Skip to main content
SpringerLink
Log in

Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

A Correction to this article was published on 19 November 2019

This article has been updated

Abstract

Cumulative evidence suggests the importance of organelle homeostasis in regulating metabolic functions in response to various cellular stresses. Particularly, the dynamism and health of the mitochondria-peroxisome network through fission and fusion are essential for cellular function; dysfunctional dynamism underlies the pathogenesis of several degenerative diseases including Parkinson’s disease. Here, we investigated the role of Fis1 in cartilage homeostasis and its relevance to osteoarthritis (OA). We found that Fis1 is significantly suppressed in human OA chondrocytes compared to that in normal chondrocytes. Fis1 depletion through siRNA induced peroxisomal dysfunction. Moreover, Fis1 suppression altered miRNA profiles, especially those implicated in lysosomal regulation. Lysosomal destruction using LAMP-1-specific targeted nanorods or lysosomal dysfunction through chloroquine treatment resulted in enhanced chondrocyte apoptosis and/or suppression of autophagy. Accordingly, lysosomal activity and autophagy were severely decreased in OA chondrocytes despite abundant LAMP-1-positive organelles. Moreover, Fis1 morpholino-injected zebrafish embryos displayed lysosome accumulation, mitochondrial dysfunction, and peroxisome reduction. Collectively, these data suggest interconnected links among Fis1-modulated miRNA, lysosomes, and autophagy, which contributes to chondrocyte survival/apoptosis. This study represents the first functional study of Fis1 with its pathological relevance to OA. Our data suggest a new target for controlling cartilage-degenerative diseases, such as OA.

Key message

  • Fis1 suppression in OA chondrocytes induces accumulation and inhibition of lysosomes.

  • Fis1 suppression alters miRNAs, especially those implicated in lysosomal regulation.

  • Lysosomal destruction results in chondrocyte apoptosis and suppression of autophagy.

  • Fis1 depletion in zebrafish causes lysosome accumulation, mitochondrial dysfunction, and peroxisome reduction.

  • This is the first functional study of Fis1 and its pathological relevance to OA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

  • 19 November 2019

    In Fig. 1C, the wrong si-control image was used by mistake.

  • 19 November 2019

    In Fig. 1C, the wrong si-control image was used by mistake.

References

  1. Nunnari J, Walter P (1996) Regulation of organelle biogenesis. Cell 84:389–394

    Article  CAS  PubMed  Google Scholar 

  2. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mishra P, Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15:634–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Parcellier A, Tintignac LA, Zhuravleva E, Hemmings BA (2008) PKB and the mitochondria: AKTing on apoptosis. Cell Signal 20:21–30

    Article  CAS  PubMed  Google Scholar 

  5. Sukhorukov VM, Dikov D, Reichert AS, Meyer-Hermann M (2012) Emergence of the mitochondrial reticulum from fission and fusion dynamics. PLoS Comput Biol 8:e1002745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Koike M, Nojiri H, Ozawa Y, Watanabe K, Muramatsu Y, Kaneko H, Morikawa D, Kobayashi K, Saita Y, Sasho T et al (2015) Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Sci Rep 5:11722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang Y, Zhao X, Lotz M, Terkeltaub R, Liu-Bryan R (2015) Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. Arthritis Rheumatol 67:2141–2153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. López de Figueroa P, Lotz MK, Blanco FJ, Caramés B (2015) Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis Rheumatol 201567:966–976

    Article  Google Scholar 

  9. Dave M, Attur M, Palmer G, Al-Mussawir HE, Kennish L, Patel J, Abramson SB (2014) The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. Arthritis Rheum 58:2786–2797

    Article  Google Scholar 

  10. Wu L, Liu H, Li L, Liu H, Cheng Q, Li H, Huang H (2014) Mitochondrial pathology in osteoarthritic chondrocytes. Curr Drug Targets 15:710–719

    Article  CAS  PubMed  Google Scholar 

  11. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Qian W, Choi S, Gibson GA, Watkins SC, Bakkenist CJ, Van Houten B (2012) Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress. J Cell Sci 125:5745–5757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Waterham HR, Ebberink MS (2012) Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 1822:1430–1441

    Article  CAS  PubMed  Google Scholar 

  15. Wanders RJ (2004) Peroxisomes, lipid metabolism, and peroxisomal disorders. Mol Genet Metab 83:16–27

    Article  CAS  PubMed  Google Scholar 

  16. Koepke JI, Nakrieko KA, Wood CS, Boucher KK, Terlecky LJ, Walton PA, Terlecky SR (2007) Restoration of peroxisomal catalase import in a model of human cellular aging. Traffic 8:1590–1600

    Article  CAS  PubMed  Google Scholar 

  17. Fransen M, Nordgren M, Wang B, Apanasets O (2012) Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta 1822:1363–1373

    Article  CAS  PubMed  Google Scholar 

  18. Delille HK, Agricola B, Guimaraes SC, Borta H, Luers GH, Fransen M, Schrader M (2010) Pex11pbeta-mediated growth and division of mammalian peroxisomes follows a maturation pathway. J Cell Sci 123:2750–2762

    Article  CAS  PubMed  Google Scholar 

  19. Li X, Gould SJ (2002) PEX11 promotes peroxisome division independently of peroxisome metabolism. J Cell Biol 156:643–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li X, Gould SJ (2003) The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J Biol Chem 278:17012–17020

    Article  CAS  PubMed  Google Scholar 

  21. Li X, Baumgart E, Morrell JC, Jimenez-Sanchez G, Valle D, Gould SJ (2002) PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function. Mol Cell Biol 22:4358–4365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baumgart E, Vanhorebeek I, Grabenbauer M, Borgers M, Declercq PE, Fahimi HD, Baes M (2001) Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse). Am J Pathol 159:1477–1494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim D, Song J, Ahn C, Kang Y, Chun CH, Jin EJ (2014) Peroxisomal dysfunction is associated with up-regulation of apoptotic cell death via miR-223 induction in knee osteoarthritis patients with type 2 diabetes mellitus. Bone 64:124–131

    Article  CAS  PubMed  Google Scholar 

  24. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reddy JK, Mannaerts GP (1994) Peroxisomal lipid metabolism. Annu Rev Nutr 14:343–370

    Article  CAS  PubMed  Google Scholar 

  26. Dirkx R, Vanhorebeek I, Martens K, Schad A, Grabenbauer M, Fahimi D, Declercq P, Van Veldhoven PP, Baes M (2005) Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology 41:868–878

    Article  CAS  PubMed  Google Scholar 

  27. Yekta S, Shih IH, Bartel DP (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304:594–596

    Article  CAS  PubMed  Google Scholar 

  28. Djuranovic S, Nahvi A, Green R (2012) miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 336:237–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Okamoto K (2014) Organellophagy: eliminating cellular building blocks via selective autophagy. J Cell Biol 205:435–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eskelinen EL, Illert AL, Tanaka Y, Schwarzmann G, Blanz J, von Figura K, Saftig P (2002) Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell 13:3355–3368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dominguez-Bautista JA, Klinkenberg M, Brehm N, Subramaniam M, Kern B, Roeper J, Auburger G, Jendrach M (2015) Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition. Eur J Cell Biol 94:148–161

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) [2013R1A2A2A01067194, 2016R1A2B4010577, 2011-0030130] to E-J Jin and NRF-2014M3A9D8034463 to Choe S-K and Park RK.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea

      Dongkyun Kim, Jinsoo Song, Yeonho Kang, Sujung Park & Eun-Jung Jin

    2. Department of Microbiology, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea

      Yong-Il Kim, Seongae Kwak, Raekil Park & Seong-Kyu Choe

    3. KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 136-701, South Korea

      Dongkwon Lim

    4. Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea

      Churl-Hong Chun

    5. Integrated Omics Institute, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea

      Seong-Kyu Choe & Eun-Jung Jin

    Authors
    1. Dongkyun Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jinsoo Song
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yeonho Kang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sujung Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yong-Il Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Seongae Kwak
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Dongkwon Lim
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Raekil Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Churl-Hong Chun
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Seong-Kyu Choe
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Eun-Jung Jin
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Seong-Kyu Choe or Eun-Jung Jin.

    Ethics declarations

    The study was approved by the institutional review boards (Wonkwang University Ethics Committees, no. WKUH 1519) and performed in compliance with the Helsinki Declaration.

    Conflict of interest

    The authors declare that they have no competing interests.

    Additional information

    Dongkyun Kim and Jinsoo Song contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Kim, D., Song, J., Kang, Y. et al. Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function. J Mol Med 94, 1373–1384 (2016). https://doi.org/10.1007/s00109-016-1445-9

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-016-1445-9

    Keywords

    Search

    Navigation