Mitophagy : Therapeutic Potentials for Liver Disease and Beyond

Sooyeon Lee,Jae-Sung Kim 한국독성학회 2014 Toxicological Research Vol.30 No.4

Mitochondrial integrity is critical for maintaining proper cellular functions. A key aspect of regulating mitochondrial homeostasis is removing damaged mitochondria through autophagy, a process called mitophagy. Autophagy dysfunction in various disease states can inactivate mitophagy and cause cell death, and defects in mitophagy are becoming increasingly recognized in a wide range of diseases from liver injuries to neurodegenerative diseases. Here we highlight our current knowledge on the mechanisms of mitophagy, and discuss how alterations in mitophagy contribute to disease pathogenesis. We also discuss mitochondrial dynamics and potential interactions between mitochondrial fusion, fission and mitophagy.

Emerging role of mitophagy in human diseases and physiology

( Jee-hyun Um ),( Jeanho Yun ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.6

Mitophagy is a process of selective removal of damaged or unnecessary mitochondria using autophagic machinery. Mitophagy plays an essential role in maintaining mitochondrial quality control and homeostasis. Mitochondrial dysfunctions and defective mitophagy in neurodegenerative diseases, cancer, and metabolic diseases indicate a close link between human disease and mitophagy. Furthermore, recent studies showing the involvement of mitophagy in differentiation and development, suggest that mitophagy may play a more active role in controlling cellular functions. A better understanding of mitophagy will provide insights about human disease and offer novel chance for treatment. This review mainly focuses on the recent implications for mitophagy in human diseases and normal physiology. [BMB Reports 2017; 50(6): 299-307]

Selective induction of mitophagy using an isoquinoline alkaloid CD1-012 improves mitochondrial dysfunction and cognitive impairment in Alzheimer’s disease model

Jee-Hyun Um,Dong Jin Shin,Young Yeon Kim,Dae Jin Jung,Jong Hyun Cho,Jeanho Yun 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Mitophagy, a selective degradation of damaged mitochondria, plays a central role in maintaining mitochondria quality control. Previous studies showed a decrease in mitophagy activity is closely related to neurodegenerative diseases including Alzheimer’s disease. Increasing mitophagy is now considered a promising strategy for the treatment of neurodegenerative diseases. However, mitophagy inducer that is effective enough to treat disease and has low toxicity is very limited. Using previously developed mitophagy assay system and single compound library from medicinal plants, we have identified isoquinoline alkaloid PA17 as a mitophagy inducers. Through chemical optimization, we developed CD1-012 that is tens of times more active in promoting mitophagy activity. CD1-012 treatment was not induced a collapse of mitochondria membrane potential and an increase of mitochondrial ROS level, indicating that CD1-012 is not act as mitochondria toxin. In addition, analysis of subcellular organelle proteins revealed that CD1-012 specifically induces degradation of mitochondria. Administration of CD1-012 to APPswd/PS2 Alzheimer’s disease mouse model for four weeks significantly improved cognition defects evidenced by Morris water maze test. More importantly, mitochondria dysfunction in hippocampus of APPswd/PS2 mouse model was also significantly rescued upon CD1-012 treatment. Taken together, our results suggest that induction of mitophagy is promising strategy for the treatment of Alzheimer’s disease and CD1-012 is a potential candidate for mitophagy-based medicine. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2016R1A5A2007009) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea (HU21C0107).

The Phosphodiesterase 4 Inhibitor Roflumilast Protects against Cigarette Smoke Extract-Induced Mitophagy-Dependent Cell Death in Epithelial Cells

( Sun Young Kyung ),( Yu Jin Kim ),( Eun Suk Son ),( Sung Hwan Jeong ),( Jeong-woong Park ) 대한결핵 및 호흡기학회 2018 Tuberculosis and Respiratory Diseases Vol.81 No.2

Background: Recent studies show that mitophagy, the autophagy-dependent turnover of mitochondria, mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure and contributes to the development of emphysema in vivo during chronic cigarette smoke (CS) exposure, although the underlying mechanisms remain unclear. Methods: In this study, we investigated the role of mitophagy in the regulation of CSE-exposed lung bronchial epithelial cell (Beas-2B) death. We also investigated the role of a phosphodiesterase 4 inhibitor, roflumilast, in CSE-induced mitophagy-dependent cell death. Results: Our results demonstrated that CSE induces mitophagy in Beas-2B cells through mitochondrial dysfunction and increased the expression levels of the mitophagy regulator protein, PTEN-induced putative kinase-1 (PINK1), and the mitochondrial fission protein, dynamin-1-like protein (DRP1). CSE-induced epithelial cell death was significantly increased in Beas-2B cells exposed to CSE but was decreased by small interfering RNA-dependent knockdown of DRP1. Treatment with roflumilast in Beas-2B cells inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting the expression of phospho-DRP1 and -PINK1. Roflumilast protected against cell death and increased cell viability, as determined by the lactate dehydrogenase release test and the MTT assay, respectively, in Beas-2B cells exposed to CSE. Conclusion: These findings suggest that roflumilast plays a protective role in CS-induced mitophagy-dependent cell death.

Mitophagy stimulation as a novel strategy for the treatment of mitochondrial diseases

Kang-Min Lee,윤진호 대한의학유전학회 2022 대한의학유전학회지 Vol.19 No.2

Mitophagy, the selective degradation of damaged or surplus mitochondria using core autophagy machinery, plays an es-sential role in maintaining cellular mitochondrial function. Impaired mitophagy is closely linked to various human diseases, including neurodegenerative diseases, cardiovascular diseases, cancers and kidney disease. Defective mitophagy induces the accumulation of damaged mitochondria and thereby results in a decline in cellular survival and tissue function. Accordingly, enhancement of mitophagy has been proposed as a novel strategy for the treatment of human diseases closely linked to mi-tochondrial dysfunction. Recent studies showing that the stimulation of mitophagy has a therapeutic effect on several disease models highlight the possibility of disease treatment using mitophagy. The development of mitophagy inducers with toxicity and the identification of molecular mechanisms will enable the clinical application of mitophagy-based treatments.

The Phosphodiesterase 4 Inhibitor Roflumilast Protects against Cigarette Smoke Extract-Induced Mitophagy-Dependent Cell Death in Epithelial Cells

Kyung, Sun Young,Kim, Yu Jin,Son, Eun Suk,Jeong, Sung Hwan,Park, Jeong-Woong The Korean Academy of Tuberculosis and Respiratory 2018 Tuberculosis and Respiratory Diseases Vol.81 No.2

Background: Recent studies show that mitophagy, the autophagy-dependent turnover of mitochondria, mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure and contributes to the development of emphysema in vivo during chronic cigarette smoke (CS) exposure, although the underlying mechanisms remain unclear. Methods: In this study, we investigated the role of mitophagy in the regulation of CSE-exposed lung bronchial epithelial cell (Beas-2B) death. We also investigated the role of a phosphodiesterase 4 inhibitor, roflumilast, in CSE-induced mitophagy-dependent cell death. Results: Our results demonstrated that CSE induces mitophagy in Beas-2B cells through mitochondrial dysfunction and increased the expression levels of the mitophagy regulator protein, PTEN-induced putative kinase-1 (PINK1), and the mitochondrial fission protein, dynamin-1-like protein (DRP1). CSE-induced epithelial cell death was significantly increased in Beas-2B cells exposed to CSE but was decreased by small interfering RNA-dependent knockdown of DRP1. Treatment with roflumilast in Beas-2B cells inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting the expression of phospho-DRP1 and -PINK1. Roflumilast protected against cell death and increased cell viability, as determined by the lactate dehydrogenase release test and the MTT assay, respectively, in Beas-2B cells exposed to CSE. Conclusion: These findings suggest that roflumilast plays a protective role in CS-induced mitophagy-dependent cell death.

Mitophagy: Therapeutic Potentials for Liver Disease and Beyond

Lee, Sooyeon,Kim, Jae-Sung Korean Society of ToxicologyKorea Environmental Mu 2014 Toxicological Research Vol.30 No.4

Mitochondrial integrity is critical for maintaining proper cellular functions. A key aspect of regulating mitochondrial homeostasis is removing damaged mitochondria through autophagy, a process called mitophagy. Autophagy dysfunction in various disease states can inactivate mitophagy and cause cell death, and defects in mitophagy are becoming increasingly recognized in a wide range of diseases from liver injuries to neurodegenerative diseases. Here we highlight our current knowledge on the mechanisms of mitophagy, and discuss how alterations in mitophagy contribute to disease pathogenesis. We also discuss mitochondrial dynamics and potential interactions between mitochondrial fusion, fission and mitophagy.

The Phosphodiesterase 4 Inhibitor Roflumilast Protects against Cigarette Smoke Extract–Induced Mitophagy-Dependent Cell Death in Epithelial Cells

경선영,김유진,손은숙,정성환,박정웅 대한결핵및호흡기학회 2018 Tuberculosis and Respiratory Diseases Vol.81 No.2

Background: Recent studies show that mitophagy, the autophagy-dependent turnover of mitochondria, mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure and contributes to the development of emphysema in vivo during chronic cigarette smoke (CS) exposure, although the underlying mechanisms remain unclear. Methods: In this study, we investigated the role of mitophagy in the regulation of CSE-exposed lung bronchial epithelial cell (Beas-2B) death. We also investigated the role of a phosphodiesterase 4 inhibitor, roflumilast, in CSE-induced mitophagy-dependent cell death. Results: Our results demonstrated that CSE induces mitophagy in Beas-2B cells through mitochondrial dysfunction and increased the expression levels of the mitophagy regulator protein, PTEN-induced putative kinase-1 (PINK1), and the mitochondrial fission protein, dynamin-1-like protein (DRP1). CSE-induced epithelial cell death was significantly increased in Beas-2B cells exposed to CSE but was decreased by small interfering RNA-dependent knockdown of DRP1. Treatment with roflumilast in Beas-2B cells inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting the expression of phospho-DRP1 and -PINK1. Roflumilast protected against cell death and increased cell viability, as determined by the lactate dehydrogenase release test and the MTT assay, respectively, in Beas-2B cells exposed to CSE. Conclusion: These findings suggest that roflumilast plays a protective role in CS-induced mitophagy-dependent cell death.

Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

Song, Young Mi,Lee, Woo Kyung,Lee, Yong-ho,Kang, Eun Seok,Cha, Bong-Soo,Lee, Byung-Wan MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.1

<P>Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our <I>ob</I>/<I>ob</I> mice were divided into three groups: (1) <I>ad libitum</I> feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in <I>ob</I>/<I>ob</I> mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed <I>ad libitum</I>. Metabolically stressed <I>ob</I>/<I>ob</I> mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins.</P>

CRIF1 deficiency induced mitophagy via p66shc-regulated ROS in endothelial cells

Piao, Shuyu,Nagar, Harsha,Kim, Seonhee,Lee, Ikjun,Choi, Su-jeong,Kim, Taehee,Jeon, Byeong Hwa,Kim, Cuk-Seong Elsevier 2020 Biochemical and biophysical research communication Vol.522 No.4

<P><B>Abstract</B></P> <P>Inhibition of mitochondrial protein CR6 interacting factor 1 (CRIF1) disturbs mitochondrial function, depolarizes membrane potential, and increases reactive oxygen species (ROS) levels in endothelial cells. Impaired mitochondrial function accompanied by oxidative damage is a major contributor to the initiation of mitophagy. We hypothesized that CRIF1 deficiency-induced harmful effects may promote mitophagy, and explored the mechanism underlying this effect in human umbilical vein endothelial cells (HUVECs). Our results showed that CRIF1 downregulation not only induced the mitophagy-related markers LC3 (LC3-II/Ⅰ), PTEN-induced putative kinase 1 (PINK1) and parkin, but also stimulated redox enzyme p66shc expression. Scavenging mitochondrial ROS markedly blunted the CRIF1 deficiency-induced increase in p66shc expression. In addition, knockdown of p66shc inhibited the CRIF1 deletion-triggered mitochondrial ROS increase, membrane potential depolarization, and mitochondrial fusion. The restoration of mitochondrial dysfunction by p66shc downregulation also decreased CRIF1 deficiency-induced mitophagy, by elevating the levels of LC3-II/Ⅰ, PINK1 and parkin. These findings suggest that CRIF1 deficiency induces mitophagy via p66shc-regulated ROS in endothelial cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CRIF1 deficiency induces significant mitophagy in HUVECs. </LI> <LI> CRIF1 deficiency induces p66shc expression in a ROS-dependent manner in HUVECs. </LI> <LI> p66Shc knockdown rescues CRIF1 deficiency-induced mitochondrial dysfunction and mitophagy in HUVECs. </LI> </UL> </P>