Dysregulation of Parkin-mediated mitophagy in thyroid Hürthle cell tumors.
Abnormal accumulation of defective mitochondria is the hallmark of oncocytes, which are frequently observed in thyroid Hürthle cell lesions. Autophagy is an essential cellular catabolic mechanism for the degradation of dysfunctional organelles and has been implicated in several human diseases. It is yet unknown how autophagic turnover of defective mitochondria in Hürthle cell tumors is regulated. We characterized the expression patterns of molecular markers including Beclin1, LC3, PINK1 and Parkin, which are required for autophagy or mitophagy, in human oncocytic lesions of the thyroid. To undertake mechanistic studies, we investigated autophagy and mitophagy using XTC.UC1 cells, the only in vitro model of Hürthle cell tumors. Beclin1 and LC3 were highly expressed in oncocytes of Hürthle cell tumors. XTC.UC1 showed autophagic responses to starvation and rapamycin treatment, whereas they displayed ineffective activation of mitophagy, which is triggered by the coordinated action of PINK1 and Parkin in response to CCCP. This resulted in a decreased turnover of abnormal mitochondria. The mechanisms underlying defective mitophagy and mitochondrial turnover were investigated by genetic analysis of the PARK2 gene in XTC.UC1 and Hürthle cell tumor tissues. XTC.UC1 and several tumors harbored the V380L mutation, resulting in dysfunctional autoubiquitination and decreased E3 ligase activity. Consistently, oncocytes in Hürthle cell tumors displayed comparable expression of PINK1 but decreased Parkin expression in comparison to normal thyrocytes. The introduction of wild-type Parkin sensitized XTC.UC1 to death induced by CCCP. This study provides a possible etiological basis for oncocytic formation in heterogeneous Hürthle cell tumors through insufficient mitophagy leading to ineffective turnover of aberrant mitochondria caused by dysfunctional Parkin-mediated pathways of mitochondria quality control.
Junguee
J
Lee
National Creative Research Initiatives Center for Energy Homeostasis Regulation, Seoul National University, Seoul 151-742, Republic of Korea.
Sujin
S
Ham
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Min Hee
MH
Lee
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Soung Jung
SJ
Kim
Department of Biochemistry, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 301-747, Republic of Korea.
Ji Hoon
JH
Park
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Seong Eun
SE
Lee
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Joon Young
JY
Chang
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Kyong Hye
KH
Joung
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-2dong, Songpagu, Seoul 138-736, Republic of Korea.
Tae Yong
TY
Kim
Department of Pathology, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 301-747, Republic of Korea.
Jin Man
JM
Kim
Hae Joung
HJ
Sul
Department of Biochemistry, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 301-747, Republic of Korea.
Gi Ryang
GR
Kweon
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Young Suk
YS
Jo
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
Koon Soon
KS
Kim
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-2dong, Songpagu, Seoul 138-736, Republic of Korea.
Young Kee
YK
Shong
Dip. Scienze Mediche e Chirurgiche-DIMEC U.O. Genetica Medica-Pad.11 Pol.S.Orsola-Malpighi, via Massarenti 9 40138, Bologna, Italy.
Giuseppe
G
Gasparre
National Creative Research Initiatives Center for Energy Homeostasis Regulation, Seoul National University, Seoul 151-742, Republic of Korea.
Jong Kyeong
JK
Chung
Department of Pharmacy and Biotechnology-FABIT, University of Bologna, Via Irnerio 42, Bologna, Italy and Interdepartmental Industrial Research Center on Health Sciences & Technologies, University of Bologna, Bologna, Italy.
Anna Maria
AM
Porcelli
Division of Endocrinology, Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea, minhos@cnu.ac.kr.
Minho
M
Shong
D018249:Adenoma, Oxyphilic; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D063306:Mitophagy; D020125:Mutation, Missense; D010101:Oxygen Consumption; D012189:Retrospective Studies; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein