MOTS-C

Li SH, Chen SQ, Lu T, Wang JH, Wang JX, Wu YX, et al.

Life sciences

In a hyperoxia-induced neonatal cardiac injury model using neonatal mice (85% O2 exposure) and H9C2 rat cardiomyocytes, hyperoxia exposure lowered serum MOTS-c and triggered oxidative stress and oxeiptosis (a reactive-oxygen-species-driven programmed cell death pathway) via the KEAP1-PGAM5-AIFM1 axis; MOTS-c preserved the KEAP1-PGAM5 interaction and blocked AIFM1 nuclear translocation, limiting oxeiptosis in this preclinical model.

Zhang YL, Huang G, Li SP, Zhang WL, Chen D, Jin LG, et al.

Redox biology

Researchers engineered an MOTS-c analog (R13A-MOTS-c) with increased hydrophobicity to improve cellular uptake via the LAT1 transporter, then studied it in MLE-12 lung epithelial cells in vitro and in a mouse model of thoracic-irradiation-induced lung injury; the analog activated Nrf2 signaling and reduced inflammatory and oxidative markers and mitochondrial dysfunction in both the cell and rodent models.

Parseh S, Shakerian S, Reza Tabandeh M, Habibi A

Diabetes research and clinical practice

In a rodent model of diet- and streptozotocin-induced diabetes (sand rats), eight weeks of high- or moderate-intensity interval exercise increased skeletal-muscle mitochondrial MOTS-C, PGC-1alpha, AMPK, and GLUT4 protein levels, with moderate-intensity exercise associated with the largest changes relative to markers of insulin resistance, supporting an AMPK-MOTS-C signaling axis linked to exercise-associated metabolic adaptation in this model.

Kim KH, Son JM, Benayoun BA, Lee C

Cell metabolism

Using HEK293 and HepG2 cell models, researchers showed that MOTS-c translocates from the cytoplasm to the nucleus following metabolic stress such as glucose restriction, in an AMPK-dependent manner, where it regulates a broad set of nuclear genes including those containing antioxidant response elements and interacts with the stress-responsive transcription factor NRF2, evidence of direct mitochondria-to-nucleus signaling.

Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al.

Cell metabolism

This landmark study identified MOTS-c, a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, and showed in cell lines and mouse models that it acts primarily in skeletal muscle by inhibiting the folate cycle and de novo purine biosynthesis, leading to AMPK activation; in aging and high-fat-diet mouse models, MOTS-c administration prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity, establishing mitochondria-encoded peptides as regulators of metabolic homeostasis.