Abstract
MOTS‐c (mitochondrial ORF of the twelve S-c) is a 16-amino-acid mitochondrial peptide that has been shown to counter insulin resistance and alleviate obesity in vivo. However, the mechanisms involved in the pharmacological action of MOTS-c remain elusive. Based on the ability of MOTS-c to improve insulin resistance and promote cold adaptation, we hypothesized that MOTS-c might play a role in boosting the number of mitochondria in a cell. We found that treatment of mammalian cells with MOTS‐c increased protein levels of TFAM, COX4, and NRF1, which are markers for mitochondrial biogenesis. However, flow cytometry analysis using MitoTracker Green revealed a sharp reduction in the mitochondrial count after MOTS‐c treatment. We then anticipated possible synchronized activation of mitofusion/mitochondrial fusion by MOTS‐c following the onset of mitochondrial biogenesis. This was confirmed after a significant increase in protein levels two GTPases, OPA1, and MFN2, both vital for the fusion of mammalian mitochondria. Finally, we found that inhibition of the two GTPases by TNFα abrogated the ability of MOTS‐c to prompt GLUT4 translocation and glucose uptake. Similar results were obtained by siRNA KD of MFN2 as well. Our results reveal for the first time a pathway that links mitofusion to MOTS-c-induced GLUT4 translocation.
Highlights
MOTS‐c is a 16-amino-acid mitochondrial peptide that has been shown to counter insulin resistance and alleviate obesity in vivo
Based on the results in this study, we propose a model relating the metabolic boosting by mitochondrial ORF of the twelve S-c (MOTS-c) to glucose transporter type 4 (GLUT4) translocation through activation of mitochondrial biogenesis, or a closely related mechanism leading to generation of specialized mitochondria
We focused on mitochondrial gene upregulation to measure a possible increase in mitochondrial DNA
Summary
MOTS‐c (mitochondrial ORF of the twelve S-c) is a 16-amino-acid mitochondrial peptide that has been shown to counter insulin resistance and alleviate obesity in vivo. We anticipated possible synchronized activation of mitofusion/mitochondrial fusion by MOTS‐c following the onset of mitochondrial biogenesis This was confirmed after a significant increase in protein levels two GTPases, OPA1, and MFN2, both vital for the fusion of mammalian mitochondria. Genetic polymorphism is proposed to contribute to the risk of Type 2 diabetes (T2D) in sedentary men by diminishing MOTS-c activity via an amino acid change from WT-MOTS-c (K14) to K14Q-MOTS-c (Q14)[17] These diverse metabolic phenotypes suggest that mitochondria may well modulate metabolism and insulin resistance in part through the synthesis of mitochondrial peptides like MOTS-c. Based on the results in this study, we propose a model relating the metabolic boosting by MOTS-c to GLUT4 translocation through activation of mitochondrial biogenesis, or a closely related mechanism leading to generation of specialized mitochondria
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