Mitofusion is required for MOTS‐c induced GLUT4 translocation

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 i...

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Autores principales:	Khushwant S. Bhullar, Nan Shang, Evan Kerek, Kaiyu Wu, Jianping Wu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/259b9f9df18f4d749f9e803d01198bb8
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spelling	oai:doaj.org-article:259b9f9df18f4d749f9e803d01198bb82021-12-02T16:08:06ZMitofusion is required for MOTS‐c induced GLUT4 translocation10.1038/s41598-021-93735-22045-2322https://doaj.org/article/259b9f9df18f4d749f9e803d01198bb82021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93735-2https://doaj.org/toc/2045-2322Abstract 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.Khushwant S. BhullarNan ShangEvan KerekKaiyu WuJianping WuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Khushwant S. Bhullar Nan Shang Evan Kerek Kaiyu Wu Jianping Wu Mitofusion is required for MOTS‐c induced GLUT4 translocation
description	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.
format	article
author	Khushwant S. Bhullar Nan Shang Evan Kerek Kaiyu Wu Jianping Wu
author_facet	Khushwant S. Bhullar Nan Shang Evan Kerek Kaiyu Wu Jianping Wu
author_sort	Khushwant S. Bhullar
title	Mitofusion is required for MOTS‐c induced GLUT4 translocation
title_short	Mitofusion is required for MOTS‐c induced GLUT4 translocation
title_full	Mitofusion is required for MOTS‐c induced GLUT4 translocation
title_fullStr	Mitofusion is required for MOTS‐c induced GLUT4 translocation
title_full_unstemmed	Mitofusion is required for MOTS‐c induced GLUT4 translocation
title_sort	mitofusion is required for mots‐c induced glut4 translocation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/259b9f9df18f4d749f9e803d01198bb8
work_keys_str_mv	AT khushwantsbhullar mitofusionisrequiredformotscinducedglut4translocation AT nanshang mitofusionisrequiredformotscinducedglut4translocation AT evankerek mitofusionisrequiredformotscinducedglut4translocation AT kaiyuwu mitofusionisrequiredformotscinducedglut4translocation AT jianpingwu mitofusionisrequiredformotscinducedglut4translocation
_version_	1718384582428983296

Mitofusion is required for MOTS‐c induced GLUT4 translocation

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