Description of MOTS-c

MOTS-c consists of 16 amino acids, and it belongs to the family of the mitochondrial-derived peptides, bioactive hormones, which are important for mitochondrial communication, and energy regulation. It has significant roles in glucose and lipid metabolic regulation, as well as in disease prevention. Research indicates that this peptide can improve insulin sensitivity, making it beneficial for type 2 diabetes, can protect against age-related decline and diseases, potentially extending longevity and healthspan by mitigating common metabolic dysfunctions associated with aging. Furthermore, it is being explored for its potential in preventing and treating obesity, cardiovascular diseases, and cancer. The discovery of MOTS-c highlights the influential role of mitochondrial peptides in cellular and systemic functions, opening new therapeutic avenues for metabolic and age-related diseases.

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Research Confirmed Effects

1. MOTS-c and Muscle Metabolism

MOTS-c is a novel peptide derived from mitochondrial DNA, which encodes 37 genes, including 22 tRNAs, 2 rRNAs, and 13 mRNAs. Mitochondria, ancient organelles with a semi-autonomous genetic system, still retain several bacterial-like qualities. MOTS-c, along with other mitochondrial-derived peptides (MDPs) like humanin, represents an expanded mitochondrial genetic repertoire with significant biological activities. These MDPs function as mitochondrial hormones, sending active signals at the cellular and organismal level. MOTS-c specifically targets skeletal muscle, enhancing glucose metabolism and improving muscle uptake of glucose by increasing the expression of glucose transporters through AMPK activation. This activation is independent of the insulin pathway, offering an alternative means of boosting glucose uptake when insulin is ineffective or insufficient. Consequently, MOTS-c improves muscle function, enhances muscle growth, and decreases functional insulin resistance. It has implications for regulating obesity, diabetes, exercise, and longevity, introducing a novel mitochondrial signaling mechanism for metabolic regulation within and between cells.

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2. MOTS-c and Fat Metabolism

In studies involving mice, MOTS-c has demonstrated promising effects in preventing metabolic dysfunction induced by ovariectomy (OVX), a procedure associated with increased adiposity and insulin resistance, common in postmenopausal women. MOTS-c treatment effectively mitigated OVX-induced obesity and insulin resistance by enhancing brown fat activation, reducing fat accumulation, and suppressing inflammatory responses in white adipose tissue. This intervention improved energy dissipation and insulin sensitivity through AMPK pathway activation, underscoring MOTS-c's potential as a chronic treatment for menopause-induced metabolic dysfunction.

Moreover, recent research sheds light on MOTS-c's role beyond mitochondrial function, revealing its ability to translocate to the nucleus in response to metabolic stress. Once in the nucleus, MOTS-c regulates the expression of nuclear genes, particularly those involved in glucose restriction and antioxidant responses. This novel mechanism highlights the intricate communication between mitochondrial and nuclear genomes, suggesting a co-evolutionary process where factors encoded in both genomes cross-regulate each other to maintain cellular homeostasis. Additionally, MOTS-c's influence on fat metabolism is mediated through the activation of the AMPK pathway, a key regulator of cellular energy metabolism, offering potential insights into its therapeutic applications in metabolic disorders and aging-related conditions.

Furthermore, MOTS-c exhibits exercise-mimetic properties and enhances insulin sensitivity in aged and diet-induced obese mice. Through an unbiased metabolomics approach, it was found that MOTS-c administration reduced sphingolipid, monoacylglycerol, and dicarboxylate metabolism pathways, which are typically upregulated in obese and type 2 diabetes (T2D) models. This effect of MOTS-c is associated with improved insulin sensitivity, increased beta-oxidation, and prevention of fat accumulation, particularly in the context of obesity. Dysregulation of fat metabolism in mitochondria, possibly due to mitochondrial dysfunction, leads to a lack of fat oxidation, resulting in increased circulating fat levels and insulin resistance.

Research suggests a link between hepatic mitochondrial dysfunction and diet-induced insulin resistance, as mitochondria play a crucial role in ATP production and lipid oxidation. Dysfunctional mitochondria may contribute to ectopic fat accumulation in the liver, leading to insulin resistance and the development of metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis. Studies show impaired hepatic mitochondrial function in obesity and insulin resistance models induced by high-fat or high-fructose diets. Understanding the role of mitochondrial dysfunction in fat metabolism and insulin resistance sheds light on the mechanisms underlying metabolic disorders and offers potential therapeutic targets. MOTS-c's ability to regulate fat metabolism and insulin sensitivity highlights its significance in addressing metabolic dysfunction and offers novel insights into interventions for obesity and diabetes management.

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3. MOTS-c and Insulin Sensitivity

Plasma MOTS-c levels are associated with insulin sensitivity, particularly in lean individuals, but not in obese individuals. Although MOTS-c concentration remains similar between lean and obese individuals, it correlates positively with insulin resistance surrogates, such as the HOMA index and Matsuda index, only in lean subjects. This suggests that plasma MOTS-c concentration depends on metabolic status, with its association with insulin sensitivity altered in the presence of obesity. These findings highlight the potential of plasma MOTS-c as a biomarker for monitoring insulin sensitivity, particularly in pre-diabetic lean individuals, where changes in MOTS-c levels could serve as an early indicator of insulin resistance. Supplementation with MOTS-c may offer a preventive strategy against insulin resistance and the development of diabetes. However, further research is needed to fully understand the role of MOTS-c in insulin regulation and its impact on metabolic homeostasis in humans.

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4. MOTS-c in Osteoporosis

MOTS-c improves osteoporosis by enhancing the synthesis of type I collagen in osteoblasts through the TGF-β/SMAD signaling pathway. In experiments with hFOB1.19 cells, MOTS-c treatment increased cell viability in a time-dependent manner and upregulated mRNA and protein expressions of TGF-β, SMAD7, COL1A1, and COL1A2. The concentration of MOTS-c influenced the expressions of these genes, and knockdown of TGF-β or SMAD7 partially reversed the increase in collagen expression, indicating the involvement of the TGF-β/SMAD pathway. Thus, MOTS-c promotes osteoblasts to synthesize type I collagen via this pathway.

Furthermore, MOTS-c is implicated in promoting osteogenesis by stimulating the differentiation of bone marrow stem cells through the TGF-β/SMAD pathway. This leads to increased formation of new bone, highlighting MOTS-c's role in both protecting osteoblasts and promoting their development from stem cells. These findings suggest that MOTS-c plays a crucial role in maintaining bone health and integrity, making it a potential therapeutic target for osteoporosis treatment.

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5. MOTS-c and Longevity

MOTS-c peptide has emerged as a potential factor in exceptional longevity, particularly in certain human populations such as the Japanese. Research suggests that a specific change in the MOTS-c gene, found exclusively in individuals with Northeast Asian ancestry, may contribute to this longevity. This change involves the substitution of a glutamate residue for the lysine normally found in position 14 of the protein, though the functional implications of this alteration are not yet fully understood. However, it is believed to affect both the structure and function of MOTS-c, potentially influencing its role in longevity.

Dr. Changhan David Lee, a researcher at USC Leonard Davis School of Gerontology, highlights the importance of mitochondrial biology in extending lifespan and healthspan in humans. Mitochondria, as the primary metabolic organelle, are strongly implicated in aging and age-related diseases. While dietary restriction has been the main method for impacting mitochondrial function and longevity, peptides like MOTS-c offer a promising avenue for directly influencing mitochondrial function. This suggests that MOTS-c and similar peptides could have significant implications for extending lifespan and improving health in humans by targeting mitochondrial function.

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6. MOTS-c and Heart Functions

The study investigated the association between circulating MOTS-c levels and endothelial dysfunction (ED) in patients without significant structural coronary lesions. Forty patients undergoing coronary angiography and endothelial function testing were included, divided into normal endothelial function and ED groups based on coronary blood flow response to acetylcholine. Aortic plasma samples revealed lower MOTS-c levels in patients with ED compared to those with normal endothelial function. Plasma MOTS-c levels correlated positively with microvascular and epicardial coronary endothelial function. While MOTS-c did not directly impact blood vessel responsiveness, pretreatment with MOTS-c improved vessel responsiveness to acetylcholine in rodent models. These findings suggest that lower circulating MOTS-c levels are associated with impaired coronary endothelial function, indicating MOTS-c as a potential therapeutic target for ED.

Mitochondria-derived peptides (MDPs) like MOTS-c play crucial roles in regulating cellular metabolism and maintaining mitochondrial function and cell viability. Recent research highlights the importance of MDPs in cardiovascular disease (CVD), with MOTS-c showing promise as a therapeutic target. Studies demonstrate that lower MOTS-c levels correlate with higher endothelial cell dysfunction, a key factor in CVD development. Additionally, MOTS-c sensitizes endothelial cells to signaling molecules like acetylcholine, improving endothelial function. MDP dysregulation is implicated in various aspects of CVD, suggesting their potential as biomarkers or therapeutic targets.

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References

1. Y. Zheng et al., “MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation”, 2023.
2. C. Lee, K. H. Kim, and P. Cohen, “MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism,” Free Radic. Biol. Med., vol. 100, pp. 182–187, Nov. 2016. [PMC]
3. H. Lu et al., “MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction,” J. Mol. Med. Berl. Ger., vol. 97, no. 4, pp. 473–485, Apr. 2019. [PubMed]
4. K. H. Kim, J. M. Son, B. A. Benayoun, and C. Lee, “The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress,” Cell Metab., vol. 28, no. 3, pp. 516-524.e7, Sep. 2018. [PMC]
5. S.-J. Kim et al., “The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity,” Physiol. Rep., vol. 7, no. 13, p. e14171, Jul. 2019. [PubMed]
6. R. Crescenzo, F. Bianco, A. Mazzoli, A. Giacco, G. Liverini, and S. Iossa, “A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance,” Eur. J. Nutr., vol. 55, no. 1, pp. 1–6, Feb. 2016. [BMJ]
7. L. R. Cataldo, R. Fernández-Verdejo, J. L. Santos, and J. E. Galgani, “Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals,” J. Investig. Med., vol. 66, no. 6, pp. 1019–1022, Aug. 2018. [PubMed]
8. N. Che et al., “MOTS-c improves osteoporosis by promoting the synthesis of type I collagen in osteoblasts via TGF-β/SMAD signaling pathway,” Eur. Rev. Med. Pharmacol. Sci., vol. 23, no. 8, pp. 3183–3189, Apr. 2019. [PubMed]
9. B.-T. Hu and W.-Z. Chen, “MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway,” Eur. Rev. Med. Pharmacol. Sci., vol. 22, no. 21, pp. 7156–7163, Nov. 2018. [PubMed]
10. N. Fuku et al., “The mitochondrial-derived peptide MOTS-c: A player in exceptional longevity?,” Aging Cell, vol. 14, Aug. 2015. [Research Gate]
11. Q. Qin et al., “Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction,” Int. J. Cardiol., vol. 254, pp. 23–27, 01 2018. [PubMed]
12. Y. Yang et al., “The role of mitochondria-derived peptides in cardiovascular disease: Recent updates,” Biomed. Pharmacother. Biomedecine Pharmacother., vol. 117, p. 109075, Jun. 2019. [PubMed]