MOTS-c

Mechanism (as reported)

A study reported that MOTS-c translocates to the nucleus after metabolic stress and regulates nuclear gene expression in an AMPK-dependent manner, including genes with antioxidant response elements (ARE) and interactions with stress-responsive transcription factors such as NFE2L2/NRF2. (PMID 29983246) Another study reported that MOTS-c actions inhibit the folate cycle and tethered de novo purine biosynthesis, leading to AMPK activation; its primary target organ was described as skeletal muscle. (PMID 25738459) In ovarian cancer, a study reported that MOTS-c interacts with LARS1 and promotes LARS1 ubiquitination and proteasomal degradation; it also described attenuation of USP7-mediated LARS1 deubiquitination via competitive binding to LARS1. (PMID 39321430)

Key findings (each cites a source)

• MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded by the mitochondrial 12S rRNA region/type-C sORF. [PMID 36761202, 25738459, 36233287, 29983246]
• A study reported that MOTS-c translocates to the nucleus following metabolic stress and regulates nuclear gene expression via an AMPK-dependent manner, including regulation of genes containing antioxidant response elements (ARE) and interaction with NFE2L2/NRF2. [PMID 29983246]
• A study reported that MOTS-c promotes metabolic homeostasis and regulates insulin sensitivity, with skeletal muscle described as a primary target organ. [PMID 25738459]
• A study reported that MOTS-c cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. [PMID 25738459]
• A study reported that MOTS-c levels decrease with age, with plasma also containing the peptide but showing reduced levels over time. [PMID 36761202, 36233287]
• A study reported that MOTS-c can improve glucose metabolism/insulin resistance phenotypes in skeletal muscle contexts and was discussed as beneficial for diseases such as diabetes, obesity, and aging in a synthesis of findings. [PMID 36761202, 25738459, 36233287, 36824008]
• A study reported reduced MOTS-c levels in serum and tumor tissues from ovarian cancer patients, associated with poor prognosis. [PMID 39321430]
• A study reported that exogenous MOTS-c inhibited proliferation, migration, and invasion of ovarian cancer cells and induced cell cycle arrest and apoptosis. [PMID 39321430]
• A study reported that in ovarian cancer, MOTS-c interacts with LARS1 to promote its ubiquitination and proteasomal degradation, and attenuates USP7-mediated LARS1 deubiquitination by competing with USP7 for LARS1 binding. [PMID 39321430]
• A study reported that MOTS-c was evaluated in a gestational diabetes mellitus (GDM) mouse model and that it alleviated hyperglycemia and improved insulin sensitivity/glucose tolerance while also addressing offspring reproductive outcomes described in that study. [PMID 36824008]
• A review summarized that MOTS-c is implicated in age-related diseases including diabetes, cardiovascular disease, osteoporosis/postmenopausal obesity, and Alzheimer, and described stress-induced nuclear regulatory roles. [PMID 36233287, 36824008, 36761202]
• A review summarized that MOTS-c is encoded by the mitochondrial 12S rRNA short open reading frame, translocates to the nucleus under stress, regulates stress adaptation-related genes with ARE, and is linked in summaries to the Folate-AICAR-AMPK pathway and connections to insulin resistance, inflammatory response, exercise, aging, and aging-related pathologies. [PMID 36670507]