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Kumagai, H.;  Miller, B.;  Kim, S.;  Leelaprachakul, N.;  Kikuchi, N.;  Yen, K.;  Cohen, P. Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/40784 (accessed on 22 December 2025).
Kumagai H,  Miller B,  Kim S,  Leelaprachakul N,  Kikuchi N,  Yen K, et al. Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/40784. Accessed December 22, 2025.
Kumagai, Hiroshi, Brendan Miller, Su-Jeong Kim, Naphada Leelaprachakul, Naoki Kikuchi, Kelvin Yen, Pinchas Cohen. "Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases" Encyclopedia, https://encyclopedia.pub/entry/40784 (accessed December 22, 2025).
Kumagai, H.,  Miller, B.,  Kim, S.,  Leelaprachakul, N.,  Kikuchi, N.,  Yen, K., & Cohen, P. (2023, February 02). Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases. In Encyclopedia. https://encyclopedia.pub/entry/40784
Kumagai, Hiroshi, et al. "Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases." Encyclopedia. Web. 02 February, 2023.
Mitochondrial Microproteins in Athletic Performance and Age-Related Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/genes14020286

Mitochondrial microproteins (also called mitochondrial-derived peptides) are novel small proteins encoded in the mitochondrial DNA and modulate athletic performance and age-related diseases.

small open reading frame microprotein mitochondrial-derived peptide

1. Introduction

Although the Human Genome Project was launched in 1990 and completed in 2003, recent studies are unraveling novel concepts hidden in the human genome: microRNA, long non-coding RNA, and small open reading frames (smORFs). Open reading frames (ORFs) are defined as DNA sequences between the start and stop codons and the term smORF is used for the ORFs with less than 100 codons that are actually translated [1][2]. Indeed, recent studies have demonstrated the existence of previously unannotated microproteins translated from smORFs on both nuclear and mitochondrial genomes. Among them, ten mitochondrial microproteins (also called mitochondrial-derived peptides: MDPs), such as humanin [3][4][5], MOTS-c (mitochondrial ORF of the 12S rRNA type-c) [6], SHLPs 1–6 (small humanin-like peptides 1 to 6) [7], SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA) [8], and Gau (gene antisense ubiquitous in mtDNAs) [9] have been identified.
Those microproteins have the potential to give us a better understanding of human biology. For example, genetic variants in the mitochondrial microproteins humanin and SHMOOSE coding region are associated with Alzheimer’s disease and cognitive decline [8][10], while that of the MOTS-c coding region is associated with type 2 diabetes risk, visceral fat area, and skeletal muscle property [11][12]. Since mitochondrial microproteins are derived from mitochondria, those are expected to have crucial roles in organs with high mitochondrial content, such as in skeletal muscle. However, little is known about the roles of mitochondrial microproteins in skeletal muscle.

2. Mitochondrial Microproteins: Mitochondrial-Derived Peptides (MDPs)

Although the Human Genome Project identified that there are over 20,000 genes encoding functional proteins, recent bioinformatics analyses have suggested that the human genome contains previously unannotated smORFs that might be translated into microproteins [13][14]. The term smORF was introduced to identify the ORFs with less than 100 codons that are actually translated, and the term “microprotein” refers to biologically active proteins shorter than 100 amino acids encoded in the smORFs [1][2]. Bioinformatics analysis predicts that there may be millions of theoretical microproteins in the human genome, and ribosome profiling experiments identified that there are tens of thousands of potential microprotein mRNAs [13][14][15]. However, most of them have not been detected via mass spectrometry yet because of their size, low abundance, or hydrophobicity.
Currently, human mtDNA is annotated with 37 genes in total: thirteen protein-coding genes, two rRNAs, and twenty-two tRNAs. However, it has been demonstrated that there are dozens of previously uncharacterized cleavage sites and small RNAs derived from tRNAs with unknown functions [16], implying the existence of mitochondrial microproteins. Indeed, recent in silico analyses discovered that mtDNA contains nearly 400 putative microproteins between 9 and 40 amino acids length in both strands [17][18][19][20]. These microproteins are called mitochondrial microprotein or mitochondrial-derived peptides and nine mitochondrial microproteins, such as humanin [3][4][5], MOTS-c [6], SHLPs 1–6 [7], and SHMOOSE [8] have been identified. Among these mitochondrial microproteins, Humanin and MOTS-c have been studied deeply after their identification. These discoveries provided a paradigm-shifting concept in mitochondrial biology and genetics because they were previously unannotated mtDNA-encoded microproteins found to exist and have biological activities. Additionally, some of the MDPs are encoded in the mtDNA, but their translation occurs in the cytoplasm using the standard genetic code, not the mitochondrial genetic code. For example, the MOTS-c smORF is encoded within the 12S rRNA and is translated into a 16-amino acid microprotein using the standard genetic code [6]. If the MOTS-c smORF is translated using the mitochondrial genetic code, the second codon becomes the termination codon, and only the first amino acid methionine is translated. Thus, although the detailed mechanisms are not clarified yet, this suggests that a polyadenylated transcript is exported from the mitochondria and is translated in the cytoplasm. These discoveries provided novel concepts in mitochondrial biology and genetics and will give us a better understanding of human biology.

2.1. MOTS-c

2.1.1. MOTS-c as a Metabolic Regulator

MOTS-c is a 16-amino acid microprotein encoded by a mitochondrial sORF within the 12S rRNA [6] and is expressed in several tissues including the skeletal muscle [6][21]. The first study reported by Lee et al. demonstrated that MOTS-c prevented weight gain in high-fat diet-fed mice and improved insulin sensitivity in old mice through increasing endogenous AICAR levels and activating AMPK [6]. Likewise, a separate study by Zempo and Kim et al. also reported that MOTS-c treatment and overexpression increased glucose uptake in myotubes and human embryonic kidney cells, respectively [11]. Additionally, three weeks of MOTS-c administration prevented increased body fat mass and impaired glucose uptake in high-fat diet-fed male mice, but not female mice [11]. On the other hand, it has also been suggested that MOTS-c increases the thermogenesis of white and brown fat, which also contributes to weight reduction [22][23]. Taken together, these studies suggest that MOTS-c regulates energy metabolism by improving insulin resistance in the skeletal muscle and thermogenesis in the fat [24][25].

2.1.2. MOTS-c and Exercise-Related Phenotypes

Insulin resistance is not only a leading cause of obesity and type 2 diabetes but also a cause of skeletal muscle wasting and weakness. Recent studies have suggested that insulin resistance accelerates the loss of skeletal muscle mass and strength in people with type 2 diabetes [26][27][28]. Therefore, MOTS-c could prevent skeletal muscle wasting and its related signaling pathways in the skeletal muscle caused by insulin resistance. Three weeks of MOTS-c administration significantly prevented skeletal muscle loss and myostatin mRNA expression, one of the strongest negative regulators of the skeletal muscle, in high-fat diet-fed mice [29]. Additionally, the study observed that MOTS-c regulated the CK2/PTEN/AKT/FOXO1 signaling pathway in the skeletal muscle, and a negative correlation between plasma MOTS-c and myostatin levels in human plasma [29]. Supporting this observation, Reynolds et al. demonstrated that long-term MOTS-c-treated middle-aged and old mice exhibited higher lean mass and muscular strength than the control groups [30]. Taken together, MOTS-c could be a potential target for regulating skeletal muscle mass through modifying classical muscle atrophy signaling and myostatin expression.
In terms of the association between MOTS-c and exercise, several studies have demonstrated that MOTS-c is an exercise-induced and exercise-mimetic microprotein. Reynolds et al. examined the effect of acute cycling exercise on the MOTS-c level in the skeletal muscle and plasma and observed that acute high-intensity interval exercise increased MOTS-c expression in both the skeletal muscle and plasma in young male subjects [30]. Although it was not statistically significant, Walden et al. also observed that acute aerobic exercise increased plasma MOTS-c levels by around 30–40% compared to prior to exercise [31]. Dieli-Conwright et al. demonstrated that a 16-week combination training of aerobic and resistance exercise increased plasma MOTS-c levels in Non-Hispanic breast cancer survivors [32]. An increased MOTS-c expression by exercise training was also observed in animal experiments [33][34]. Hyatt J.K. and Kang et al. reported that running exercise training increased MOTS-c expression in the rat skeletal muscle and mouse hypothalamus, respectively [33][34]. On the other hand, however, Ramanjaneya et al. showed that MOTS-c did not increase after 8-week aerobic exercise training in women with polycystic ovarian syndrome [35]. Differences in a study subject, exercise protocol, detection method, and/or sampling timing may cause these different observations. Although more research is necessary to confirm these observations, exercise likely increases MOTS-c expression in not only skeletal muscle but also in other tissues.
It has been suggested that MOTS-c has an exercise-mimetic effect and improved aerobic exercise performance. Reynolds et al. have demonstrated that a long-term MOTS-c administration into young and old mice significantly increased the running time and distance compared to the control mice [30]. Hyatt J.K. has confirmed this observation by a single MOTS-c administration experiment with a cross-over design [33]. Consistent with the findings reported by Reynolds et al., the running time and distance were significantly higher in the MOTS-c-administrated trial than the saline-administrated trial, and all of the examined mice exhibited an improvement in their exercise performance compared to the saline-administrated trial [33]. These studies suggest that MOTS-c clearly increases aerobic exercise performance, and a long-term administration has an aerobic exercise training-like effect in mice. Additionally, since MOTS-c is induced by exercise, MOTS-c may also be associated with a response to exercise stress. Indeed, although MOTS-c mainly localizes in the mitochondria, MOTS-c translocates from mitochondria to the nucleus following metabolic stress and regulates the nuclear DNA-encoded genes involved in oxidative stress response by interacting with the nuclear-factor erythroid 2-related factor 2 (NRF2) [36]. Therefore, MOTS-c is an exercise-induced and exercise-mimetic microprotein and contributes to aerobic exercise performance.
A recent study showed that a MOTS-c analogue has the potential to prevent cognitive decline induced by the amyloid beta (Aβ) or LPL [37]. Although the peripheral administration of MOTS-c did not cross the blood–brain barrier, administration of the cell-penetrating MOTS-c analogue significantly prevented memory impairment by suppressing neuroinflammation [37]. Since Kang et al. demonstrated that exercise training increased MOTS-c expression in the hypothalamus, upregulation of MOTS-c in the brain could be one of the underlying mechanisms of improvement in cognitive function by exercise.

2.1.3. Genetic Polymorphism in the MOTS-c Coding Region

In the MOTS-c coding region, there is an East Asian-specific genetic variant m.1382A>C (rs111033358), and this mutation causes amino acid replacement, from positively charged lysine (K) to neutral glutamine (Q) at the 14th residue of the MOTS-c (K14Q). Zempo and Kim et al. conducted a series of experiments to understand the biological function of this K14Q mutation [11]. A meta-analysis in 11,224 Japanese males demonstrated that the males with the K14Q mutation exhibited a 1.34 times higher risk of type 2 diabetes mellitus (T2DM) as well as higher visceral fat area than the wild type (WT) carriers [11]. Additionally, the WT MOTS-c administration prevented impaired glucose metabolism in high-fat diet-fed mice, while K14Q failed to improve impaired glucose metabolism induced by a high-fat diet, suggesting that K14Q-MOTS-c is a bio-inactive form of MOTS-c [11]. Interestingly, this amino acid replacement is predicted to change the charge and hydrophobicity of the MOTS-c, which could substantially alter the interactions with its binding partners [11]. Although the functional direct molecular target of MOTS-c has not been identified yet, it is expected that the WT MOTS-c and K14Q MOTS-c differentially interact with the binding partners and show different biological functions.
This K14Q mutation is one of the genetic markers for athletic performance in the East-Asian population. Among the Japanese population, the frequency of the K14Q mutation is 2.9% in endurance athletes, 5.1% in non-athlete controls, and 6.5% in sprint/power athletes, suggesting that the K14Q is more beneficial for sprint/power performance than the WT carriers [12]. To confirm this observation, additional analyses in two independent Japanese cohorts were conducted and they demonstrated that the K14Q mutation carriers exhibited higher muscular strength as well as a higher proportion of myosin heavy chain (MHC)-IIX than the WT carriers [12]. Furthermore, mice treated with the MOTS-c neutralizing antibody, mimicking the K14Q carriers, exhibited a significantly higher protein expression of MHC-fast than the control mice [12]. The possible underlying mechanisms are the proliferation-activated receptor co-activator 1 (PGC-1α) and FOXO1 expression levels because they partially regulate muscle fiber-type composition. It has been demonstrated that overexpression and knock-out of PGC-1α in mice increase slow- and fast-twitch fibers, respectively [38][39]. Additionally, muscle-specific overexpression of FOXO1 decreased slow-twitch fiber-related gene expression levels [40]. Interestingly, recent studies demonstrated that MOTS-c treatment increased PGC-1α protein expression in the C2C12 myotube [41] and decreased FOXO1 protein expression in the mouse skeletal muscle [29]. These studies suggest that MOTS-c could regulate muscle-fiber composition by modifying PGC-1α and FOXO1 expression levels. Taken together, the m.1382A>C polymorphism causing K14Q amino acid replacement of MOTS-c contributes to sprint/power performance by regulating skeletal muscle fiber composition in the East-Asian population.

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Subjects: Genetics & Heredity
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Hiroshi Kumagai , Brendan Miller , Su-Jeong Kim ,
Naphada Leelaprachakul
, Naoki Kikuchi , Kelvin Yen , Pinchas Cohen
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Update Date: 03 Feb 2023
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