Lupine Publishers| Journal of Diabetes and Obesity
Abstract
Objective: In addition to its role in energy production and metabolism, mitochondria play a major role in apoptosis, oxidative stress, and calcium homeostasis. This review highlights the intricate role of mitochondria derived peptides (MPs), oxidative stress, and age-related disease such as diabetes.
Key Findings: The mitochondria produce MDPs: specific peptides that mediate transcriptional stress response by its translocation into the nucleus and interaction with DNA. MDPs are regulators of metabolism with cytoprotective effects through anti-oxidative stress, anti-inflammatory responses and anti-apoptosis. This class of peptides comprises: humanin (HN), MOTS-c, Small HN-like peptides. HN inhibits mitochondrial complex 1 activity and limits oxidative stress level in the cell. HN has been shown to prevent apoptosis by decreasing the reactive oxygen species production. Mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of diabetes. Data suggested that MDPs had a role in improving type 2 diabetes (T2D).
Summary: The goal of this review is to discuss the newly emerging functions of MDPs and their biological role in ageing and age-related diseases such as T2D.
Keywords:Mitochondrial-Derived-Peptides; Humanin; Oxidative Stress; Diabetes
Introduction
Mitochondria play a critical role in maintaining cellular function by ATP production. In addition to its role in energy production and metabolism, mitochondria play a major role in apoptosis, oxidative stress, and calcium homeostasis. A mitochondrial stress signal, or a ‘mitokine’, could confer protection and promote survival, while priming the cell’s readiness for subsequent insults with increasing severity. The term ‘mitohormesis’ for such a phenomenon has been created [1]. The mitochondrial unfolded protein response (UPRmt) is a central part of the “mitohormetic” response. The UPRmt may be an alternative way in relationship with mitochondria signal in the cell. The mitochondria produce some specific peptides that mediate transcriptional stress response by the translocation into the nucleus and interaction with DNA. Mitochondrial derived peptides (MDPs) are regulators of metabolism and various studies have shown that MDPs exerted cytoprotective effects through anti-oxidative stress, anti-inflammatory responses and anti-apoptosis [2,3]. The goal of this review is to discuss the newly emerging functions of MDPs and their biological role in ageing and metabolic diseases such as T2D.
Mitochondrial Metabolism Modulation
Functions in the Mitonuclear Communication Pathways
Mitochondria booked a portion of the original bacterial genomes that co-evolved with nuclear genome. However, mitochondria import over a thousand proteins encoded in the nuclear genome to maintain their diverse functions, reflecting their adjacent relationship [4].
The mitochondrial genome inherits bacterial-like traits: the DNA molecules (mtDNA) are circular, double stranded, small (16,569 nucleotides in humans) and compact. mtDNA contains 37 genes, including 22 tRNAs, 2 rRNAs (12S and 16S rRNA) and 13 mRNAs encoding the proteins of the electron transport chain [5]. The mtDNA has no introns but a few non-coding nucleotides between adjacent genes and small open reading frames that encode functional MDPs. This class of peptides comprises humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) and expands the expression of mitochondrial proteome [6]. It has been established that mitochondria can export peptides and also import cytosolic peptides. It is the class of “cell-penetrating peptides” designed also as “mitochondrial cell-penetrating peptides” [7]. Many age-induced processes and degenerative diseases are related to mitochondrial dysfunction, further highlighting the critical importance of this organelle [8]. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OXPHOS) function.
Overview on Concepts of Retrograde Signaling and Unfolded Protein
Numerous implications of these anterograde and retrograde signaling pathways between the mitochondria and the nucleus are appropriate for therapeutic exploitation with bioactive molecules.
Concept of Retrograde Signaling
The hallmark of mitochondrial retrograde signaling is the modification of the expression of nuclear genes induced by a signal from mitochondria [9]. Retrograde signaling must be triggered by a mitochondrial signal that in turn is relayed via molecules that finally reach the nucleus. In mammalian cells, altered nuclear expression in response to mitochondrial dysfunction is reported; a number of signaling pathways being implicated in this retrograde communication [10]. Mitochondrial retrograde signaling is a signaling pathway connecting mitochondria and the nucleus. Signal transducers in the yeast retrograde response are Rtg1p, Rtg2p, and Rtg3p proteins [11]. The outcomes of mitochondrial retrograde signaling go far beyond the maintenance or biogenesis of the organelle, affecting the homeostasis of the whole organism through body weight or immunity.
Concept of Unfolded Protein
Mitochondrial protein homeostasis is maintained through proper folding and assembly of newly translated polypeptides. Several factors challenge the mitochondrial protein-folding environment including reactive oxygen species (ROS) that are generated within mitochondria, as well as environmental situations such as exposure to toxic compounds. To promote efficient mitochondrial protein folding mitochondria possess molecular chaperones located in both the intermembrane space and matrix [12].
UPRmt is a mitochondria-to-nuclear communication mechanism that promotes adaptive regulation of nuclear genes related to mitochondrial response, and metabolism, implicated in the cellular homeostasis [13].
Mitochondrial-Derived Peptides: Classification
MDPs are a series of peptides encoded by mitochondrial DNA. This class of peptides comprises HN, MOTS-c, Small HN-like peptides (SHLPs) and expands the expression of mitochondrial proteome [6].
Humanin
The first MDP discovered back in 2001 was HN; the term based
on the potential of this peptide for restoring the “humanity” of
Alzheimer’s disease (AD) patients. HN promotes cell survival in
response to a variety of insults.
It is a small, secreted, 24 or 21 amino acid peptide, depending
on cytoplasmic or mitochondrial translation, respectively. If HN is
translated within the mitochondria, the peptide will be 21 amino
acids; and if it is translated in the cytoplasm, then the result is a
24 amino acid peptide [14]. HN is encoded by an HN open reading
frame (ORF) within the gene for the 16S ribosomal subunit within
the mitochondrial genome [15]. HN was discovered during a search
for survival factors in unaffected areas of an AD patient’s brain.
The initial studies were first performed in cell culture and then
followed by in vivo studies using both pharmacological mimetics of
AD as well as mutant gene: amyloid-β precursor protein. The most
recent studies used transgenic models of AD. As HN is a relatively
short peptide, exhaustive mutational analysis of the importance of
each amino acid has been possible. Interestingly, single amino acid
substitutions of HN can lead to significant alterations in its potency
and biologic functions. S14G-HN in which the serine at position 14
is replaced by glycine, is a highly potent analogue of HN.
Finally, HN may be the first small peptide of its kind
representing a putative set of MDPs, a novel concept that modifies
the established concept about retrograde mitochondrial signaling
as well as mitochondrial gene expression. HN is a neuroprotective
peptide and a cytoprotective factor against oxidative stress [16].
Mitochondrial Open Reading Frame of the 12S rRNA-c ( MOTS-c)
In addition to HN, an in-silico search of the mitochondrial genome revealed additional potential MDPs. MOTS-c is expressed in various tissues and in circulation (plasma) in rodents and humans, suggesting both a cell-autonomous and hormonal role. Its primary target organ appears to be skeletal muscle and fat. The mitochondrially derived peptide MOTS-c was recently discovered. It is a 16 amino acid peptide located in the 12S rRNA gene. The first 11 amino acid residues of MOTS-c are highly conserved in 14 mammalian species [17]. MOTS-c has been identified as a gene expression regulator in the nucleus, leading to retrograde signaling via its interaction with transcription factors. MOTS-c polymorphism has been found to be associated with human longevity [18]. MOTS-c can prevent insulin resistance, dietmediated obesity, and ameliorate diabetes. MOTS-c oxidizes fatty acids and inhibits oxidative respiration [19]. MOTS-c increased the levels of carnitine metabolism, which transport activated fatty acids into the mitochondria for β-oxidation, increased the level of a β-oxidation intermediate. MOTS-c inhibited the folate cycle at the level of 5Me-THF, resulting in an accumulation of 5-aminoimidazole- 4-carboxamide ribonucleotide, an AMP-activated protein kinase (AMPK) activator. MOTS-c also increased cellular NAD+ levels, which are nucleotide precursors [17,20]. 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 [21].
Small HN-like Peptides
Recently, six additional peptides encoded within the mitochondrial 16S rRNA region of mtDNA have been discovered and designed as SHLP1-6. SHLP2 and SHLP3 share similar biological effects with HN. The circulating levels of MOTS-c and SHLP2 decline with age. Various studies suggest that SHLP2 and SHLP3 may participate in the pathogenesis of age-related neurodegenerative diseases. The anti-oxidative stress function of SHLP2, and its neuroprotective effect indicate that SHLP2 has a role in the regulation of aging and age-related diseases [5].
Ageing and Plasma MDPs Levels
Ageing and longevity are or are not characterized by high levels of MDPs? It is speculated that MDPs production turns from protective to detrimental adaptive response; in these conditions, the levels increasing during aging. In some studies, HN levels significantly decline with age in humans. Plasma HN level was significantly lower in the older group (1.3 ± 0.2 ng/mL) than that of the younger group (1.7 ± 0.1 ng/mL) [22]. In other studies, it is reported that HN levels significantly decline with age in humans and animals. HN levels in plasma were measured in young and old mice and across age in humans. HN levels decreased with age in both mice and human (Human plasma levels: 45-65 years: 1400 pg/mL; 80-110 years: 1000 pg/mL) [5].
New results are in contrast with these data. HN plasma levels
are evaluated in 693 subjects aged from 21 to 113 years. HN levels
increased in old age (>500 pg/mL), with the highest levels found
in centenarians (> 1000 pg/mL). The plasmatic levels of HN are
significantly positively correlated with age. No gender differences
were observed for HN. HN plasma level is associated negatively with
body mass index in elderly patients [23]. Concerning the other MDPs,
it is reported that MOTS-c and SHLP2 circulating levels decline with
age. The circulating SHLP2 levels significantly decreased with age
in both male and female C57BL/6 mice (young, 3 months old: 3000
pg/mL; aged, 18 months old: 2500 pg/mL). Male mice had higher
SHLP2 levels than female mice in both the young and old groups
[5]. The results of these studies should be interpreted considering
the following limitations. First, the relatively small sample size in
each group represents a potential limitation. Second, mitochondrial
diseases are an expanding group of disorders with many metabolic
deficiencies. In the ideal case, the used patient cohort should display
a homogeneous phenotype, disease stage, and organ specificity.
Moreover, the discovery of ageing-related biomarkers is supported
by the development of advanced proteomics technology. Changes
in the circulating concentrations of human proteins can serve as
predictive measures of health and disease [24].
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