Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells

Wang, Hsiang Tsui; Jing, Lin; Yang, James Chih‐Hsin; Haung, Chun Hao; Weng, Ching Wen; Lin, Anya Maan Yuh; Lo, Yu Li; Chen, Wei Shen; Tang, Moon Shong

doi:10.18632/oncotarget.19710

Cited by 40 publications

(46 citation statements)

References 65 publications

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“…Several DNA-damaging agents were shown to initiate autophagy [67,68] and mitophagy [69] to remove damaged macromolecules or organelles including mitochondria, which prompted us to explore if UVB and PARPi-induced mitochondrial biogenesis and morphological changes of mitochondria affects autophagy or mitophagy. We used dual labelling of Mitotracker CMxROS to stain mitochondria and microtubule-associated proteins 1A/1B light chain 3B (LC3A/B) antibody to detect autophagosomes.…”

Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

“…Furthermore, a dose-dependent mitochondrial elongation was observed after UVB and PARP inhibition in Figure 4A,B indicating mitochondrial fusion. Since fused mitochondria are protected from mitophagy [76], and mitophagy-coupled elimination of mitochondria is usually preceded by fission [69] and decline in mitochondrial function [77], the here experienced induction in autophagy is considered as general autophagy and suggest that mitochondrial morphological rearrangements induced by UVB and PARPi may interfere with the initiation of mitophagy.…”

Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

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PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM. IntroductionMitochondria regulate their shape, number, distribution, mass, content of mitochondrial DNA (mtDNA), and metabolic capacity in a process called mitochondrial biogenesis, which requires the orchestration of complex transcriptional control of both nuclear and mitochondrial genes [1,2]. The function of mitochondrial biogenesis is to provide quality control of mitochondria by regulating mitochondrial fission, fusion, and mitophagy [3,4] to maximize the energy utilization of mitochondria [5] to meet cellular and environmental demands. Imbalances or perturbations in these processes can lead to mitochondrial dysfunction [3,6].Accumulating evidence suggests that mitochondria also play a central role in skin physiology. Although, involvement of other organ systems predominates in classical mitochondrial disorders, several cutaneous diseases can be linked to mitochondrial dysfunctions [7]. Interestingly, mitochondria lack functional nucleotide excision repair (NER) pathway [8,9] which is responsible for the removal of ultraviolet (UV)-induced DNA lesions including cyclobutane pyrimidine dimers (CPD). Accumulation of these DNA photoproducts in mtDNA leads to mutations and deletions resulting in mitochondrial alterations which have been associated with photoaging [10,11] and are present in melanoma [12], as well as in non-melanoma skin cancers [13,14]. The other types of mitochondrial alterations such as upregulated oxidative phosphorylation (OXPHOS), mitochondrial memb...

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Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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“…revealed that acrolein promotes mitochondrial ROS over-production, resulting in the formation of the mtDNA 4977 and also depletion of mtDNA content in human lung cells. 74…”

Section: The Endogenous and Exogenous Source Of The Mtdna4977 Formationmentioning

confidence: 99%

A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies

Yusoff¹,

Abdullah²,

Khair³

et al. 2019

Oncol Rev

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Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA4977) and it has been explored since two decades. In spite of that, its implication in carcinogenesis still unknown and its predictive and prognostic impact remains controversial. This review article provides an overview of some of the cellular and molecular mechanisms underlying mDNA4977 formation and a detailed summary about mDNA4977 reported in various types of cancers. The current knowledges of mDNA4977 as a prognostic and predictive marker are also discussed.

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“…In Parkin-mediated mitophagy, the depolarized mitochondria stabilize phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) on the outer mitochondrial membrane, which subsequently recruits the E3 ubiquitin ligase Parkin to initiate the autophagic degradation of damaged mitochondria [11,12]. Although most studies on Parkin-dependent mitophagy have been related to neurodegenerative diseases (e.g., Parkinson's disease) [8,13], a previous study found that mitophagy acts as an important modulator in human pulmonary diseases and could represent a potential therapeutic target [14][15][16]. Therefore, we investigated the role of Parkin-dependent mitophagy as a protective mechanism against mitochondria-dependent apoptosis in LPS-induced ARDS.…”

Section: Introductionmentioning

confidence: 99%

Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome

Liu

et al. 2019

Laboratory Investigation

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Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin−/− mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.

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Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells

Cited by 40 publications

References 65 publications

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies

Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome

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