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Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Each eukaryotic cell contains several hundred copies of mitochondrion, which are unique organelles under dual genome regulation. Although the majority of DNA is enclosed within the nucleus (nDNA), mitochondria also contain their own and separate DNA, the mitochondrial (mtDNA), which is the small circular chromosome located in mitochondria. The human mtDNA is a double-stranded, circular molecule of 16, 569 base pairs and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 subunits of the ETC complexes. The human mtDNA encodes the peptide, humanin, known to have important pro-survival and metabolic regulatory functions. Mitochondrial-encoded subunits of the oxidative phosphorylation system assemble with nuclear-encoded subunits into enzymatic complexes. Recent findings show that mitochondrial translation is linked to other mitochondrial functions, as well as to cellular processes. In turn, translation in mitochondria controls cellular proliferation, and mitochondrial ribosomal subunits contribute to the cytoplasmic stress response. Thus, translation in mitochondria is apparently integrated into cellular processes16.
Mitochondrial Redox Regulation in Adaptation to Exercise
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Christopher P. Hedges, Troy L. Merry
In addition to encode 13 protein-coding genes that form essential subunits of the oxidative phosphorylation (OXPHOS) complexes, the mitochondrial genome is now recognised to also harbour short open-reading frames that transcribe small regulatory peptides named mitochondrial-derived peptide (MDP’s) (Guo et al., 2003; Lee et al., 2015; Cobb et al., 2016). Currently, eight mitochondrial peptides have been described, with the majority being responsive to metabolic perturbations (Merry et al., 2020). Humanin, small humanin-like-peptide 6 (SHLP6) and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) have been shown to increase in human plasma or skeletal muscle in response to high-intensity interval exercise (Gidlund et al., 2016; Reynolds et al., 2019; Woodhead et al., 2020). The exercise stimuli that regulates MDP’s, or their molecular targets in an exercise context, are yet to be fully elucidated; however, it appears that cell redox status is a driver of at least MOTS-c expression. In cell culture, oxidative stress rapidly induces MOTS-c translocation from mitochondria to the nucleus, where it can bind to nuclear DNA and interact with the known exercise and oxidative stress sensitive transcription factor NFE2L2 (Nrf2) to regulate gene expression (Kim et al., 2018). This potentially provides a pathway whereby redox signalling in mitochondria can directly regulate nuclear gene expression during exercise. Consistent with this, treatment of mice with exogenous MOTS-c enhances exercise capacity and can promote exercise-like adaptations that improve metabolic function in response to ageing and high-calorie diet (Lee et al., 2015; Reynolds et al., 2021).
Mitochondrial Dysfunction in Chronic Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Christopher Newell, Heather Leduc-Pessah, Aneal Khan, Jane Shearer
mtDNA encodes for a total of 37 genes and several mitochondrially derived peptides, including the cytoprotective agent humanin (69) and the metabolic homeostasis regulator MOTS-c (70). Initially transcribed in the mitochondria, MOTS-c is then translated in the cytosol and regulates nuclear gene expression in response to metabolic stressors. These data indicate that nuclear and mitochondrial genomes regulate one another and this route of communication is genetically integrated (61). The 37 genes result in 13 proteins of the ETS, 2 ribosomal RNAs, and 22 transfer RNAs (8). The 13 ETS proteins correspond to Complexes I, III, IV, and V with the remaining ∼70 proteins, including the entirety of Complex II, being encoded by nDNA and imported into the mitochondria for assembly. Transcription of mtDNA is controlled by a series of three promoters, heat shock proteins 1 and 2 (HSP1 and HSP2) which are found on the H-strand, and LSP which is found on the L-strand (7). LSP is responsible for transcribing the entire L-strand, and HSP2 transcribes nearly all the H-strand; HSP1 only transcribes for the two ribosomal RNA molecules. Although currently being debated, TFAM has been studied as another key contributor to mtDNA transcription. As the main factor responsible for packaging mtDNA into nucleoprotein complexes, TFAM also binds to mtDNA upstream of the three mtDNA promoters causing a bend in mtDNA, which may be vital for proper positioning of mtDNA transcription machinery (65, 120). Finally, the translation of mtDNA is the least understood maintenance process. Known to involve the importation of nDNA encoded factors (133), several elongation factors (72), a termination factor (142), and other molecular pieces, the mechanism is still poorly understood.
Comparison of serum concentrations of humanin in women with and without gestational diabetes mellitus
Published in Gynecological Endocrinology, 2018
Yuhang Ma, Shumei Li, Xiaohui Wei, Jingjing Huang, Mengyu Lai, Nian Wang, Qianfang Huang, Li Zhao, Yongde Peng, Yufan Wang
Humanin (MT-RNR2) is an endogenous polypeptide with 24 amino acids, and it was first identified in the undamaged brain tissue of Alzheimer's patients [6]. Humanin plays an important role in both intracellular and extracellular activity. Intracellularly, humanin can combine with insulin-like growth factor-binding protein 3 (IGF-BP3) and reduce IGF-BP3-mediated apoptosis in SH-SY5Y neuroblastoma and mouse cortical primary neurons [7]. Extracellularly, secreted humanin has been found to be involved in many diseases, including T2DM [8–10]. Voigt et al. [11] found that humanin levels were lower in individuals during impaired fasting glucose (IFG) than in controls; thus, humanin may be a biomarker for impaired fasting and glucose-related oxidative stress.
Mining for missed sORF-encoded peptides
Published in Expert Review of Proteomics, 2019
Xinqiang Yin, Yuanyuan Jing, Hanmei Xu
The products encoded by sORFs are named sORF-encoded peptides (SEPs) or micropeptides. Combinations of computational and experimental techniques have been successfully used to discover several functional micropeptides [10–24], (see Table 1). Some SEPs, encoded by the sORFs in annotated long non-coding RNAs (lncRNAs), function in muscle contraction [11,14,16], muscle regeneration [21], or mRNA degradation [23]. sORFs within 5ʹ leader sequences are commonly referred to as upstream ORFs (uORFs). uORF-encoded peptides often regulate downstream ORF expression [9]. Recently, translation of circular RNAs has also been disclosed: one example is circ-ZNF609, a circular RNA that can be translated and functions in myogenesis [25]. Another example is circMbl3, a protein encoded by a circRNA generated from the gene muscleblind (Mbl) [26]. Furthermore, two mitochondrial-derived peptides have also been identified. The first one named humanin plays a regulatory role in apoptosis, inflammatory response, oxidative stress, and starvation [22]. The second one called MTOS-c can promote metabolic homeostasis, reduce obesity and insulin resistance [24]. In addition, analyses of EST data and RNA seq data detect numerous noncanonical RNA sequences. Some correspond to systematic deletions of 1 or 2 nucleotides after each transcribed trinucleotide, called delRNAs. Numerous peptides detected in MS data match the translation of these noncanonical RNAs [27,28]. Other RNAs correspond to systematic exchanges between nucleotides, called swinger RNAs. Numerous peptides detected in MS data match the translation of these noncanonical RNAs [29–33]. Although not a topic of this review, sORFs, and their encoded micropeptides have also been discovered in bacteria and plants [34–36].