Journal
CARCINOGENESIS
Volume 36, Issue 11, Pages 1407-1418Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgv122
Keywords
-
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning, Korea [2012R1A2A1A03002833, 2014M3A9D8034464]
- Ministry of Science, ICT and Future Planning, Research fund of Chungnam National University [NRF-2014R1A6A1029617]
- Italian Association for Cancer Research AIRC [IG 14242]
- EU-Marie Curie Action ITN-People grant MEET - Mitochondrial European Educational Training [GA: 317433]
- National Creative Research Initiatives grant - Korea government (MSIP) [2010-0018291]
- National Research Foundation of Korea [2014M3A9D8034464, 2012R1A2A1A03002833] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
Abnormal accumulation of defective mitochondria is the hallmark of oncocytes, which are frequently observed in thyroid Hurthle 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 Hurthle 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 Hurthle cell tumors. Beclin1 and LC3 were highly expressed in oncocytes of Hurthle cell tumor tissues. 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 Hurthle cell tumor tissues. XTC.UC1 and several tumors harbored the V380L mutation, resulting in dysfunctional autoubiquitination and decreased E3 ligase activity. Consistently, oncocytes in Hrthle 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 Hrthle cell tumors through insufficient mitophagy leadinto ineffective turnover of aberrant mitochondria caused by dysfunctional Parkin-mediated pathways of mitochondria quality control.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available