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Zhang Y, Ye Y, Feng Y, Li X, Chen L, Zou X, Yan G, Chen Y, Nan L, Xu W, Chen L, Li H. Kirenol alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the CK2/AKT pathway. Free Radic Biol Med 2025; 232:353-366. [PMID: 40090600 DOI: 10.1016/j.freeradbiomed.2025.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/18/2025]
Abstract
Ischemic stroke represents a predominant cause of morbidity and mortality globally, resulting from abrupt vascular occlusion or rupture, which precipitates considerable neuronal damage. This study aims to shed more light on the specific neuroprotective mechanisms of Kirenol, a bioactive diterpene derived from traditional herbal medicine, with a particular focus on its regulation of mitochondrial dynamics via the CK2/AKT signalling pathway and its impact on the mitochondrial fusion protein Optic atrophy 1 (Opa1). The effects of Kirenol on neuronal viability, mitochondrial function, and pertinent signalling pathways were evaluated by employing a middle cerebral artery occlusion (MCAO) model in rats and subjecting HT22 neuronal cells to oxidative stress. Treatment with Kirenol significantly improved neurological outcomes, augmented Opa1 expression, and restored apoptotic-related protein markers, antioxidative factors, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels (P < 0.01). Mechanistically, Kirenol elevated CK2 levels and phosphorylated AKT while inhibiting CK2/AKT signalling attenuated Kirenol's protective effects on Opa1 expression. Furthermore, silencing Opa1 using siRNA diminished the neuroprotective effects of Kirenol on oxidative stress and apoptosis-related markers, underscoring the critical role of Opa1. In vitro assessments demonstrated that Kirenol effectively mitigated oxidative stress-induced neuronal damage, restoring cell morphology and viability. Kirenol exhibited dose-dependent neuroprotective effects in the MCAO model (P < 0.01). These findings elucidate the neuroprotective role of Kirenol in ischemic stroke through Opa1-mediated mitochondrial fusion and highlight the CK2/AKT pathway as a promising therapeutic target.
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Affiliation(s)
- Yuqin Zhang
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Yonghua Ye
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Yi Feng
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Xuezhen Li
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Lingxuan Chen
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Xiaoxue Zou
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Guohong Yan
- Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Yaping Chen
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Lihong Nan
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
| | - Wei Xu
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
| | - Lixia Chen
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
| | - Hua Li
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China; Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
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Tang L, Zhang W, Liao Y, Wang W, Deng X, Wang C, Shi W. Autophagy: a double-edged sword in ischemia-reperfusion injury. Cell Mol Biol Lett 2025; 30:42. [PMID: 40197222 PMCID: PMC11978130 DOI: 10.1186/s11658-025-00713-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 03/04/2025] [Indexed: 04/10/2025] Open
Abstract
Ischemia-reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.
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Affiliation(s)
- Lingxuan Tang
- Basic Medical University, Naval Medical University, Shanghai, 200433, China
| | - Wangzheqi Zhang
- School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yan Liao
- School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Weijie Wang
- Basic Medical University, Naval Medical University, Shanghai, 200433, China
| | - Xiaoming Deng
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| | - Changli Wang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| | - Wenwen Shi
- School of Nursing, Navy Military Medical University, Shanghai, China.
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Chen TH, Lin SH, Lee MY, Wang HC, Tsai KF, Chou CK. Mitochondrial alterations and signatures in hepatocellular carcinoma. Cancer Metastasis Rev 2025; 44:34. [PMID: 39966277 PMCID: PMC11836208 DOI: 10.1007/s10555-025-10251-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 02/09/2025] [Indexed: 02/20/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide. Its primary risk factors are chronic liver diseases such as metabolic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C viral infections. These conditions contribute to a specific microenvironment in liver tumors which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways. HCC involves abnormal mitochondrial functions, such as accumulation of reactive oxygen species, oxidative stress, hypoxia, impairment of the mitochondrial unfolded protein response, irregularities in mitochondrial dynamic fusion/fission mechanisms, and mitophagy. Cell death mechanisms, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis, contribute to hepatocarcinogenesis and play a significant role in chemoresistance. The relationship between mitochondrial dynamics and HCC is thus noteworthy. In this review, we summarize the recent advances in mitochondrial alterations and signatures in HCC and attempt to elucidate its molecular biology. Here, we provide an overview of the mitochondrial processes involved in hepatocarcinogenesis and offer new insights into the molecular pathology of the disease. This may help guide future research focused on improving patient outcomes using innovative therapies.
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Affiliation(s)
- Tsung-Hsien Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan
| | - Shu-Hsien Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan
| | - Ming-Yang Lee
- Division of Hemato-Oncology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan
- Min-Hwei Junior College of Health Care Management, Tainan, 73658, Taiwan
| | - Hsiang-Chen Wang
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi, 62102, Taiwan
| | - Kun-Feng Tsai
- Department of Internal Medicine, Gastroenterology and Hepatology Section, An Nan Hospital, China Medical University, Tainan, 70965, Taiwan.
- Department of Medical Sciences Industry, Chang Jung Christian University, Tainan, 71101, Taiwan.
| | - Chu-Kuang Chou
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan.
- Obesity Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan.
- Department of Medical Quality, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 60002, Taiwan.
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Li J, Liu W, Zhang J, Sun C. The Role of Mitochondrial Quality Control in Liver Diseases: Dawn of a Therapeutic Era. Int J Biol Sci 2025; 21:1767-1783. [PMID: 39990657 PMCID: PMC11844277 DOI: 10.7150/ijbs.107777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/28/2025] [Indexed: 02/25/2025] Open
Abstract
The liver is a vital metabolic organ that detoxifies substances, produces bile, stores nutrients, and regulates versatile metabolic processes. Maintaining normal liver cell function requires the prompt and delicate modulation of mitochondrial quality control (MQC), which encompasses a spectrum of processes such as mitochondrial fission, fusion, biogenesis, and mitophagy. Recent studies have shown that disruptions to this homeostatic status are closely linked to the advent and progression of a variety of acute and chronic liver diseases, including but not limited to alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease. However, the explicit mechanisms by which mitochondrial dysfunction impacts inflammatory pathways and cell death in the context of liver diseases remain unclear. In this narrative review, we provide a detailed description of MQC, analyze the mechanisms underpinning mitochondrial dysfunction induced by different detrimental insults, and further elucidate how imbalanced/disrupted MQC promotes the progression and aggravation of liver diseases, ultimately shedding light on the mitochondrion-centric therapeutic strategies for these pathophysiological entities.
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Affiliation(s)
- Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Wenqin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
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Ulrich H, Glaser T, Thomas AP. Purinergic signaling in liver disease: calcium signaling and induction of inflammation. Purinergic Signal 2025; 21:69-81. [PMID: 39320433 PMCID: PMC11958897 DOI: 10.1007/s11302-024-10044-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 08/15/2024] [Indexed: 09/26/2024] Open
Abstract
Purinergic signaling regulates many metabolic functions and is implicated in liver physiology and pathophysiology. Liver functionality is modulated by ionotropic P2X and metabotropic P2Y receptors, specifically P2Y1, P2Y2, and P2Y6 subtypes, which physiologically exert their influence through calcium signaling, a key second messenger controlling glucose and fat metabolism in hepatocytes. Purinergic receptors, acting through calcium signaling, play an important role in a range of liver diseases. Ionotropic P2X receptors, such as the P2X7 subtype, and certain metabotropic P2Y receptors can induce aberrant intracellular calcium transients that impact normal hepatocyte function and initiate the activation of other liver cell types, including Kupffer and stellate cells. These P2Y- and P2X-dependent intracellular calcium increases are particularly relevant in hepatic disease states, where stellate and Kupffer cells respond with innate immune reactions to challenges, such as excess fat accumulation, chronic alcohol abuse, or infections, and can eventually lead to liver fibrosis. This review explores the consequences of excessive extracellular ATP accumulation, triggering calcium influx through P2X4 and P2X7 receptors, inflammasome activation, and programmed cell death. In addition, P2Y2 receptors contribute to hepatic steatosis and insulin resistance, while inhibiting the expression of P2Y6 receptors can alleviate alcoholic liver steatosis. Adenosine receptors may also contribute to fibrosis through extracellular matrix production by fibroblasts. Thus, pharmacological modulation of P1 and P2 receptors and downstream calcium signaling may open novel therapeutic avenues.
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Affiliation(s)
- Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
| | - Talita Glaser
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
| | - Andrew P Thomas
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
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Xue S, Lin Y, Chen H, Yang Z, Zha J, Jiang X, Han Z, Wang K. Mechanisms of autophagy and their implications in dermatological disorders. Front Immunol 2024; 15:1486627. [PMID: 39559368 PMCID: PMC11570406 DOI: 10.3389/fimmu.2024.1486627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/18/2024] [Indexed: 11/20/2024] Open
Abstract
Autophagy is a highly conserved cellular self-digestive process that underlies the maintenance of cellular homeostasis. Autophagy is classified into three types: macrophage, chaperone-mediated autophagy (CMA) and microphagy, which maintain cellular homeostasis through different mechanisms. Altered autophagy regulation affects the progression of various skin diseases, including psoriasis (PA), systemic lupus erythematosus (SLE), vitiligo, atopic dermatitis (AD), alopecia areata (AA) and systemic sclerosis (SSc). In this review, we review the existing literature focusing on three mechanisms of autophagy, namely macrophage, chaperone-mediated autophagy and microphagy, as well as the roles of autophagy in the above six dermatological disorders in order to aid in further studies in the future.
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Affiliation(s)
- Shenghao Xue
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Haoran Chen
- Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Zhengyu Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
| | - Junting Zha
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xuan Jiang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
| | - Zhongyu Han
- Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Ke Wang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
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Chen P, Yao L, Yuan M, Wang Z, Zhang Q, Jiang Y, Li L. Mitochondrial dysfunction: A promising therapeutic target for liver diseases. Genes Dis 2024; 11:101115. [PMID: 38299199 PMCID: PMC10828599 DOI: 10.1016/j.gendis.2023.101115] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/15/2023] [Accepted: 08/10/2023] [Indexed: 02/02/2024] Open
Abstract
The liver is an important metabolic and detoxification organ and hence demands a large amount of energy, which is mainly produced by the mitochondria. Liver tissues of patients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mitochondrial lesions, mitochondrial DNA damage, disturbed mitochondrial dynamics, and compromised ATP production. Overproduction of mitochondrial reactive oxygen species induces oxidative damage to mitochondrial proteins and mitochondrial DNA, decreases mitochondrial membrane potential, triggers hepatocyte inflammation, and promotes programmed cell death, all of which impair liver function. Mitochondrial DNA may be a potential novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus. We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease. This review also discusses mitochondrion-centric therapies for treating liver diseases.
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Affiliation(s)
- Ping Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zheng Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
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Feng MX, Zou H, Lu YQ. Severe liver injury and clinical characteristics of occupational exposure to 2-amino-5-chloro-N,3-dimethylbenzamide: A case series. Hepatobiliary Pancreat Dis Int 2024; 23:186-194. [PMID: 37903709 DOI: 10.1016/j.hbpd.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/20/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and pharmaceuticals. However, no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in humans. This study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. METHODS This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July 2022. The entire course of the incidents was described in detail. Blood 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass spectrometer. Hematoxylin and eosin staining was performed to assess liver injury, and immunofluorescence was used to evaluate hepatic mitophagy. RESULTS The 2-amino-5-chloro-N,3-dimethylbenzamide powder (99% purity) entered the human body mainly via the skin and respiratory tract due to poor personal protective measures. The typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency, rash, fever, organic damage, and recovery phases in accordance with the clinical evolution. Rash and fever may be the important premonitory symptoms for further organ injuries. The chemical was detected in the blood of all patients and caused multiple organ injuries, predominantly liver injury, including kidney, myocardium, and microcirculation. Three patients recovered smoothly after comprehensive treatments, including artificial liver therapy, continuous renal replacement therapy, glucocorticoids, and other symptomatic and supportive treatments. One patient survived by liver transplantation. The postoperative pathological findings of the removed liver showed acute liver failure, and immunofluorescence staining confirmed the abundance of mitophagy in residual hepatocytes. CONCLUSIONS This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. The chemical enters the body through the respiratory tract and skin during industrial production. The 2-amino-5-chloro-N,3-dimethylbenzamide poisoning causes multiple-organ dysfunction with a predominance of liver injury. Liver transplantation may be an effective option for patients with severe liver failure. The mechanisms of liver injury induced by 2-amino-5-chloro-N,3-dimethylbenzamide might involve abnormal mitochondrial function and mitophagy.
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Affiliation(s)
- Meng-Xiao Feng
- Department of Emergency Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China
| | - Hua Zou
- Occupational Health and Radiation Protection Institute, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
| | - Yuan-Qiang Lu
- Department of Emergency Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China.
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9
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Zhao H, Gao H, Zhang Y, Lan T, Wang J, Zhao H, Zhang H, Xue M, Liang H. Folic Acid Protects against Ethanol-Induced Hepatic Mitophagy Imbalance by ROS Scavenging and Attenuating the Elevated Hcy Levels. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:14276-14288. [PMID: 37738285 DOI: 10.1021/acs.jafc.3c01851] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Abstract
Ample evidence indicates that ethanol-induced oxidative stress and mitochondrial dysfunction are central to the pathogenesis of alcoholic liver disease (ALD). As an adaptive quality control mechanism, mitophagy removes dysfunctional mitochondria to avert hepatic lesions in ALD. Folic acid exhibits potential radical scavenging properties and has been proven to ameliorate mitochondrial disorder in oxidative stress-related diseases. In this study, we aimed to uncover the mitophagy regulatory effects of folic acid in a 10w alcohol C57BL/6J mice feeding model (56% v/v) and L02 cells model cultured with ethanol (2.5% v/v). The results showed that folic acid alleviates ethanol-induced liver injury, decreasing oxidative stress and restoring liver enzyme. Furthermore, folic acid improved the mitochondrial function and inhibited ethanol-activated mitophagy through decreasing PINK1-Parkin and Drp1 expression, which inhibited the release of mitochondrial cytochrome C to the cytoplasm, preventing hepatocyte apoptosis. Intriguingly, folic acid attenuates the elevated hepatic homocysteine (Hcy) level. Additionally, the pretreatment of L02 cells with folic acid also ameliorated Hcy-induced oxidative damage, mitochondrial fission, and mitophagy. In summary, these results suggest that folic acid has beneficial effects in mitophagy remodeling by ROS scavenging and facilitating Hcy metabolism and could be developed as a potential therapeutic agent against ALD.
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Affiliation(s)
- Huichao Zhao
- Qingdao Municipal Hospital, Qingdao University. Qingdao 266071, China
| | - Haiqi Gao
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao 266071, China
| | - Yabin Zhang
- Department of Nutrition and Food Hygiene, College of Public Health, Qingdao University, Qingdao 266071, China
| | - Tongtong Lan
- Department of Nutrition and Food Hygiene, College of Public Health, Qingdao University, Qingdao 266071, China
| | - Jingwen Wang
- Department of Nutrition and Food Hygiene, College of Public Health, Qingdao University, Qingdao 266071, China
| | - Haifeng Zhao
- Qingdao Institute of Food and Drug Inspection, Qingdao 266071, China
| | - Huaqi Zhang
- Department of Nutrition and Food Hygiene, College of Public Health, Qingdao University, Qingdao 266071, China
| | - Meilan Xue
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao 266071, China
| | - Hui Liang
- Department of Nutrition and Food Hygiene, College of Public Health, Qingdao University, Qingdao 266071, China
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Subramaiyam N. Insights of mitochondrial involvement in alcoholic fatty liver disease. J Cell Physiol 2023; 238:2175-2190. [PMID: 37642259 DOI: 10.1002/jcp.31100] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 08/31/2023]
Abstract
Alcoholic liver disease (ALD) is a global concern affecting most of the population and leading to the development of end-stage liver disease. Metabolic alterations due to increased alcohol consumption surge the hepatic accumulation of lipids and develop into a severe form of alcoholic steatohepatitis (ASH), depending on age and the consumption rate. The mitochondria in the hepatocyte actively regulate metabolic homeostasis and are disrupted in ALD pathogenesis. The increased NADH upon ethanol metabolism inhibits the mitochondrial oxidation of fatty acids, alters oxidative phosphorylation, and favors de novo lipogenesis. The higher mitochondrial respiration in early ALD increases free radical generation, whereas mitochondrial respiration is uncoupled in chronic ALD, affecting the cellular energy status. The defective glutathione importer due to excessive cholesterol loading and low adenosine triphosphate accounts for additional oxidative stress leading to hepatocyte apoptosis. The defective mitochondrial transcription machinery and sirtuins function in ALD affect mitochondrial function and biogenesis. The metabolites of ethanol metabolism epigenetically alter the gene expression profile of hepatic cell populations by modulating the promoters and sirtuins, aiding hepatic fibrosis and inflammation. The defect in mitophagy increases the accumulation of megamitochondria in hepatocytes and attracts immune cells by releasing mitochondrial damage-associated molecular patterns to initiate hepatic inflammation and ASH progression. Thus, maintaining mitochondrial lipid homeostasis and antioxidant capacity pharmacologically could provide a better outcome for ALD management.
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Affiliation(s)
- Nithyananthan Subramaiyam
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Tian J, Xu Q, Wang X, Zhang X, Chen X, Rui X, Zhang Q, Dong M, Li W. Protective effects and mechanism of Paecilomyces cicadae TJJ1213 intracellular polysaccharide against H 2 O 2 -induced PC12 cells damage. Chem Biol Drug Des 2023; 102:471-485. [PMID: 37072242 DOI: 10.1111/cbdd.14253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/20/2023]
Abstract
Oxidative stress is a key process in the development of neurodegenerative diseases. More attention is needed to screen natural antioxidants and explore pharmacological mechanisms. Natural product polysaccharides with no toxic side effects have powerful antioxidant activity. Two purified intracellular polysaccharide fractions (IPS1 and IPS2) from Paecilomyces cicadae TJJ1213 was isolated. Then, a model of H2 O2 -induced oxidative stress in PC12 cells was established to investigate the neuroprotective role of IPS and elucidate the potential protection mechanism. Results showed that IPS1 and IPS2 reduced reactive oxygen species (ROS) production, inhibited the leakage of lactate dehydrogenase (LDH) and Ca2+ and attenuated the expression of apoptotic proteins. In addition, western blots displayed that IPS1 and IPS2 significantly inhibited mitophagy induced by H2 O2 in PC12 cells via PINK/Parkin pathway. Therefore, IPS1 and IPS2 deserved further investigation as protective agents against neurodegenerative diseases.
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Affiliation(s)
- Juanjuan Tian
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
- College of Tea and Food Science Technology, Jiangsu Vocational College of Agriculture and Forestry, Jurong, China
| | - Qing Xu
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Xiaomeng Wang
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Xueliang Zhang
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Xiaohong Chen
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Xin Rui
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Qiuqin Zhang
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Mingsheng Dong
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Wei Li
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
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12
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Li Y, Kong MW, Jiang N, Ye C, Yao XW, Zou XJ, Hu HM, Liu HT. Vine tea extract ameliorated acute liver injury by inhibiting hepatic autophagy and reversing abnormal bile acid metabolism. Heliyon 2023; 9:e20145. [PMID: 37809393 PMCID: PMC10559920 DOI: 10.1016/j.heliyon.2023.e20145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/08/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023] Open
Abstract
Gut microbiota disturbance, autophagy dysregulation, and accumulation of hepatic bile acids (BAs) are essential features of liver injury. Therefore, regulating autophagy and BA metabolism are potential strategies for treating liver diseases. Vine tea has been seen beyond a pleasant tea in food science. Our previous study found that vine tea extract (VTE) intervention alleviated acute liver injury (ALI) by restoring gut microbiota dysbiosis. In this study, we aim to investigate the effect of VTE on carbon tetrachloride (CCl4)-induced hepatic autophagy and BA metabolism disorder in mice. The results showed that VTE effectively suppressed CCl4-induced liver fibrosis and hepatic autophagy. LC-MS/MS assay suggested that VTE affected fecal BA production by reducing the fecal BA levels and improving cholestasis in ALI mice. Besides, VTE inhibited BA synthesis, promoted BA transport in the liver, and enhanced BA reabsorption in the ileum through the farnesoid X receptor (FXR)-related signaling pathway. The hepatic expressions of Fxr and Abca1 were elevated by VTE. Finally, the depletion of gut microbiota in ALI mice had a negative impact on abnormal autophagy and BA metabolism. It was also noted that the administration of VTE did not provide any additional improvement in this regard. Overall, VTE ameliorated ALI by reversing hepatic autophagy and abnormal BA metabolism, and the beneficial effects of VTE on liver injury depended on the existence of gut microbiota.
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Affiliation(s)
- Ying Li
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Ming-Wang Kong
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Nan Jiang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, PR China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan 430074, PR China
| | - Chen Ye
- Wuhan Customs Technology Center, Qintai Avenue 588, Wuhan 430050, PR China
| | - Xiao-Wei Yao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Xiao-Juan Zou
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hai-Ming Hu
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hong-Tao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
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13
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Wang S, Long H, Hou L, Feng B, Ma Z, Wu Y, Zeng Y, Cai J, Zhang DW, Zhao G. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther 2023; 8:304. [PMID: 37582956 PMCID: PMC10427715 DOI: 10.1038/s41392-023-01503-7] [Citation(s) in RCA: 223] [Impact Index Per Article: 111.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 05/03/2023] [Accepted: 05/16/2023] [Indexed: 08/17/2023] Open
Abstract
Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.
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Affiliation(s)
- Shouliang Wang
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Haijiao Long
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
- Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lianjie Hou
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Baorong Feng
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Zihong Ma
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Ying Wu
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Yu Zeng
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Jiahao Cai
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China
| | - Da-Wei Zhang
- Group on the Molecular and Cell Biology of Lipids and Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
| | - Guojun Zhao
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China.
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14
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Chaiyarit S, Thongboonkerd V. Mitochondria-derived vesicles and their potential roles in kidney stone disease. J Transl Med 2023; 21:294. [PMID: 37131163 PMCID: PMC10152607 DOI: 10.1186/s12967-023-04133-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/14/2023] [Indexed: 05/04/2023] Open
Abstract
Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are formed to carry the malfunctioned mitochondrial components, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be eliminated to restore normal mitochondrial structure and functions. Under severe oxidative stress condition, mitochondrial dynamics (fission/fusion) and mitophagy are predominantly activated to rescue mitochondrial structure and functions. Additionally, MDVs generation can be also triggered as the major MQC machinery to cope with unhealthy mitochondria when mitophagy is unsuccessful for eliminating the damaged mitochondria or mitochondrial fission/fusion fail to recover the mitochondrial structure and functions. This review summarizes the current knowledge on MDVs and discuss their roles in physiologic and pathophysiologic conditions. In addition, the potential clinical relevance of MDVs in therapeutics and diagnostics of kidney stone disease (KSD) are emphasized.
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Affiliation(s)
- Sakdithep Chaiyarit
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 6th Floor, SiMR Building, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 6th Floor, SiMR Building, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand.
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15
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Lin M, Yu H, Xie Q, Xu Z, Shang P. Role of microglia autophagy and mitophagy in age-related neurodegenerative diseases. Front Aging Neurosci 2023; 14:1100133. [PMID: 37180741 PMCID: PMC10169626 DOI: 10.3389/fnagi.2022.1100133] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 12/28/2022] [Indexed: 05/16/2023] Open
Abstract
Microglia, characterized by responding to damage, regulating the secretion of soluble inflammatory mediators, and engulfing specific segments in the central nervous system (CNS), function as key immune cells in the CNS. Emerging evidence suggests that microglia coordinate the inflammatory responses in CNS system and play a pivotal role in the pathogenesis of age-related neurodegenerative diseases (NDDs). Remarkably, microglia autophagy participates in the regulation of subcellular substances, which includes the degradation of misfolded proteins and other harmful constituents produced by neurons. Therefore, microglia autophagy regulates neuronal homeostasis maintenance and process of neuroinflammation. In this review, we aimed at highlighting the pivotal role of microglia autophagy in the pathogenesis of age-related NDDs. Besides the mechanistic process and the co-interaction between microglia autophagy and different kinds of NDDs, we also emphasized potential therapeutic agents and approaches that could be utilized at the onset and progression of these diseases through modulating microglia autophagy, including promising nanomedicines. Our review provides a valuable reference for subsequent studies focusing on treatments of neurodegenerative disorders. The exploration of microglia autophagy and the development of nanomedicines greatly enhances current understanding of NDDs.
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Affiliation(s)
- Mingkai Lin
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongwen Yu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiuyan Xie
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiyun Xu
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pei Shang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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16
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Banarase TA, Sammeta SS, Wankhede NL, Mangrulkar SV, Rahangdale SR, Aglawe MM, Taksande BG, Upaganlawar AB, Umekar MJ, Kale MB. Mitophagy regulation in aging and neurodegenerative disease. Biophys Rev 2023; 15:239-255. [PMID: 37124925 PMCID: PMC10133433 DOI: 10.1007/s12551-023-01057-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 03/24/2023] [Indexed: 04/07/2023] Open
Abstract
Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.
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Affiliation(s)
- Trupti A. Banarase
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Shivkumar S. Sammeta
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Nitu L. Wankhede
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Shubhada V. Mangrulkar
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Sandip R. Rahangdale
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Manish M. Aglawe
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Brijesh G. Taksande
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Aman B. Upaganlawar
- SNJB’s Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra India 423101
| | - Milind J. Umekar
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
| | - Mayur B. Kale
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra India 441002
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17
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Li C, Zhu Y, Liu W, Xiang W, He S, Hayashi T, Mizuno K, Hattori S, Fujisaki H, Ikejima T. Impaired mitophagy causes mitochondrial DNA leakage and STING activation in ultraviolet B-irradiated human keratinocytes HaCaT. Arch Biochem Biophys 2023; 737:109553. [PMID: 36842493 DOI: 10.1016/j.abb.2023.109553] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 02/27/2023]
Abstract
Ultraviolet B (UVB) irradiation causes skin damages. In this study, we focus on the involvement of mitochondrial disorders in UVB injury. Surprisingly, UVB irradiation increases the amounts of mitochondria in human immortalized keratinocytes HaCaT. However, further analysis shows that ATP levels decreased by UVB treatment in accordance with the collapse of mitochondrial membrane potential (MMP), suggesting an accumulation of dysfunctional mitochondria in UVB-irradiated HaCaT cells. Mitophagy, mainly mediated by PINK1 and parkin, is critical for the elimination of damaged mitochondria. Western blot results show that the levels of both PINK1 and parkin are decreased in UVB-irradiated cells, indicating the impairment of mitophagy. Silencing the expression of PINK1 or parkin by transfection of siRNA shows essentially the same damage to the cells as UVB irradiation does, including increased mitochondrial amount, decreased MMP and ATP production, and enhanced apoptosis, evidencing that repression of PINK1/parkin-mediated mitophagy plays a primary cause of UVB-caused cells damages. We previously found that HaCaT cells exposed to UVB showed activation of the cGAS-STING pathway and apoptosis. Here, silencing PINK1 or parkin also increases the protein levels of cGAS and STING, facilitates nuclear accumulation of NF-κB, and promotes the transcription of IFNβ, suggesting for the activation of STING pathway. Mitophagy impairment either by UVB-irradiation or by PINK1/parkin silencing initiates caspase-3-mediated apoptosis, as shown by the activation of caspase-3 and cleavage of PARP, as well as the increase of Hoechst-positive stained cells and Annexin V-positive cells. Further studies find that Bax-mediated permeabilization of mitochondrial membrane is critical for cell apoptosis, as well as the cytosolic leakage of mtDNA in UVB-treated cells, which results in cGAS-STING activation, and these processes are negatively-regulated by PINK1/parkin-mediated mitophagy. This study reveals the involvement of dysfunctional mitochondria due to impaired mitophagy in the damaging effect of UVB irradiation on HaCaT cells. Restoring the mitophagy has the potential to be developed as a new strategy to protect skin from UVB damages.
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Affiliation(s)
- Can Li
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China
| | - Yuying Zhu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China
| | - Weiwei Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China
| | - Wendie Xiang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China
| | - Sijun He
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China
| | - Toshihiko Hayashi
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China; Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Kazunori Mizuno
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Hitomi Fujisaki
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Takashi Ikejima
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, China.
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18
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Wang L, Klionsky DJ, Shen HM. The emerging mechanisms and functions of microautophagy. Nat Rev Mol Cell Biol 2023; 24:186-203. [PMID: 36097284 DOI: 10.1038/s41580-022-00529-z] [Citation(s) in RCA: 227] [Impact Index Per Article: 113.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2022] [Indexed: 02/08/2023]
Abstract
'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.
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Affiliation(s)
- Liming Wang
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Han-Ming Shen
- Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China. .,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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19
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Shen X, Sun P, Zhang H, Yang H. Mitochondrial quality control in the brain: The physiological and pathological roles. Front Neurosci 2022; 16:1075141. [PMID: 36578825 PMCID: PMC9791200 DOI: 10.3389/fnins.2022.1075141] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
The human brain has high energetic expenses and consumes over 20% of total oxygen metabolism. Abnormal brain energy homeostasis leads to various brain diseases. Among multiple factors that contribute to these diseases, mitochondrial dysfunction is one of the most common causes. Maintenance of mitochondrial integrity and functionality is of pivotal importance to brain energy generation. Mitochondrial quality control (MQC), employing the coordination of multiple mechanisms, is evolved to overcome many mitochondrial defects. Thus, not surprisingly, aberrant mitochondrial quality control results in a wide range of brain disorders. Targeting MQC to preserve and restore mitochondrial function has emerged as a promising therapeutic strategy for the prevention and treatment of brain diseases. Here, we set out to summarize the current understanding of mitochondrial quality control in brain homeostasis. We also evaluate potential pharmaceutically and clinically relevant targets in MQC-associated brain disorders.
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20
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Samuvel DJ, Li L, Krishnasamy Y, Gooz M, Takemoto K, Woster PM, Lemasters JJ, Zhong Z. Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice. Autophagy 2022; 18:2671-2685. [PMID: 35293288 PMCID: PMC9629059 DOI: 10.1080/15548627.2022.2046457] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/15/2022] Open
Abstract
Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing.Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.
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Affiliation(s)
- Devadoss J. Samuvel
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Li Li
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Yasodha Krishnasamy
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Monika Gooz
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Kenji Takemoto
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Patrick M. Woster
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - John J. Lemasters
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhi Zhong
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
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21
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Virgana R, Gunadi JW, Atik N, Limdawati K, Jasaputra DK, Wahyudianingsih R, Suardi NNA, Soetadji RS, Goenawan H, Lesmana R, Kartasasmita AS. MitoTEMPOL modulates mitophagy and histopathology of Wistar rat liver after streptozotocin injection. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:1382-1388. [PMID: 36474569 PMCID: PMC9699945 DOI: 10.22038/ijbms.2022.65285.14375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/14/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVES This study aims to explore the effect of mitoTEMPOL on histopathology, lipid droplet, and mitophagy gene expression of Wistar rat's liver after injection of streptozotocin (STZ). MATERIALS AND METHODS Twenty male Wistar rats were divided into 4 groups: Control (n=5); 100 mg/kg BW/day mitoTEMPOL orally (n=5); 50 mg/kg BW STZ intraperitoneal injection (n=5); and mitoTEMPOL+STZ (n=5). STZ was given a single dose, while mitoTEMPOL was given for 5 weeks after 1 week of STZ injection. Histopathological appearance, lipid droplets, mitophagy, and autophagy gene expression were examined after the mitoTEMPOL treatment. RESULTS We found metabolic zone shifting that might be correlated with the liver activity of fatty acid oxidation in the STZ group, a decrease of lipid droplets in mitoTEMPOL and mitoTEMPOL + STZ compared with Control and STZ groups were found in this study. We also found significant changes in PINK1, Parkin, BNIP3, Mfn1, and LC3 gene expression, but no difference in Opa1, Fis1, Drp1, and p62 gene expression, suggesting a change of mitochondrial fusion rather than mitochondrial fission correlated with mitophagy. CONCLUSION All this concluded that mitoTEMPOL could act as a modulator of mitophagy and metabolic function of the liver, thus amplifying its crucial role in preventing mitochondrial damage in the liver in the early onset of diabetes mellitus.
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Affiliation(s)
- Rova Virgana
- Department of Ophthalmology, Universitas Padjadjaran, Bandung, West Java, Indonesia,Cicendo National Eye Hospital, Bandung, West Java, Indonesia, These authors contributed eqully to this work
| | - Julia Windi Gunadi
- Department of Physiology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia , These authors contributed eqully to this work,Corresponding author: Julia Windi Gunadi. Department of Physiology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia. Tel: +622-2012186; Fax: +622-2015154;
| | - Nur Atik
- Biology Cell Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
| | - Kwee Limdawati
- Department of Internal Medicine, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia
| | - Diana Krisanti Jasaputra
- Department of Pharmacology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia
| | - Roro Wahyudianingsih
- Department of Pathology Anatomy, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia
| | | | | | - Hanna Goenawan
- Physiology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia ,Physiology Molecular Laboratory, Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Jatinangor, West Java, Indonesia
| | - Ronny Lesmana
- Physiology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia ,Physiology Molecular Laboratory, Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Jatinangor, West Java, Indonesia
| | - Arief Sjamsulaksan Kartasasmita
- Department of Ophthalmology, Universitas Padjadjaran, Bandung, West Java, Indonesia,Cicendo National Eye Hospital, Bandung, West Java, Indonesia
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22
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Aryapour E, Kietzmann T. Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology. J Cell Biochem 2022; 123:1634-1646. [PMID: 35924961 PMCID: PMC9804494 DOI: 10.1002/jcb.30312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 01/05/2023]
Abstract
Liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) have increased over the past few decades due to the absence or ineffective therapeutics. Recently, it has been shown that inappropriate regulation of hepatic mitophagy is linked to the pathogenesis of the above-mentioned liver diseases. As mitophagy maintains cellular homeostasis by removing damaged and nonfunctional mitochondria from the cell, the proper function of the molecules involved are of utmost importance. Thereby, mitochondrial E3 ubiquitin ligases as well as several deubiquitinases (DUBs) appear to play a unique role for the degradation of mitochondrial proteins and for proper execution of the mitophagy process by either adding or removing ubiquitin chains from target proteins. Therefore, these enzymes could be considered as valuable liver disease biomarkers and also as novel targets for therapy. In this review, we focus on the role of different DUBs on mitophagy and their contribution to NAFLD, NASH, alcohol-related liver disease, and especially HCC.
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Affiliation(s)
- Elham Aryapour
- Faculty of Biochemistry and Molecular Medicine, and Biocenter OuluUniversity of OuluOuluFinland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, and Biocenter OuluUniversity of OuluOuluFinland
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23
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Gao Y, Wang C, Jiang D, An G, Jin F, Zhang J, Han G, Cui C, Jiang P. New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival. Front Cell Dev Biol 2022; 10:994037. [PMID: 36187470 PMCID: PMC9524158 DOI: 10.3389/fcell.2022.994037] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.
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Affiliation(s)
- Yahao Gao
- Clinical Medical School, Jining Medical University, Jining, China
| | - Changshui Wang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Di Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gang An
- Clinical Medical School, Jining Medical University, Jining, China
| | - Feng Jin
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Junchen Zhang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Guangkui Han
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Changmeng Cui
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
| | - Pei Jiang
- Department of Clinical Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
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24
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Fang Z, Liu G, Zhu M, Wang S, Jiang Q, Loor JJ, Yu H, Hao X, Chen M, Gao W, Lei L, Song Y, Wang Z, Du X, Li X. Low abundance of mitophagy markers is associated with reactive oxygen species overproduction in cows with fatty liver and causes reactive oxygen species overproduction and lipid accumulation in calf hepatocytes. J Dairy Sci 2022; 105:7829-7841. [PMID: 35863923 DOI: 10.3168/jds.2021-21774] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/27/2022] [Indexed: 11/19/2022]
Abstract
Mitochondria are the main site of fatty acid oxidation and reactive oxygen species (ROS) formation. Damaged or dysfunctional mitochondria induce oxidative stress and increase the risk of lipid accumulation. During the process of mitophagy, PTEN induced kinase 1 (PINK1) accumulates on damaged mitochondria and recruits cytoplasmic Parkin to mitochondria. As an autophagy receptor protein, sequestosome-1 (p62) binds Parkin-ubiquitinated outer mitochondrial membrane proteins and microtubule-associated protein 1 light chain 3 (LC3) to facilitate degradation of damaged mitochondria. In nonruminants, clearance of dysfunctional mitochondria through the PINK1/Parkin-mediated mitophagy pathway contributes to reducing ROS production and maintaining metabolic homeostasis. Whether PINK1/Parkin-mediated mitophagy plays a similar role in dairy cow liver is not well known. Thus, the objective of this study was to investigate mitophagy status in dairy cows with fatty liver and its role in free fatty acid (FFA)-induced oxidative stress and lipid accumulation. Liver and blood samples were collected from healthy dairy cows (n = 10) and cows with fatty liver (n = 10) that had a similar number of lactations (median = 3, range = 2 to 4) and days in milk (median = 6 d, range = 3 to 9 d). Calf hepatocytes were isolated from 5 healthy newborn female Holstein calves (1 d of age, 30-40 kg). Hepatocytes were transfected with small interfering RNA targeted against PRKN for 48 h or transfected with PRKN overexpression plasmid for 36 h, followed by treatment with FFA (0.3 or 1.2 mM) for 12 h. Mitochondria were isolated from fresh liver tissue or calf hepatocytes. Serum concentrations of β-hydroxybutyrate were higher in dairy cows with fatty liver. Hepatic malondialdehyde (MDA) and hydrogen peroxide (H2O2) were greater in cows with fatty liver. The lower protein abundance of PINK1, Parkin, p62, and LC3-II in hepatic mitochondrial fraction of dairy cows with fatty liver indicated the mitophagy was impaired. In hepatocytes, knockdown of PRKN decreased protein abundance of p62 and LC3-II in the mitochondrial fraction, and increased contents of triacylglycerol (TG), MDA, and H2O2. In addition, protein abundances of PINK1, Parkin, p62, and LC3-II were lower in the mitochondrial fraction from hepatocytes treated with 1.2 mM FFA than the hepatocytes treated with 0.3 mM FFA, whereas the content of TG, MDA, and H2O2 increased. In 1.2 mM FFA-treated hepatocytes, PRKN overexpression increased protein abundance of p62 and LC3-II in the mitochondrial fraction and decreased contents of TG, MDA, and H2O2. Together, our data demonstrate that low abundance of mitophagy markers is associated with ROS overproduction in dairy cows with fatty liver and impaired mitophagy induced by a high concentration of FFA promotes ROS production and lipid accumulation in female calf hepatocytes.
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Affiliation(s)
- Zhiyuan Fang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Guowen Liu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Mengyao Zhu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Shu Wang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Hao Yu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Xue Hao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Meng Chen
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Wenwen Gao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Lin Lei
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Yuxiang Song
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Zhe Wang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Xiliang Du
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China.
| | - Xinwei Li
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China.
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25
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Quercetin Protects Ethanol-Induced Hepatocyte Pyroptosis via Scavenging Mitochondrial ROS and Promoting PGC-1α-Regulated Mitochondrial Homeostasis in L02 Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4591134. [PMID: 35879991 PMCID: PMC9308520 DOI: 10.1155/2022/4591134] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/21/2022] [Accepted: 07/07/2022] [Indexed: 01/08/2023]
Abstract
Alcoholic liver disease (ALD) is a multifaceted process that involves excessive lipid, reactive oxygen species (ROS) production, unbalanced mitochondrial homeostasis, and ultimate cell death. Quercetin is a dietary phytochemical presented in various fruits and vegetables, which has anti-inflammatory and antioxidant effects. According to recent advances in pharmanutritional management, the effects of quercetin on various mitochondrial processes have attracted attention. In the study, we explored whether quercetin could attenuate ethanol-induced hepatocyte pyroptosis by maintaining mitochondrial homeostasis and studied its hepatoprotective effect and the underlying mechanism. We chose L02 cells to establish an in vitro model with ethanol-induced hepatocyte pyroptosis. Then, the cells at approximately 80% confluence were treated with quercetin (80, 40, and 20 μM). The cell viability (CCK-8) was used to investigate the effect of quercetin on ethanol-induced L02 cell proliferation. Relative assay kits were used to measure oxidative stress index (OSI = TOS/TAS), lipid peroxidation (LPO) release, and mitochondrial membrane potential (δΨm). The morphology of mitochondria was characterized by transmission electron microscopy- (TEM-) based analysis. Mitochondrial dynamics (Mito Tracker Green), mitROS (MitoSOX Red Mitochondrial Superoxide) production, and nuclear DNA (nDNA) damage (γH2AX) markers were detected by immunofluorescence. The mRNA levels of mitochondrial function (including mitochondrial DNA (mtDNA) transcription genes TWNK, MTCO1, and MFND) and pyroptosis-related genes were detected by RT-qPCR, and the protein levels of NLRP3, ASC, caspase1, cleaved-caspase1, IL-18, IL-1β, and GSDMD-N were detected by western blot. The results showed that quercetin treatment downregulated redox status, lipid droplets, and LPO release, restored damaged mitochondrial membrane potential, and repaired mtDNA damage, PGC-1α nuclear transfer, and mitochondrial dynamics. The gene and protein expressions of NLRP3, ASC, cleaved-caspase1, IL-18, IL-1β, and GSDMD-N were decreased, which effectively inhibited cell pyroptosis. Therefore, the results indicated that quercetin protected ethanol-induced hepatocyte pyroptosis via scavenging mitROS and promoting PGC-1α-mediated mitochondrial homeostasis in L02 cells.
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26
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Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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27
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Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance. Angiogenesis 2022; 25:307-329. [PMID: 35303170 DOI: 10.1007/s10456-022-09835-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
Abstract
Coronary microvascular endothelial dysfunction is both a culprit and a victim of diabetes, and can accelerate diabetes-related microvascular and macrovascular complications by promoting vasoconstrictive, pro-inflammatory and pro-thrombotic responses. Perturbed mitochondrial function induces oxidative stress, disrupts metabolism and activates apoptosis in endothelial cells, thus exacerbating the progression of coronary microvascular complications in diabetes. The mitochondrial quality surveillance (MQS) system responds to stress by altering mitochondrial metabolism, dynamics (fission and fusion), mitophagy and biogenesis. Dysfunctional mitochondria are prone to fission, which generates two distinct types of mitochondria: one with a normal and the other with a depolarized mitochondrial membrane potential. Mitochondrial fusion and mitophagy can restore the membrane potential and homeostasis of defective mitochondrial fragments. Mitophagy-induced decreases in the mitochondrial population can be reversed by mitochondrial biogenesis. MQS abnormalities induce pathological mitochondrial fission, delayed mitophagy, impaired metabolism and defective biogenesis, thus promoting the accumulation of unhealthy mitochondria and the activation of mitochondria-dependent apoptosis. In this review, we examine the effects of MQS on mitochondrial fitness and explore the association of MQS disorders with coronary microvascular endothelial dysfunction in diabetes. We also discuss the potential to treat diabetes-related coronary microvascular endothelial dysfunction using novel MQS-altering drugs.
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28
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Lu X, Xuan W, Li J, Yao H, Huang C, Li J. AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. Autophagy 2021; 17:3622-3643. [PMID: 33719895 PMCID: PMC8632272 DOI: 10.1080/15548627.2021.1886829] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 01/22/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Recent reports indicated that mitophagy protects against alcohol-induced liver injury, which helps remove damaged mitochondria to reduce the accumulation of reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction research. However, the inner mechanism, whether AMPK can regulate mitophagy in ALD, remains unknown. Here we found that AMPK can significantly reduce alcohol-induced liver injury and enhances hepatocytes' mitophagy level. Next, we identified that AMPK rescued alcohol-induced low expression of UQCRC2 (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression (OE) can significantly increase mitophagy to attenuate liver injury. Also, we identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays helped us understand that AMPK enhanced UQCRC2 gene transcription through activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the regulation of mitophagy levels in the liver, suggesting a possible therapeutic strategy to treat ALD.Abbreviations: AAV: AENO-associated virus; ALD: alcoholic liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic obstructive pulmonary disease; EM: electron microscope; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WB: western blot; ΔΨ: mitochondrial membrane potential.
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Affiliation(s)
- Xinyi Lu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Wenting Xuan
- Department of Anesthesiology, Drum Tower Hospital, Medical College of Nanjing University, Nanjing, China
| | - Juanjuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Hongwei Yao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
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29
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Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem 2021; 12:87-103. [PMID: 34630912 PMCID: PMC8473419 DOI: 10.4331/wjbc.v12.i5.87] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression are still to be fully elucidated. Oxidative stress, mitochondrial dysfunction, gut dysbiosis and altered immune system response plays an important role in disease pathogenesis, triggering the activation of inflammatory pathways and apoptosis. Despite many recent clinical studies treatment options for ALD are limited, especially at the alcoholic hepatitis stage. We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.
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Affiliation(s)
- Lucy Petagine
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Vinood B Patel
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
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30
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Lemasters JJ. Metabolic implications of non-electrogenic ATP/ADP exchange in cancer cells: A mechanistic basis for the Warburg effect. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2021; 1862:148410. [PMID: 33722515 PMCID: PMC8096716 DOI: 10.1016/j.bbabio.2021.148410] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/07/2021] [Indexed: 12/20/2022]
Abstract
In post-mitotic cells, mitochondrial ATP/ADP exchange occurs by the adenine nucleotide translocator (ANT). Driven by membrane potential (ΔΨ), ANT catalyzes electrogenic exchange of ATP4- for ADP3-, leading to higher ATP/ADP ratios in the cytosol than mitochondria. In cancer cells, ATP/ADP exchange occurs not by ANT but likely via the non-electrogenic ATP-Mg/phosphate carrier. Consequences of non-electrogenic exchange are: 1) Cytosolic ATP/ADP decreases to stimulate aerobic glycolysis. 2) Without proton utilization for exchange, ATP/O increases by 35% for complete glucose oxidation. 3) Decreased cytosolic ATP/ADPPi increases NAD(P)H/NAD(P)+. Increased NADH increases lactate/pyruvate, and increased NADPH promotes anabolic metabolism. Fourth, increased mitochondrial NADH/NAD+ magnifies the redox span across Complexes I and III, which increases ΔΨ, reactive oxygen species generation, and susceptibility to ferroptosis. 5) Increased mitochondrial NADPH/NADP+ favors a reverse isocitrate dehydrogenase-2 reaction with citrate accumulation and export for biomass formation. Consequently, 2-oxoglutarate formation occurs largely via oxidation of glutamine, the preferred respiratory substrate of cancer cells. Overall, non-electrogenic ATP/ADP exchange promotes aerobic glycolysis (Warburg effect) and confers specific growth advantages to cancer cells.
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Affiliation(s)
- John J Lemasters
- Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States of America.
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31
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Zhao H, Liu S, Zhao H, Liu Y, Xue M, Zhang H, Qiu X, Sun Z, Liang H. Protective effects of fucoidan against ethanol-induced liver injury through maintaining mitochondrial function and mitophagy balance in rats. Food Funct 2021; 12:3842-3854. [PMID: 33977968 DOI: 10.1039/d0fo03220d] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
For alcoholic liver disease (ALD), mitophagy has been reported as a promising therapeutic strategy to alleviate the hepatic lesion elicited by ethanol. This study was conducted to investigate the regulatory effects of fucoidan on mitophagy induced by chronic ethanol administration in rats. Here, 20 male rats in each group were treated with fucoidan (150 and 300 mg per kg body weight) by gavage once daily. Up to 56% liquor (7 to 9 mL per kg body weight) was orally administered 1 h after the fucoidan treatment for 20 weeks. The results showed that chronic ethanol consumption elevated the levels of hepatic enzymes (ALT, AST, and GGT) and triglyceride (TG) contents, with liver antioxidant enzymes being decreased and lipid peroxidation products increased and thus initiating the mitochondria-induced endogenous apoptotic pathway. Furthermore, ethanol-induced excessive oxidative stress inhibited the function of mitochondria and promoted damaged mitochondria accumulation which stimulated the PTEN-induced putative kinase 1 (PINK1) and Parkin associated mitophagic pathway in the liver. In contrast, the fucoidan pretreatment alleviated ethanol-induced histopathological changes, disorders of lipid metabolism, and oxidative damage with mitophagy related proteins and mitochondrial dynamics-related proteins namely mitochondrial E3 ubiquitin ligase 1 (Mul1), mitofusin2 (Mfn2) and dynamin-related protein 1 (Drp1) being restored to a normal level. In summary, our findings suggest that fucoidan pretreatment protects against ethanol-induced damaged mitochondria accumulation and over-activated mitophagy, which plays a pivotal role in maintaining mitochondrial homeostasis and ensuring mitochondrial quality.
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Affiliation(s)
- Huichao Zhao
- The Institute of Human Nutrition, Qingdao University, Ning Xia Road 308, Qingdao 266071, China.
| | - Shuang Liu
- The Institute of Human Nutrition, Qingdao University, Ning Xia Road 308, Qingdao 266071, China.
| | - Hui Zhao
- The Institute of Human Nutrition, Qingdao University, Ning Xia Road 308, Qingdao 266071, China.
| | - Ying Liu
- Basic Medical College, Qingdao University, Ning Xia Road 308, Qingdao 266071, China
| | - Meilan Xue
- Basic Medical College, Qingdao University, Ning Xia Road 308, Qingdao 266071, China
| | - Huaqi Zhang
- The Institute of Human Nutrition, Qingdao University, Ning Xia Road 308, Qingdao 266071, China.
| | - Xia Qiu
- State Key Laboratory of Bioactive Seaweed Substances, Qingdao Bright Moon Seaweed Group Co., Ltd, Qingdao 266400, China
| | - Zhanyi Sun
- State Key Laboratory of Bioactive Seaweed Substances, Qingdao Bright Moon Seaweed Group Co., Ltd, Qingdao 266400, China
| | - Hui Liang
- The Institute of Human Nutrition, Qingdao University, Ning Xia Road 308, Qingdao 266071, China.
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32
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Longo M, Paolini E, Meroni M, Dongiovanni P. Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC. Int J Mol Sci 2021; 22:4173. [PMID: 33920670 PMCID: PMC8073183 DOI: 10.3390/ijms22084173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver ("mitochondrial plasticity"). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic-lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
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Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
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33
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Doblado L, Lueck C, Rey C, Samhan-Arias AK, Prieto I, Stacchiotti A, Monsalve M. Mitophagy in Human Diseases. Int J Mol Sci 2021; 22:3903. [PMID: 33918863 PMCID: PMC8069949 DOI: 10.3390/ijms22083903] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.
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Affiliation(s)
- Laura Doblado
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (L.D.); (C.L.); (C.R.)
| | - Claudia Lueck
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (L.D.); (C.L.); (C.R.)
| | - Claudia Rey
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (L.D.); (C.L.); (C.R.)
| | - Alejandro K. Samhan-Arias
- Department of Biochemistry, Universidad Autónoma de Madrid e Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
| | - Ignacio Prieto
- Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Isaac Peral 42, 28015 Madrid, Spain;
| | - Alessandra Stacchiotti
- Department of Biomedical Sciences for Health, Universita’ Degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
- U.O. Laboratorio di Morfologia Umana Applicata, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
| | - Maria Monsalve
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (L.D.); (C.L.); (C.R.)
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Longo M, Meroni M, Paolini E, Macchi C, Dongiovanni P. Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending? Metabolism 2021; 117:154708. [PMID: 33444607 DOI: 10.1016/j.metabol.2021.154708] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.
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Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy
| | - Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
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35
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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36
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Li X, Huang L, Lan J, Feng X, Li P, Wu L, Peng Y. Molecular mechanisms of mitophagy and its roles in neurodegenerative diseases. Pharmacol Res 2020; 163:105240. [PMID: 33053441 DOI: 10.1016/j.phrs.2020.105240] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/30/2020] [Accepted: 10/04/2020] [Indexed: 12/21/2022]
Abstract
Neurodegenerative diseases are the most common diseases of the nervous system in elderly people, which are currently incurable and cause great burden to families and societies. Mitochondria are the energy factory of the cell and have extremely important effects on neuronal function. The elimination of dysfunctional mitochondria is essential for the mitochondrial metabolic homeostasis, energy supply, and neuronal survival. Recent studies suggest that the impaired mitophagy may lead to the accumulation of damaged mitochondria and therefore contribute to the progression of neurodegenerative diseases. This review mainly focuses on mitophagy, mitochondrial dynamics, and their abnormal changes in neurodegenerative diseases, as well as the therapeutic strategies targeting mitophagy that have shown promise in recent preclinical and clinical studies.
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Affiliation(s)
- Xinnan Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Longjian Huang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Jiaqi Lan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Xinhong Feng
- Department of Neurology, Beijing Tsinghua Changgung Hospital, Beijing 102218, China
| | - Pingping Li
- China National Center for Biotechnology Development, Beijing 100039, China
| | - Lei Wu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
| | - Ying Peng
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
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Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
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Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
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38
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Palma E, Riva A, Moreno C, Odena G, Mudan S, Manyakin N, Miquel R, Degré D, Trepo E, Sancho-Bru P, Altamirano J, Caballeria J, Zamalloa A, Menon K, Heaton N, Williams R, Bataller R, Chokshi S. Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease. Alcohol Clin Exp Res 2020; 44:856-865. [PMID: 32020641 PMCID: PMC7166173 DOI: 10.1111/acer.14299] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/22/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. METHODS Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1-like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). RESULTS A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. CONCLUSIONS The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.
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Affiliation(s)
- Elena Palma
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- King’s College London, Faculty of Life Sciences and Medicine, London, United Kingdom
| | - Antonio Riva
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- King’s College London, Faculty of Life Sciences and Medicine, London, United Kingdom
| | - Christophe Moreno
- CUB Hôpital Erasme, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Gemma Odena
- Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | | | - Rosa Miquel
- Institute of Liver Studies, King’s College London, London, United Kingdom
| | - Delphine Degré
- CUB Hôpital Erasme, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Eric Trepo
- CUB Hôpital Erasme, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Pau Sancho-Bru
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Jose Altamirano
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan Caballeria
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Ane Zamalloa
- Institute of Liver Studies, King’s College London, London, United Kingdom
| | - Krishna Menon
- Institute of Liver Studies, King’s College London, London, United Kingdom
| | - Nigel Heaton
- Institute of Liver Studies, King’s College London, London, United Kingdom
| | - Roger Williams
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- King’s College London, Faculty of Life Sciences and Medicine, London, United Kingdom
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- King’s College London, Faculty of Life Sciences and Medicine, London, United Kingdom
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Ma X, McKeen T, Zhang J, Ding WX. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020; 9:cells9040837. [PMID: 32244304 PMCID: PMC7226762 DOI: 10.3390/cells9040837] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 12/12/2022] Open
Abstract
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
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Affiliation(s)
- Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Tara McKeen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Jianhua Zhang
- Department of Pathology, Division of Molecular Cellular Pathology, University of Alabama at Birmingham, 901 19th street South, Birmingham, AL 35294, USA;
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
- Correspondence: ; Tel.: +1-913-588-9813
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40
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Su Z, Nie Y, Huang X, Zhu Y, Feng B, Tang L, Zheng G. Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns. Front Pharmacol 2019; 10:1193. [PMID: 31649547 PMCID: PMC6795753 DOI: 10.3389/fphar.2019.01193] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 09/17/2019] [Indexed: 12/23/2022] Open
Abstract
Metabolic syndrome, characterized by central obesity, hypertension, and hyperlipidemia, increases the morbidity and mortality of cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and other metabolic diseases. It is well known that insulin resistance, especially hepatic insulin resistance, is a risk factor for metabolic syndrome. Current research has shown that hepatic fatty acid accumulation can cause hepatic insulin resistance through increased gluconeogenesis, lipogenesis, chronic inflammation, oxidative stress and endoplasmic reticulum stress, and impaired insulin signal pathway. Mitochondria are the major sites of fatty acid β-oxidation, which is the major degradation mechanism of fatty acids. Mitochondrial dysfunction has been shown to be involved in the development of hepatic fatty acid–induced hepatic insulin resistance. Mitochondrial autophagy (mitophagy), a catabolic process, selectively degrades damaged mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial dynamics and function. Therefore, mitophagy can promote mitochondrial fatty acid oxidation to inhibit hepatic fatty acid accumulation and improve hepatic insulin resistance. Here, we review advances in our understanding of the relationship between mitophagy and hepatic insulin resistance. Additionally, we also highlight the potential value of mitophagy in the treatment of hepatic insulin resistance and metabolic syndrome.
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Affiliation(s)
- Zuqing Su
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yutong Nie
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiufang Huang
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.,The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Zhu
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bing Feng
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lipeng Tang
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangjuan Zheng
- Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
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Yin XM. Autophagy in liver diseases: A matter of what to remove and whether to keep. LIVER RESEARCH 2018; 2:109-111. [PMID: 32042470 PMCID: PMC7010265 DOI: 10.1016/j.livres.2018.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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