The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro

Yu, Won Dong; Kim, Yu Jin; Cho, Min Jeong; Seok, Jin; Kim, Gi Jin; Lee, Changhan; Ko, Jung Jae; Kim, You Shin; Lee, Jae Ho

doi:10.1016/j.mito.2021.02.010

Cited by 12 publications

(7 citation statements)

References 23 publications

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“…CCN1 triggers ROS accumulation and mitochondrial outer membrane permeabilization (MOMP) by binding to integrin α6β1 and activation of ERK and JNK to target ubiquitinated mitochondria and stimulate autophagy ( 43 ). MOTS-c enhanced mitochondrial homeostasis by decreasing ROS production ( 44 ), and CCN1 inhibition may play an important role in this process.…”

Section: Discussionmentioning

confidence: 99%

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Wang

Wang²,

Pang³

et al. 2023

Front. Nutr.

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Cardiac structure remodeling and dysfunction are common complications of diabetes, often leading to serious cardiovascular events. MOTS-c, a mitochondria-derived peptide, regulates metabolic homeostasis by accelerating glucose uptake and improving insulin sensitivity. Plasma levels of MOTS-c are decreased in patients with diabetes. MOTS-c can improve vascular endothelial function, making it a novel therapeutic target for the cardiovascular complications of diabetes. We investigated the effects of MOTS-c on cardiac structure and function and analyzed transcriptomic characteristics in diabetic rats. Our results indicate that treatment with MOTS-c for 8-week repaired myocardial mitochondrial damage and preserved cardiac systolic and diastolic function. Transcriptomic analysis revealed that MOTS-c altered 47 disease causing genes. Functional enrichment analysis indicated MOTS-c attenuated diabetic heart disease involved apoptosis, immunoregulation, angiogenesis and fatty acid metabolism. Moreover, MOTS-c reduced myocardial apoptosis by downregulating CCN1 genes and thereby inhibiting the activation of ERK1/2 and the expression of its downstream EGR1 gene. Our findings identify potential therapeutic targets for the treatment of T2D and diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Wang

Wang²,

Pang³

et al. 2023

Front. Nutr.

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“…Khorraminejad-Shirazi et al determined that the inhibition of mTORC1 by antioxidants or the activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) enhanced the function of MSC. In our previous study, we also reported that the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) enhanced the homeostasis of hPD-MSCs by activating AMPK and inhibiting the mTORC1 pathway, thereby promoting mitochondrial function and quiescence [ 50 ]. Moreover, the inhibition of mTORC1 has been considered a promising clinical strategy due to its ability to improve the autophagy and functionality of tissues and organs [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

MIT-001 Restores Human Placenta-Derived Mesenchymal Stem Cells by Enhancing Mitochondrial Quiescence and Cytoskeletal Organization

Kim

Cho

et al. 2021

IJMS

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Inflammation is a major cause of several chronic diseases and is reported to be recovered by the immuno-modulation of mesenchymal stem cells (MSCs). While most studies have focussed on the anti-inflammatory roles of MSCs in stem cell therapy, the impaired features of MSCs, such as the loss of homeostasis by systemic aging or pathologic conditions, remain incompletely understood. In this study, we investigated whether the altered phenotypes of human placenta-derived MSCs (hPD-MSCs) exposed to inflammatory cytokines, including TNF-α and IFN-γ, could be protected by MIT-001, a small anti-inflammatory and anti-necrotic molecule. MIT-001 promoted the spindle-like shape and cytoskeletal organization extending across the long cell axis, whereas hPD-MSCs exposed to TNF-α/IFN-γ exhibited increased morphological heterogeneity with an abnormal cell shape and cytoskeletal disorganization. Importantly, MIT-001 improved mitochondrial distribution across the cytoplasm. MIT-001 significantly reduced basal respiration, ATP production, and cellular ROS levels and augmented the spare respiratory capacity compared to TNF-α/IFN-γ-exposed hPD-MSCs, indicating enhanced mitochondrial quiescence and homeostasis. In conclusion, while TNF-α/IFN-γ-exposed MSCs lost homeostasis and mitochondrial quiescence by becoming over-activated in response to inflammatory cytokines, MIT-001 was able to rescue mitochondrial features and cellular phenotypes. Therefore, MIT-001 has therapeutic potential for clinical applications to treat mitochondrion-related inflammatory diseases.

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“…As a key downstream molecule of MOTS-c, AMPK mediates a variety of effects such as metabolic homeostasis, insulin resistance, fat accumulation, exercise, inflammation, osteoporosis, cardiovascular protection, and aging [7,9,[44][45][46][47][48][49].…”

Section: The Pathways Regulated By Mots-c Ampkmentioning

confidence: 99%

“…In addition, MOTS-c treatment promoted the stabilization of the internal environment of aged mesenchymal stem cells (MSCs) by reducing oxygen consumption and ROS production, thereby significantly enhancing intramitochondrial homeostasis [49]. In a different approach, cytoplasmic hybrid (cybrid cells) containing 3243 A to G mutant mitochondrial DNA were generated, which resulted in mitochondrial dysfunction.…”

Section: Mots-c Regulates the Activation Of Brown Adipose Tissuementioning

confidence: 99%

Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging

et al. 2023

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MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.

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The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro

Cited by 12 publications

References 23 publications

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

MIT-001 Restores Human Placenta-Derived Mesenchymal Stem Cells by Enhancing Mitochondrial Quiescence and Cytoskeletal Organization

Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging

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