nano Research
Volume 13 Issue 8,
August 2020
Pages 2149-2155
DOI: 10.1007/s12274-020-2822-9
Cite this article:
Shao X, Chen Q, Hu L, et al. Super-resolution quantification of nanoscale damage to mitochondria in live cells. Nano Research, 2020, 13(8): 2149-2155. https://doi.org/10.1007/s12274-020-2822-9
Topics:
CytologyDiagnosisMorphology

899

Views

36

Crossref

N/A

Web of Science

33

Scopus

0

CSCD

Altmetrics
Received: 26 March 2020
Revised: 17 April 2020
Accepted: 18 April 2020
Published: 05 August 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
Return