Diabetes & Metabolism Journal

Original Articles

Basic Research
PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca²⁺ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes: Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang; Received August 12, 2023 Accepted March 26, 2024 Published online July 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0275 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods
High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca²⁺ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results
PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca²⁺ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion
PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca²⁺ into the mitochondria.

Basic Research
DGAT2 Plays a Crucial Role to Control ESRRA-PROX1 Transcriptional Network to Maintain Hepatic Mitochondrial Sustainability: Yoseob Lee, Yeseong Hwang, Minki Kim, Hyeonuk Jeon, Seyeon Joo, Sungsoon Fang, Jae-Woo Kim; Diabetes Metab J. 2024;48(5):901-914. Published online April 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0368

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Abstract PDF Supplementary Material PubReader ePub: Background
Diacylglycerol O-acyltransferase 2 (DGAT2) synthesizes triacylglycerol (TG) from diacylglycerol; therefore, DGAT2 is considered as a therapeutic target for steatosis. However, the consequence of inhibiting DGAT2 is not fully investigated due to side effects including lethality and lipotoxicity. In this article, we observed the role of DGAT2 in hepatocarcinoma.
Methods
The role of DGAT2 is analyzed via loss-of-function assay. DGAT2 knockdown (KD) and inhibitor treatment on HepG2 cell line was analyzed. Cumulative analysis of cell metabolism with bioinformatic data were assessed, and further compared with different cohorts of liver cancer patients and non-alcoholic fatty liver disease (NAFLD) patients to elucidate how DGAT2 is regulating cancer metabolism.
Results
Mitochondrial function is suppressed in DGAT2 KD HepG2 cell along with the decreased lipid droplets. In the aspect of the cancer, DGAT2 KD upregulates cell proliferation. Analyzing transcriptome of NAFLD and hepatocellular carcinoma (HCC) patients highlights negatively correlating expression patterns of 73 lipid-associated genes including DGAT2. Cancer patients with the lower DGAT2 expression face lower survival rate. DGAT2 KD cell and patients’ transcriptome show downregulation in estrogen- related receptor alpha (ESRRA) via integrated system for motif activity response analysis (ISMARA), with increased dimerization with corepressor prospero homeobox 1 (PROX1).
Conclusion
DGAT2 sustains the stability of mitochondria in hepatoma via suppressing ESRRA-PROX1 transcriptional network and hinders HCC from shifting towards glycolytic metabolism, which lowers cell proliferation.

Brief Report

Genetics
Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea: Eun Hoo Rho, Sang Ik Baek, Heerah Lee, Moon-Woo Seong, Jong-Hee Chae, Kyong Soo Park, Soo Heon Kwak; Diabetes Metab J. 2024;48(3):482-486. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0078

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Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Citations

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Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)
Eun Hoo Rho, Soo Heon Kwak
Diabetes & Metabolism Journal.2024; 48(4): 818. CrossRef
MIDD Patients Should Not Be Confused with MELAS Patients, Even Though Both Carry the m.3243A>G Variant
Josef Finsterer, Sounira Mehri
Diabetes & Metabolism Journal.2024; 48(4): 816. CrossRef

Reviews

Basic Research
Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases: Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong; Diabetes Metab J. 2024;48(1):1-18. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2023.0115

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Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPR^mt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPR^mt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

Citations

Citations to this article as recorded by

Mitochondria: fundamental characteristics, challenges, and impact on aging
Runyu Liang, Luwen Zhu, Yongyin Huang, Jia Chen, Qiang Tang
Biogerontology.2024;[Epub] CrossRef

Basic Research
Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases: Byung Soo Kong, Changhan Lee, Young Min Cho; Diabetes Metab J. 2023;47(3):315-324. Published online February 24, 2023; DOI: https://doi.org/10.4093/dmj.2022.0333

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Mitochondria are complex metabolic organelles with manifold pathophysiological implications in diabetes. Currently published mitochondrial-encoded peptides, which are expressed from the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c), 16S rRNA (humanin and short humanin like peptide 1-6 [SHLP1-6]), or small human mitochondrial open reading frame over serine tRNA (SHMOOSE) are associated with regulation of cellular metabolism and insulin action in age-related diseases, such as type 2 diabetes mellitus. This review focuses mainly on recent advances in MOTS-c research with regards to diabetes, including both type 1 and type 2. The emerging understanding of MOTS-c in diabetes may provide insight into the development of new therapies for diabetes and other age or senescence-related diseases.

Citations

Citations to this article as recorded by

Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives
Satadeepa Kal, Sumana Mahata, Suborno Jati, Sushil K. Mahata
Peptides.2024; 172: 171147. CrossRef
Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases
Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong
Diabetes & Metabolism Journal.2024; 48(1): 1. CrossRef
Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes
Alejandra María Rivera Nieves, Brian Michael Wauford, Accalia Fu
Frontiers in Molecular Biosciences.2024;[Epub] CrossRef
Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome
Petr Pecina, Kristýna Čunátová, Vilma Kaplanová, Guillermo Puertas-Frias, Jan Šilhavý, Kateřina Tauchmannová, Marek Vrbacký, Tomáš Čajka, Ondřej Gahura, Markéta Hlaváčková, Viktor Stránecký, Stanislav Kmoch, Michal Pravenec, Josef Houštěk, Tomáš Mráček, A
Communications Biology.2024;[Epub] CrossRef
Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner
Yanli Zhang, Jianfeng Huang, Shengpeng Li, Junlin Jiang, Jiaojiao Sun, Dan Chen, Qingfeng Pang, Yaxian Wu
Journal of Agricultural and Food Chemistry.2024; 72(38): 20944. CrossRef

Basic Research
The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4: Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee; Diabetes Metab J. 2023;47(2):153-163. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0305

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Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.

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Synthesis, activatory effects, molecular docking and ADME studies as rabbit muscle pyruvate kinase activators of ureido phenyl substituted 1,4-dihydropyridine derivatives
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Yanmei Miao, Leiyu Xie, Jiamei Song, Xing Cai, Jinghe Yang, Xinglong Ma, Shaolin Chen, Peng Xie
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Zonghao Qian, Yuzhen Huang, Yucong Zhang, Ni Yang, Ziwei Fang, Cuntai Zhang, Le Zhang
Frontiers in Genetics.2024;[Epub] CrossRef
Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation
Tangtian Chen, Qiumin Xie, Bin Tan, Qin Yi, Han Xiang, Rui Wang, Qin Zhou, Bolin He, Jie Tian, Jing Zhu, Hao Xu
Inflammation.2024; 47(4): 1356. CrossRef
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Majid Mohabbat, Hamid Arazi
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Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3
Xuliang Huang, Yuhao Zheng, Nan Wang, Mingming Zhao, Jinhui Liu, Wen Lin, Ye Zhu, Xiaofan Xie, Ya Lv, Junlu Wang, Yunchang Mo
Inflammation.2024;[Epub] CrossRef
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Ester Sara Di Filippo, Sara Chiappalupi, Stefano Falone, Vincenza Dolo, Fernanda Amicarelli, Silvia Marchianò, Adriana Carino, Gabriele Mascetti, Giovanni Valentini, Sara Piccirillo, Michele Balsamo, Marco Vukich, Stefano Fiorucci, Guglielmo Sorci, Stefan
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Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases
Yue Zhang, Meiyan Sun, Hongxiang Zhao, Zhengyan Wang, Yanan Shi, Jianxin Dong, Kaifang Wang, Xi Wang, Xingyue Li, Haiyan Qi, Xiaoyong Zhao
International Journal of Nanomedicine.2023; Volume 18: 7559. CrossRef

Sulwon Lecture 2021

Basic Research
Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c): Tae Kwan Yoon, Chan Hee Lee, Obin Kwon, Min-Seon Kim; Diabetes Metab J. 2022;46(3):402-413. Published online May 25, 2022; DOI: https://doi.org/10.4093/dmj.2022.0092

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Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPR^mt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.

Citations

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Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives
Satadeepa Kal, Sumana Mahata, Suborno Jati, Sushil K. Mahata
Peptides.2024; 172: 171147. CrossRef
Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging
Se Hee Min, Gil Myoung Kang, Jae Woo Park, Min-Seon Kim
Yonsei Medical Journal.2024; 65(2): 55. CrossRef
Roles of Myokines and Muscle-Derived Extracellular Vesicles in Musculoskeletal Deterioration under Disuse Conditions
Jie Zhang, Yunfang Gao, Jiangwei Yan
Metabolites.2024; 14(2): 88. CrossRef
The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration
Wacili Da, Quan Chen, Bin Shen
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Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial b
Lingfei Xu, Xihui Tang, Long Yang, Min Chang, Yuqing Xu, Qingsong Chen, Chen Lu, Su Liu, Jinhong Jiang
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MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis
Long Yang, Miaomiao Li, Yucheng Liu, Yang Bai, Tianyu Yin, Yangyang Chen, Jinhong Jiang, Su Liu
Acta Biochimica et Biophysica Sinica.2024;[Epub] CrossRef
Adipose thermogenic mechanisms by cold, exercise and intermittent fasting: Similarities, disparities and the application in treatment
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Fabiola Olivieri, Francesco Prattichizzo, Fabrizia Lattanzio, Anna Rita Bonfigli, Liana Spazzafumo
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MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation
Yuejun Zheng, Zilin Wei, Tianhui Wang
Frontiers in Endocrinology.2023;[Epub] CrossRef
MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria
Zewei Zhang, Dongmei Chen, Kaili Du, Yaping Huang, Xingzhe Li, Quwen Li, Xiaoting Lv
Mitochondrion.2023; 71: 76. CrossRef
Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases
Byung Soo Kong, Changhan Lee, Young Min Cho
Diabetes & Metabolism Journal.2023; 47(3): 315. CrossRef
MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake—A Preliminary Study
Remigiusz Domin, Michał Pytka, Mikołaj Żołyński, Jan Niziński, Marcin Rucinski, Przemysław Guzik, Jacek Zieliński, Marek Ruchała
International Journal of Molecular Sciences.2023; 24(19): 14951. CrossRef
Unique Properties of Apicomplexan Mitochondria
Ian M. Lamb, Ijeoma C. Okoye, Michael W. Mather, Akhil B. Vaidya
Annual Review of Microbiology.2023; 77(1): 541. CrossRef

Original Article

Metabolic Risk/Epidemiology
Effect of Low-Dose Persistent Organic Pollutants on Mitochondrial Function: Human and in Vitro Evidence: Se-A Kim, Hoyul Lee, Sung-Mi Park, Mi-Jin Kim, Yu-Mi Lee, Young-Ran Yoon, Hyun-Kyung Lee, Hyo-Bang Moon, In-Kyu Lee, Duk-Hee Lee; Diabetes Metab J. 2022;46(4):592-604. Published online January 26, 2022; DOI: https://doi.org/10.4093/dmj.2021.0132

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Background
Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells.
Methods
Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, β-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells.
Results
The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/μg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/μg according to the PCB quintiles of summary measure (P trend <0.001), and this inverse association was consistently observed in all subgroups stratified by age, sex, obesity, type 2 diabetes mellitus, and hypertension, respectively. In vitro experimental studies have also demonstrated that chronic exposure to low-dose POPs could decrease OCR levels.
Conclusion
The findings from human and in vitro studies suggest that chronic exposure to low-dose POPs can induce mitochondrial dysfunction by impairing oxidative phosphorylation.

Citations

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Persistent Organic Pollutants released from decomposed adipose tissue affect mitochondrial enzyme function in the brain and eyes other than the liver
Dongshin Yang, Eun Ko, Hwayeon Lim, Hyojin Lee, Kitae Kim, Moonsung Choi, Sooim Shin
Environmental Science and Pollution Research.2024; 31(7): 10648. CrossRef
Obesity paradox can be a fact: unveiling the hidden role of adipose tissue
Duk-Hee Lee
European Heart Journal.2024; 45(24): 2167. CrossRef
Reduced bioenergetics and mitochondrial fragmentation in human primary cytotrophoblasts induced by an EGFR-targeting chemical mixture
Anita A. Waye, Elvis Ticiani, Zinat Sharmin, Vanessa Perez Silos, Thilini Perera, Alex Tu, Irina A. Buhimschi, Carlos A. Murga-Zamalloa, Ying S. Hu, Almudena Veiga-Lopez
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Robert K. Naviaux
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Review

Basic Research
Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases: Jin-Ho Koh, Yong-Woon Kim, Dae-Yun Seo, Tae-Seo Sohn; Diabetes Metab J. 2021;45(6):853-865. Published online November 22, 2021; DOI: https://doi.org/10.4093/dmj.2021.0138

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Graphical Abstract Abstract PDF PubReader ePub

Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca²⁺) for appropriate responses. Overflux of Ca²⁺ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca²⁺ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca²⁺ flux and describe the mechanisms by which Tfam affects mitochondrial Ca²⁺ flux in response to metabolic challenges.

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Original Article

Basic Research
Umbilical Cord-Mesenchymal Stem Cell-Conditioned Medium Improves Insulin Resistance in C2C12 Cell: Kyung-Soo Kim, Yeon Kyung Choi, Mi Jin Kim, Jung Wook Hwang, Kyunghoon Min, Sang Youn Jung, Soo-Kyung Kim, Yong-Soo Choi, Yong-Wook Cho; Diabetes Metab J. 2021;45(2):260-269. Published online July 10, 2020; DOI: https://doi.org/10.4093/dmj.2019.0191

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Background

Umbilical cord-mesenchymal stem cell-conditioned medium (UC-MSC-CM) has emerged as a promising cell-free therapy. The aim of this study was to explore the therapeutic effects of UC-MSC-CM on insulin resistance in C2C12 cell.

Methods

Insulin resistance was induced by palmitate. Effects of UC-MSC-CM on insulin resistance were evaluated using glucose uptake, glucose transporter type 4 (GLUT4) translocation, the insulin-signaling pathway, and mitochondrial contents and functions in C2C12 cell.

Results

Glucose uptake was improved by UC-MSC-CM. UC-MSC-CM treatment increased only in membranous GLUT4 expression, not in cytosolic GLUT4 expression. It restored the insulin-signaling pathway in insulin receptor substrate 1 and protein kinase B. Mitochondrial contents evaluated by mitochondrial transcription factor A, mitochondrial DNA copy number, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha were increased by UC-MSC-CM. In addition, UC-MSC-CM significantly decreased mitochondrial reactive oxygen species and increased fatty acid oxidation and mitochondrial membrane potential. There was no improvement in adenosine triphosphate (ATP) contents, but ATP synthesis was improved by UC-MSC-CM. Cytokine and active factor analysis of UC-MSC-CM showed that it contained many regulators inhibiting insulin resistance.

Conclusion

UC-MSC-CM improves insulin resistance with multiple mechanisms in C2C12 cell.

Citations

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Sulwon Lecture 2019

Pathophysiology
The Role of Growth Differentiation Factor 15 in Energy Metabolism: Joon Young Chang, Hyun Jung Hong, Seul Gi Kang, Jung Tae Kim, Ben Yuan Zhang, Minho Shong; Diabetes Metab J. 2020;44(3):363-371. Published online June 29, 2020; DOI: https://doi.org/10.4093/dmj.2020.0087

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Abstract PDF PubReader

Growth differentiation factor 15 (GDF15) is receiving great interest beyond its role as an aging and disease-related biomarker. Recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), suggests a central role in appetite regulation. However, there is also considerable evidence that GDF15 may have peripheral activity through an as-of-yet undiscovered mode of action. This raises the question as to whether increased GDF15 induction during pathophysiologic conditions also suppresses appetite. The present review will briefly introduce the discovery of GDF15 and describe the different contexts under which GDF15 is induced, focusing on its induction during mitochondrial dysfunction. We will further discuss the metabolic role of GDF15 under various pathophysiological conditions and conclude with possible therapeutic applications.

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Review

Basic Research
Mitochondrial Mechanisms in Diabetic Cardiomyopathy: Johannes Gollmer, Andreas Zirlik, Heiko Bugger; Diabetes Metab J. 2020;44(1):33-53. Published online February 21, 2020; DOI: https://doi.org/10.4093/dmj.2019.0185

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Abstract PDF PubReader

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca²⁺ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

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Original Article

Basic Research
Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy: Chang-Yun Woo, Ji Yeon Baek, Ah-Ram Kim, Chung Hwan Hong, Ji Eun Yoon, Hyoun Sik Kim, Hyun Ju Yoo, Tae-Sik Park, Ranjan Kc, Ki-Up Lee, Eun Hee Koh; Diabetes Metab J. 2020;44(4):581-591. Published online November 4, 2019; DOI: https://doi.org/10.4093/dmj.2019.0063

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Background

Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy.

Methods

We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control- or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes.

Results

OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity.

Conclusion

We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

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Review

Others
Mitochondrial Toxins and Healthy Lifestyle Meet at the Crossroad of Hormesis: Yu-Mi Lee, Duk-Hee Lee; Diabetes Metab J. 2019;43(5):568-577. Published online October 24, 2019; DOI: https://doi.org/10.4093/dmj.2019.0143

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Mitochondrial function is crucial for the maintenance of cellular homeostasis under physiological and stress conditions. Thus, chronic exposure to environmental chemicals that affect mitochondrial function can have harmful effects on humans. We argue that the concept of hormesis should be revisited to explain the non-linear responses to mitochondrial toxins at a low-dose range and develop practical methods to protect humans from the negative effects of mitochondrial toxins. Of the most concern to humans are lipophilic chemical mixtures and heavy metals, owing to their physical properties. Even though these chemicals tend to demonstrate no safe level in humans, a non-linear dose-response has been also observed. Stress response activation, i.e., hormesis, can explain this non-linearity. Recently, hormesis has reemerged as a unifying concept because diverse stressors can induce similar stress responses. Besides potentially harmful environmental chemicals, healthy lifestyle interventions such as exercise, calorie restriction (especially glucose), cognitive stimulation, and phytochemical intake also activate stress responses. This conceptual link can lead to the development of practical methods that counterbalance the harm of mitochondrial toxins. Unlike chemical hormesis with its safety issues, the activation of stress responses via lifestyle modification can be safely used to combat the negative effects of mitochondrial toxins.

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Sulwon Lecture 2018

Pathophysiology
Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation: Chang-Yun Woo, Jung Eun Jang, Seung Eun Lee, Eun Hee Koh, Ki-Up Lee; Diabetes Metab J. 2019;43(3):247-256. Published online March 27, 2019; DOI: https://doi.org/10.4093/dmj.2018.0221

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Adipose tissue inflammation is considered a major contributing factor in the development of obesity-associated insulin resistance and cardiovascular diseases. However, the cause of adipose tissue inflammation is presently unclear. The role of mitochondria in white adipocytes has long been neglected because of their low abundance. However, recent evidence suggests that mitochondria are essential for maintaining metabolic homeostasis in white adipocytes. In a series of recent studies, we found that mitochondrial function in white adipocytes is essential to the synthesis of adiponectin, which is the most abundant adipokine synthesized from adipocytes, with many favorable effects on metabolism, including improvement of insulin sensitivity and reduction of atherosclerotic processes and systemic inflammation. From these results, we propose a new hypothesis that mitochondrial dysfunction in adipocytes is a primary cause of adipose tissue inflammation and compared this hypothesis with a prevailing concept that “adipose tissue hypoxia” may underlie adipose tissue dysfunction in obesity. Recent studies have emphasized the role of the mitochondrial quality control mechanism in maintaining mitochondrial function. Future studies are warranted to test whether an inadequate mitochondrial quality control mechanism is responsible for mitochondrial dysfunction in adipocytes and adipose tissue inflammation.

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