The mitochondrial‐derived peptide <scp>MOTS</scp>‐c: a player in exceptional longevity?

Fuku, Noriyuki; Pareja‐Galeano, Helios; Zempo, Hirofumi; Alis, Rafael; Arai, Yasumichi; Lucía, Alejandro; Hirose, Nobuyoshi

doi:10.1111/acel.12389

Cited by 88 publications

(69 citation statements)

References 21 publications

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“…MOTS-c treatment reversed age-dependent skeletal muscle insulin resistance in mice (Lee et al, 2015), and a MOTS-c polymorphism has been associated with human longevity (Fuku et al, 2015). Thus, considering that glucose depletion, AMPK activation, and increased ROS formation have all been linked to C. elegans longevity (Schulz et al, 2007), MOTS-c may hold key implications for aging and age-related diseases by promoting cellular homeostasis in response to metabolic stress (Bratic and Larsson, 2013; Fuku et al, 2015; Quirós et al, 2016) and maintaining mitonuclear genomic compatibility (Hamilton, 2015; Latorre-Pellicer et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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SUMMARY 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 mono-phosphate-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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…The mitochondrial m.1382A>C polymorphism, which is found specifically in the D4b2 haplogroup that is associated with exceptional longevity in the Japanese population [88]. This polymorphism occurs within the MOTS-c ORF and causes a Lys14Gln change that may have functional alterations [89]. Further studies are required to test if MOTS-c, and its analogs, can positively extend healthspan and/or lifespan in model organisms.…”

Section: Mitochondrial-derived Peptides (Mdps): a Newly Recognizedmentioning

confidence: 99%

MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism

Lee

Kim

Cohen

2016

Free Radical Biology and Medicine

142

129

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Mitochondria are ancient organelles that are thought to have emerged from once free-living α-proto-bacteria. As such, they still possess several bacterial-like qualities, including a semi-autonomous genetic system, complete with an independent genome and a unique genetic code. The bacterial-like circular mitochondrial DNA (mtDNA) has been described to encode 37 genes, including 22 tRNAs, 2 rRNAs, and 13 mRNAs. Two additional peptides reported to originate from the mtDNA, namely humanin (Hashimoto et al., 2001; Ikone et al., 2003; Guo et al., 2003) [1–3] and MOTS-c (mitochondrial ORF of the twelve S c) (Lee et al., 2015) [4], indicate a larger mitochondrial genetic repertoire (Shokolenko and Alexeyev, 2015) [5]. These mitochondrial-derived peptides (MDPs) have profound and distinct biological activities and provide a paradigm-shifting concept of active mitochondrial-encoded signals that act at the cellular and organismal level (i.e. mitochondrial hormone) (da Cunha et al., 2015; Quiros et al., 2016) [6,7]. Considering that mitochondria are the single most important metabolic organelle, it is not surprising that these MDPs have metabolic actions. MOTS-c has been shown to target the skeletal muscle and enhance glucose metabolism. As such, MOTS-c has implications in the regulation of obesity, diabetes, exercise, and longevity, representing an entirely novel mitochondrial signaling mechanism to regulate metabolism within and between cells.

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“…The virtual absence of this allele in the Japanese population is in line with that observed in a cohort of healthy young Han Chinese men (frequency of KK genotype of 93.6%) [14], suggesting a highly conserved myostatin activity (that in turn could modulate a shift towards a more oxidative phenotype) [15]. In this regard, we recently postulated that the m.1382A>C polymorphism located in the mtDNA region encoding the recently discovered mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), which is specific for the Northeast Asian population and is associated with metabolic homeostasis and insulin sensitivity, may be among the putative biological mechanisms explaining the high longevity of Japanese people [16]. …”

Section: Resultsmentioning

confidence: 99%

Muscle-Related Polymorphisms (MSTN rs1805086 and ACTN3 rs1815739) Are Not Associated with Exceptional Longevity in Japanese Centenarians

et al. 2016

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Myostatin (MSTN) and α-actinin-3 (ACTN3) genes are potentially associated with preservation of muscle mass and oxidative capacity, respectively. To explore the possible role of these genes in exceptional longevity (EL), the allele/genotype frequency distribution of two polymorphisms in MSTN (rs1805086, K153R) and ACTN3 (rs1815739, R577X) was studied in Japanese centenarians of both sexes (n = 742) and healthy controls (n = 814). The rs1805086 R-allele (theoretically associated with muscle mass preservation at the expense of oxidative capacity) was virtually absent in the two groups, where genotype distributions were virtually identical. Likewise, no differences in allele (p = 0.838 (women); p = 0.193 (men); p = 0.587 (both sexes)) or genotype distribution were found between groups for ACTN3 rs1815739 (p = 0.975 (women), p = 0.136 (men), p = 0.752 (both sexes)). Of note, however, the frequency of the rs1805086 R-allele observed here is the lowest been reported to date whereas that of the ‘highly oxidative/efficient’ rs1815739 XX genotype in Japanese male centenarians (33.3%) or supercentenarians of both sexes (≥110 years) are the highest (32.6%), for a non-American population. No definite conclusions can be inferred in relation to EL owing to its lack of association with both rs1815739 and rs1805086. However, it cannot be excluded that these gene variants could eventually be related to a “healthy” metabolic phenotype in the Japanese population. Further research might determine if such metabolic profile is among the factors that can potentially predispose these individuals to live longer than Caucasians and what genetic variants might be actually involved.

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The mitochondrial‐derived peptide MOTS‐c: a player in exceptional longevity?

Cited by 88 publications

References 21 publications

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

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

MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism

Muscle-Related Polymorphisms (MSTN rs1805086 and ACTN3 rs1815739) Are Not Associated with Exceptional Longevity in Japanese Centenarians

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