title: Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function.
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.
  
  
  
  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.
authors: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea.
authors: Dongkyun
authors: D
authors: Kim
authors: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea.
authors: Jinsoo
authors: J
authors: Song
authors: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea.
authors: Yeonho
authors: Y
authors: Kang
authors: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea.
authors: Sujung
authors: S
authors: Park
authors: Department of Microbiology, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea.
authors: Yong-Il
authors: YI
authors: Kim
authors: Department of Microbiology, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea.
authors: Seongae
authors: S
authors: Kwak
authors: KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 136-701, South Korea.
authors: Dongkwon
authors: D
authors: Lim
authors: Department of Microbiology, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea.
authors: Raekil
authors: R
authors: Park
authors: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea.
authors: Churl-Hong
authors: CH
authors: Chun
authors: Department of Microbiology, Wonkwang University School of Medicine, Iksan, Chunbuk, 570-749, South Korea. seongkyu642@wu.ac.kr.|Integrated Omics Institute, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea. seongkyu642@wu.ac.kr.
authors: Seong-Kyu
authors: SK
authors: Choe
authors: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea. jineunjung@wku.ac.kr.|Integrated Omics Institute, Wonkwang University, Iksan, Chunbuk, 570-749, South Korea. jineunjung@wku.ac.kr.
authors: Eun-Jung
authors: EJ
authors: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002738:Chloroquine / Q000494:pharmacology; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004625:Embryo, Nonmammalian; D005786:Gene Expression Regulation; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D002738:Chloroquine; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D060172:Morpholinos; D034741:RNA, Small Interfering; C476525:FIS1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1
keywords: Apoptosis; Chondrocytes; Fis1; Lysosome; Mitochondria; Osteoarthritis; Peroxisome; Zebrafish