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Mitochondrial-derived peptide mots3 regulates metabolism and cell survival

a mitochondrial-derived peptide and mot3 technology, applied in the field of mitochondrial-derived peptides, can solve the problems of retrograde signaling and poorly understood biological processes

Inactive Publication Date: 2014-10-02
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes an isolated polypeptide and its use in treating diabetes, obesity, fatty liver disease, and cancer. The polypeptide has a high degree of sequence identity to a specific protein found in humans. The patent also includes methods for using the polypeptide in treating these diseases, as well as cDNAs and expression vectors for its use. Overall, the patent provides a technical solution for developing new treatments for these conditions.

Problems solved by technology

However, retrograde signaling, whereby the mitochondria communicate back to the cell, is a poorly understood biological process.
Accordingly, MOTS3 and pharmaceutical formulations thereof can be used to treat various age-related disease with much metabolic implications such as cancer, diabetes, obesity, and neurodegenerative diseases are not sufficient to cure the disease.

Method used

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  • Mitochondrial-derived peptide mots3 regulates metabolism and cell survival
  • Mitochondrial-derived peptide mots3 regulates metabolism and cell survival
  • Mitochondrial-derived peptide mots3 regulates metabolism and cell survival

Examples

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Effect test

example 1

[0135]3′ RACE analysis revealed that MOTS3 is polyadenylated, similar to HN (FIG. 1A). After initial screening as described below, MOTS 3 was determined to have potent biological activity, and its peptide sequence is well conserved in various species (FIG. 1B). We have generated anti-MOTS3 polyclonal rabbit antibodies that can detect endogenous and overexpressed MOTS3 by cloning the ORF into an expression vector in cell culture as well GFP-tagged MOTS3 (FIG. 1C). Using these validated antibodies, we can detect MOTS3 in rat heart, liver, and testis at similar molecular weights and in the brain at a slightly higher molecular weight (FIG. 1D). The expression level appears to be highest in the heart, an organ with one of the highest mitochondrial density. Further, rho-O HeLa cells, which have been purged of mitochondrial DNA using ethidium bromide, do not express MOTS3 as well as other well described mitochondria-encoded proteins such as cytochrome oxidase I and II (COI and COII), confi...

example 2

[0136]Exogenous treatment of synthetic MOTS3 causes a mitochondria-dependent metabolic shift, measured by oxygen consumption rate (OCR) measured by Seahorse technology as wells as MTT reduction (under 10% and 1% FBS conditions) (FIG. 2). Both exogenous MOTS 3 treatments with synthetic peptides (FIG. 3), as well as the endogenous expression by cloning (FIG. 4) inhibited mitochondrial activity. Notably, exogenous MOTS3 treatment reduced cellular ATP levels and mitochondrial activity (MTT), which simultaneously occurred with increased autophagy (FIG. 5).

[0137]MOTS3 treatment induced an increase in glucose uptake as measured by residual glucose levels in the culture medium and by fluorescence-labeled glucose analog uptake (FIG. 6A and FIG. 6B). As expected, lactate secretion was increased in keep with elevated glucose consumption (FIG. 6A). Notably, by 96 hours of MOTS3 treatment, when most of the glucose in the medium has been consumed, AMPK activation is significantly higher in the MO...

example 3

[0139]In mice, 4 days of MOTS3 injections (i.p.; 0.5 or 5.0 mg / kg / day) led to significant weight loss without significant alteration of food intake (FIG. 11). Further, in agreement with our in vitro studies, liver mitochondrial respiration capacity was diminished following MOTS3 treatment at both tested doses (FIG. 11). Notably, MOTS3 treatment significantly reduced blood glucose levels (FIG. 12A) and also had higher insulin levels (FIG. 12B), suggesting increased glucose uptake similar to that observed in cell culture (FIG. 6).

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Abstract

MOTS3 is a novel polypeptide. Methods of treating diseases such as diabetes, obesity, fatty liver, and cancer using MOTS3 and pharmaceutical compositions thereof are disclosed herein.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to U.S. Provisional Application No. 61 / 801,474, filed Mar. 15, 2013, which is incorporated herein by reference in its entirety for all purposes.GOVERNMENT RIGHTS[0002]This invention was made with Government support under Grant Nos. AG034430 and GM090311, awarded by the National Institutes of Health. The Government has certain rights in the invention.FIELD OF THE INVENTION[0003]This invention relates to a novel mitochondrial-derived peptide (MOTS3). This novel peptide can be used in methods of treating diseases such as diabetes, obesity, fatty liver, and cancer.BACKGROUND[0004]Mitochondria, central to metabolic processes, is involved energy production, programmed cell death, and reactive oxygen species (ROS) generation, and is heavily implicated in various stages of major diseases including cancer, diabetes, neurodegenerative diseases, and aging; yet its role in the pathogenesis still remains largely...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K16/18
CPCC07K7/08C07K14/47C07K16/18A61K38/1709A61P1/16A61P3/04A61P3/10A61P35/00A61P35/02A61K9/0019
Inventor COHEN, PINCHASLEE, CHANGHANCOBB, LAURA J.
Owner RGT UNIV OF CALIFORNIA
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