Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation

Wei, Ming; Gan, Lu; Sha, Xianyi; Lu, Huanyu; Jiang, Yinghao; Li, Xiaoying; Xu, Chenyu; Ruan, Banjun; Li, Wang; Lu, Zifan

doi:10.1016/j.bbrc.2016.05.135

Cited by 77 publications

(75 citation statements)

References 34 publications

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“…Within 30 min of treatment, FITC-MOTS-c showed mitochondrial and nuclear localization, with a notable punctate pattern throughout the nucleus (Figures 1D and S1D). This suggests that the biological effects of exogenously treated MOTS-c peptide (Lee et al, 2015; Ming et al, 2016) may be, in part, mediated by its actions within the nucleus. To obtain additional spatial information on intracellular MOTS-c, we expressed MOTS-c tagged with an enhanced green fluorescent protein (EGFP-MOTS-c), a widely used technique to determine subcellular protein localization that is complementary to immunofluorescence (Stadler et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…We next set out to identify stress-responsive pathways that intersect with MOTS-c. AMP-activated protein kinase (AMPK) is a key energy-sensing kinase and a master metabolic regulator that is activated by metabolic stress (Hardie et al, 2016) and also mediates the metabolic actions of MOTS-c (Lee et al, 2015; Ming et al, 2016). To that end, we investigated if AMPK was also required for the stress-responsive nuclear translocation of MOTS-c. Pharmacological and genetic interventions that inhibit AMPK activity (compound C [C.C.]…”

Section: Resultsmentioning

confidence: 99%

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The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

et al. 2018

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SUMMARY Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5′-adenosine mono-phosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

et al. 2018

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“…Some of the biological responses mediated by MOTS‐c were due to its ability to upregulate cellular accumulation of 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), a potent activator of the AMP‐activated protein kinase ( AMPK) pathway and mitochondrial metabolism (24). MOTS‐c treatment suppressed bone loss following ovariectomy via activation of an AMPK‐dependent pathway, suggesting the importance of MOTS‐c in bone metabolism and osteoporosis …”

Section: Introductionmentioning

confidence: 99%

Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

Ramanjaneya

Jerobin

Bettahi

et al. 2019

Clinical Endocrinology

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Objective Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder associated with mitochondrial dysfunction and insulin resistance (IR). MOTS‐c, a mitochondrial peptide, promotes insulin sensitivity (IS) through activating AKT and AMPK‐dependent pathways. The current study was designed to examine the response of MOTS‐c to lipids (intralipid) followed by insulin in PCOS and healthy subjects. Methods All subjects underwent 5‐hour intralipid/saline infusion with a hyperinsulinemic‐euglycaemic clamp in the final 2 hours. Plasma samples were collected to measure circulating MOTS‐c using a commercial ELISA kit. Subsequently, this was repeated following an eight‐week exercise intervention. Results Intralipid significantly increased plasma MOTS‐c both in controls and PCOS subjects, whilst the insulin infusion blunted the intralipid‐induced response seen for both lipids and MOT‐c. Intralipid elevated plasma MOTS‐c to 232 ± 124% of basal in control (P < 0.01) and to 349 ± 206% of basal in PCOS (P < 0.001) subjects. Administration of insulin suppressed intralipid‐induced MOTS‐c from 232 ± 124% to 165 ± 97% (NS) in control and from 349 ± 206% to 183 ± 177% (P < 0.05) in PCOS subjects, respectively. Following exercise, intralipid elevated plasma MOTS‐c to 305 ± 153% of basal in control (P < 0.01) and to 215 ± 103% of basal in PCOS (P < 0.01) subjects; insulin suppressed intralipid‐induced MOTS‐c only in controls. Conclusions In conclusion, this is the first study to show increased lipid enhanced circulating MOTS‐c whilst insulin attenuated the MOTS‐c response in human. Further, eight weeks of moderate exercise training did not show any changes in circulating MOTS‐c levels in healthy controls and in women with PCOS.

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“…Due to its pharmacological effects of regulating metabolic homeostasis, especially the stimulation of glucose uptake and clearance as well as the activation of fatty acid metabolism, MOTS‐c can be regarded as a potential exercise mimetic agent and insulin sensitizer. To corroborate its function as a systemic metabolic hormone, MOTS‐c was tested in mice treated by intraperitoneal injections . Here, it was shown that MOTS‐c prevents age‐dependent insulin resistance and (high‐fat‐) diet‐induced insulin resistance and obesity.…”

Section: Introductionmentioning

confidence: 99%

“…Here, it was shown that MOTS‐c prevents age‐dependent insulin resistance and (high‐fat‐) diet‐induced insulin resistance and obesity. The stimulation of AMPK was found to result in an inhibition of osteoclast formation and bone loss (osteoporosis) after ovariectomy and, furthermore, mitochondrial biogenesis is enhanced triggered by PPARγ‐1α (peroxisome proliferator‐activated receptor γ coactivator 1α) activation …”

Section: Introductionmentioning

confidence: 99%

Development of a mass spectrometry based detection method for the mitochondrion‐derived peptide MOTS‐c in plasma samples for doping control purposes

Knoop

Thomas

Thevis

2019

Rapid Comm Mass Spectrometry

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Rationale The mitochondrial open reading frame of 12S rRNA type‐c (MOTS‐c) peptide was recently discovered and described to control metabolic homeostasis through AMPK activation along with AICAR accumulation. Consequently, it appears advisable to monitor the potential use of synthetic MOTS‐c in sports, and a detection method suitable for sports drug testing purposes is necessary. Methods For the detection of MOTS‐c in doping control plasma samples, a test method employing liquid chromatography and mass spectrometry (LC/MS) was developed. Following optimization, the assay was comprehensively validated and additional parameters such as the (long‐term) stability and in vitro metabolism of the peptide were evaluated. In order to determine endogenous MOTS‐c reference limits, the results generated by LC/MS‐based detection were compared with those obtained with a commercially available enzyme‐linked immunosorbent assay (ELISA). Results The LC/MS‐based test method was fully validated for quantitative results interpretation according to the World Anti‐Doping Agency's International Standard for Laboratories (WADA's ISL). It was found to be specific and sensitive, enabling a lower limit of detection (LLOD) for hMOTS‐c in plasma at 100 pg/mL. Following optimization, animal MOTS‐c analogues and four metabolites as well as two oxidation products were implemented. However, endogenous levels of a reference population of 20 healthy subjects studied by ELISA experiments (45.9–218.5 ng/mL) could not be confirmed by LC/MS. Conclusions A mass spectrometric detection assay for MOTS‐c in human plasma samples was developed and successfully validated according to WADA's ISL, providing an additional tool for future doping control purposes. Besides MOTS‐c, the assay also includes four in vitro derived metabolites and two oxidation products, which might further improve the traceability of the drug. The analytical approach was compared with a commercially available ELISA, and considerable differences in measured MOTS‐c levels were observed.

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Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation

Cited by 77 publications

References 34 publications

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

Development of a mass spectrometry based detection method for the mitochondrion‐derived peptide MOTS‐c in plasma samples for doping control purposes

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