MOTS-c

Associations of Serum MOTS-c with Exercise Capacity and Antioxidant Markers in Young Males: A Cross-Sectional Study.

2026 · Human evidence

Mots-c attenuates diabetic nephropathy by downregulating LARS1 to promote lipophagy and suppress tubular senescence.

2026 · Biochemical pharmacology · Preclinical

Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease, but current therapies do not halt its progression. Mitochondrial-derived peptides have garnered attention for their roles in metabolic regulation, yet whether Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) participates in DN pathogenesis has not been fully elucidated. In this study, MOTS-c treatment led to dose-dependent preservation of urinary albumin-to-creatinine ratio (UACR), accompanied by attenuated tubular injury, diminished lipid deposition, and reduced macrophage accumulation. Transcriptomic analyses revealed significant enrichment of pathways related to senescence and lipid metabolism. Moreover, MOTS-c suppressed p16 INK4A , γH2AX, and SA-β-gal activity, while restoring lipid homeostasis through regulation of CPT1A and ADRP. Mechanistically, MOTS-c downregulated LARS1, an established negative modulator of lipophagy, thereby facilitating LC3-mediated clearance of lipid droplets (LDs). LARS1 overexpression in HK-2 cells effectively abrogated these protective phenotypes. Furthermore, co-administration of the autophagy inhibitor 3-MA in db/db mice largely reversed the renoprotective effects of MOTS-c, supporting the functional relevance of lipophagy in this process. Our findings indicate that MOTS-c protects against diabetic kidney injury by downregulating LARS1, thereby promoting lipophagy, reducing lipid deposition, and suppressing tubular senescence. Targeting the LARS1-lipophagy-senescence axis may offer a new strategy for DN treatment.

MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.

2021 · Nature communications · Preclinical

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.

2018 · Cell metabolism · Preclinical

Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.

The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.

2015 · Cell metabolism · Preclinical

Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.