MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation

Zheng, Yong; Wei, Zengxin; Wang, Tianhui

doi:10.3389/fendo.2023.1120533

Cited by 12 publications

(5 citation statements)

References 50 publications

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“…MOTS-C, a short cytoprotective peptide secreted by mitochondria, has been shown to improve glucose metabolism in skeletal muscle, suggesting a benefit in disease such as diabetes, obesity and aging. 26 Previous studies have found that circulating MOTS-C is significantly reduced in obese children and adolescents and is associated with insulin resistance and obesity markers, and the present study showed similar results. 13 However, Cataldo et al found that obese and normal-weight adults have similar plasma MOTS-C levels, which may be affected by the study sample (n=10 per group).…”

Section: Discussionsupporting

confidence: 89%

“…However, MOTS-c has been used less frequently in disease treatment, and no effective method of applying MOTS-c in the clinic has been developed. As Zheng et al suggested, the use of synthetic biology techniques provide the possibility of using MOTS-C for disease treatment, 26 but there is still much to understand about MOTS-c, including basic molecular mechanisms, stability in biological systems, and oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

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Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

Luo¹,

Xie²,

Li³

et al. 2023

DMSO

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The increasing prevalence of obesity in children and its associated risk with cardiovascular diseases demand more discovery of the novel biomarkers for developing new treatment options for this complex disease. This study aimed to investigate the association of serum MOTS-C (a peptide encoded in the mitochondrial genome) levels and vascular endothelial function in obese children. Patients and Methods: A total of 225 obese children (aged 8.1 ± 2.6 years) and 218 healthy children (aged 7.9 ± 2.2 years) were enrolled. Related anthropometric assessment and biochemical evaluation were done in all subjects. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, was used for evaluation of peripheral endothelial function. Enzyme-linked immunosorbent assay (ELISA) was used to measure the level of serum MOTS-C. Results: Levels of serum MOTS-C and RHI were lower in the obese children compared with the healthy children (P < 0.01). The RHI level was independently associated with body mass index, high-density lipoprotein cholesterol, and MOTS-C in linear regression analysis. Further analysis showed a significant mediating effect of MOTS-C on the correlation between body mass index and RHI in children, with the ratio of mediating effect value of 9.12%. Conclusion: These data identify that MOTS-C is a previously unknown regulator in the development process of obesity-induced vascular changes.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

Luo¹,

Xie²,

Li³

et al. 2023

DMSO

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“…This study identified a unique and synergistic advantage of MOTS-c as a therapeutic strategy for the treatment of BCP. MOTS-c, a recently discovered mitochondrialderived peptide, has been reported to be involved in regulating diabetes, insulin resistance, inflammation, aging, and osteoporosis [11][12][13]15]. Here, our study demonstrated that chronic intraperitoneal administration of MOTS-c robustly attenuated bone cancerinduced pain, indicating the potential pharmacological effects of MOTS-c peptide as a therapeutic agent against cancer-induced pain.…”

Section: Discussionsupporting

confidence: 60%

“…MOTS-c, or the mitochondrial open reading frame of 12S rRNA type-c, is a recently discovered mitochondrial-derived peptide [10]. Several recent studies have shown that MOTS-c is involved in the regulation of diabetes [11,12], insulin resistance [10,13], inflammation [14,15], aging [16] and osteoporosis [17,18] through the AMPactivated protein kinase (AMPK) pathway. In particular, AMPK has attracted a great deal of attention as a therapeutic target for the regulation of chronic pain [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated <?A3B2 pi6?>mitochondrial biogenesis

Yang,

Li,

Liu

et al. 2024

ABBS

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Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα 1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

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“…MOTS-c, another mitochondrial polypeptide, assumes a pivotal role in the retrograde signal transduction pathway [64]. In an AMPK-dependent manner, MOTS-c translocates to the nucleus, where it interacts with ARE-regulating stress-responsive transfer factors, including Nrf2, thereby enhancing cellular stress resistance [65,66]. MOTSc further contributes to metabolic reprogramming by regulating downstream effectors such as HSF1 and HO-1, ultimately restoring mitochondrial function [58,67].…”

Section: Uprmtmentioning

confidence: 99%

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration

Da,

Chen,

Shen

2024

Biol Res

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It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

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MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation

Cited by 12 publications

References 50 publications

Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated <?A3B2 pi6?>mitochondrial biogenesis

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration

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MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation

Cited by 12 publications

References 50 publications

Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated &lt;?A3B2 pi6?&gt;mitochondrial biogenesis

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration

Contact Info

Product

Resources

About

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated <?A3B2 pi6?>mitochondrial biogenesis