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

Dongkyun Kim, Jinsoo Song, Yeonho Kang, Sujung Park, Yong Il Kim, Seongae Kwak, Dong-Kwon Lim, Raekil Park, Churl Hong Chun, Seong Kyu Choe, Eun Jung Jin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1373-1384
Number of pages12
JournalJournal of Molecular Medicine
Volume94
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

Fingerprint

Chondrocytes
Osteoarthritis
Autophagy
Lysosomes
Peroxisomes
MicroRNAs
Zebrafish
Apoptosis
Organelles
Homeostasis
Cartilage Diseases
Nanotubes
Morpholinos
Chloroquine
Small Interfering RNA
Cartilage
Parkinson Disease
Mitochondria
Embryonic Structures
Health

Keywords

  • Apoptosis
  • Chondrocytes
  • Fis1
  • Lysosome
  • Mitochondria
  • Osteoarthritis
  • Peroxisome
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function. / Kim, Dongkyun; Song, Jinsoo; Kang, Yeonho; Park, Sujung; Kim, Yong Il; Kwak, Seongae; Lim, Dong-Kwon; Park, Raekil; Chun, Churl Hong; Choe, Seong Kyu; Jin, Eun Jung.

In: Journal of Molecular Medicine, Vol. 94, No. 12, 01.12.2016, p. 1373-1384.

Research output: Contribution to journalArticle

Kim, D, Song, J, Kang, Y, Park, S, Kim, YI, Kwak, S, Lim, D-K, Park, R, Chun, CH, Choe, SK & Jin, EJ 2016, 'Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function', Journal of Molecular Medicine, vol. 94, no. 12, pp. 1373-1384. https://doi.org/10.1007/s00109-016-1445-9
Kim, Dongkyun ; Song, Jinsoo ; Kang, Yeonho ; Park, Sujung ; Kim, Yong Il ; Kwak, Seongae ; Lim, Dong-Kwon ; Park, Raekil ; Chun, Churl Hong ; Choe, Seong Kyu ; Jin, Eun Jung. / Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function. In: Journal of Molecular Medicine. 2016 ; Vol. 94, No. 12. pp. 1373-1384.
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AU - Kim, Yong Il

AU - Kwak, Seongae

AU - Lim, Dong-Kwon

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AU - Choe, Seong Kyu

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AB - 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.

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