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HGNC Approved Gene Symbol: MT-RNR2
MTRNR2 is transcribed into the large 16S mitochondrial ribosomal RNA (rRNA) (Kearsey and Craig, 1981). MTRNR2 also harbors a short ORF that is translated into the 24-amino acid humanin (HN) peptide that was originally identified due to its antiapoptotic properties (Guo et al., 2003).
The cytoprotective effects of HN appear to be mediated by specific receptors (summary by Lee et al. (2013)).
Mitochondrial 16S rRNA is encoded by nucleotides 1671-3229.
Mitochondrial Humanin
Hashimoto et al. (2001) noted that important clues in the development of therapy for Alzheimer disease (AD; 104300) come from the study of molecules that suppress familial AD (FAD) gene-induced death in neuronal cells in culture. Using the death-trap screening method devised by Vito et al. (1996) to screen a cDNA library from an occipital lobe of an AD patient brain, they identified a long cDNA that encoded a deduced 24-amino acid polypeptide, which they called humanin (HN). Hashimoto et al. (2001) found that the cDNA sequence of HN is 99% identical to the sequence of 16S mitochondrial rRNA (MTRNR2), as well as 99% identical to some nuclear-encoded human cDNAs, suggesting the possibility that HN cDNA represents a nuclear transcribed mRNA. Northern blot analysis detected expression of major 1.6- and minor 3.0- and 1.0-kb transcripts at high levels in heart, skeletal muscles, kidney, and liver, at lower but significant levels in brain and the gastrointestinal tract, and at barely detectable levels in the immune system.
Tajima et al. (2002) raised an anti-HN antibody and found that long cDNAs containing the ORF of HN (HN-ORF) produced the HN peptide in mammalian cells, dependent on the presence of the full-length HN-ORF. Immunoblot analysis detected a 3-kD protein with HN immunoreactivity in mouse testes and colon. The findings suggested that the HN peptide can be produced in vivo. HN immunoreactivity was detected in neurons and glia of AD brains, whereas few immunopositive neuronal cells were detected in normal brains.
Using quantitative RT-PCR, Bodzioch et al. (2009) found that HNM was highly expressed in testis, kidney, and heart, with moderate expression in skeletal muscle, whole adult and fetal brain, and adult liver. Lower expression was detected in fetal liver and in adult thyroid and bone marrow.
By Western blot analysis, Muzumdar et al. (2009) found that the rat ortholog of HN, called rattin (Rn), was expressed in muscle, liver, and hypothalamus, but not in epididymal fat.
Using immunohistochemical analysis, Bachar et al. (2010) found HN expression in the endothelial layer of human internal mammary arteries, atherosclerotic coronary arteries, and sections of the greater saphenous vein. HN was also expressed in human aortic endothelial cells (HAECs).
Guo et al. (2003) identified the humanin ORF within the sequence of the mitochondrial 16S rRNA gene, MTRNR2.
Humanin Gene Family
Using bioinformatic and expression data, Bodzioch et al. (2009) identified 13 nuclear MTRNR2-like loci that were predicted to maintain the ORFs of 15 distinct full-length HN-like peptides. Sequence comparison revealed 2 consensus motifs, encompassing residues 5-11 (GF(S/N)CLLL) and 14-19 (SEIDL(P/S)). At least 10 of these genes were variably expressed in human tissues. Most were expressed in testis, but at a level at least 100-fold lower than that measured for mitochondrial HN. Most nuclear isoforms protected human umbilical vein endothelial cells (HUVECs) from staurosporin-induced apoptosis. Most, including mitochondrial HN, were downregulated following exposure of HUVECs to antiapoptotic beta-carotene. Variable numbers of HN orthologs were detected in primates. In most other organisms, the mitochondrial ORF was well maintained and the nuclear forms were less frequent.
Methylation of Mitochondrial 16S rRNA
Using knockdown analysis in HeLa cells, Bar-Yaacov et al. (2016) demonstrated that human TRMT61B (619404) was directly responsible for posttranslational methylation of adenosine at position 947 (m1A947) of mitochondrial 16S rRNA. RNA-sequencing analysis supported the modification at position 947 of 16S rRNA and indicated that the modification is highly conserved throughout vertebrate evolution. Moreover, examination of isolated mitoribosomes from Sus scrofa liver confirmed high enrichment of m1A947 modification in the mature mitoribosome. Further analysis showed that mitochondrial 16S rRNA position 947 should either be m1A, thymine, or guanine to maintain proper mitoribosomal activity. Modeling analysis using cryoelectron microscopy structures of the mitoribosome suggested that m1A, thymine, or guanine at 16S rRNA position 947 likely forms stabilizing interactions within the mitoribosome.
Mitochondrial Humanin
Hashimoto et al. (2001) found that the transfected HN cDNA peptide suppressed neuronal cell death induced by 3 FAD genes: amyloid precursor protein (APP; 104760), presenilin-1 (PS1; 104311), and presenilin-2 (PS2; 600759). The peptide also abolished death caused by A-beta amyloid, but had no effect on death by expanded polyglutamine repeats (Q79) or superoxide dismutase-1 (SOD1; 147450) mutants. The rescue action clearly depended on the primary structure of HN. They determined that HN is secreted into the extracellular medium and acts on the outside of cells and suggested that there was a specific binding site on the cell surface. Hashimoto et al. (2001) demonstrated that HN neurotoxicity inhibition occurs with many APP and PS mutations and beta-amyloid peptides. HN did not suppress neurotoxicity by glutamate or prion fragments, further demonstrating that the antagonistic activities of HN are selective. Detailed structural analysis of the HN protein showed the essential roles of cys8, ser14, and the domain from pro3 to pro19 in the rescue action.
By means of a yeast 2-hybrid screening assay, Niikura et al. (2003) identified TRIM11 (607868) as an HN-interacting protein. TRIM11 is a member of a protein family containing a tripartite motif, including a RING finger domain that acts as a putative E3 ubiquitin ligase. Both the coiled-coil domain and the C-terminal RFP (602165)-like domain of TRIM11 were necessary for interaction with HN. Coexpression of HN and TRIM11 diminished intracellular levels of HN, suggesting that intracellular HN levels are regulated by TRIM11-linked ubiquitin-mediated protein degradation pathways.
Bax (600040) is an apoptosis-inducing protein that undergoes conformational changes that result in its translocation to mitochondrial membranes where Bax inserts and causes release of cytochrome c and other apoptotic proteins. Guo et al. (2003) found that Bax coimmunoprecipitated with humanin and that humanin rescued rat hippocampal neurons from Bax-induced lethality. Humanin prevented the translocation of Bax from the cytosol to the mitochondria and suppressed cytochrome c release. The nuclear-encoded peptide and the mitochondrial-encoded peptide (which is most likely not expressed in mitochondria) were both able to directly bind Bax and prevent apoptosis. Guo et al. (2003) suggested that the HN gene arose from the mitochondria and transferred to the nuclear genome, providing a protective mechanism from Bax for additional organelles.
Using yeast 2-hybrid analysis followed by protein pull-down and coimmunoprecipitation analysis, Ikonen et al. (2003) identified a direct interaction between HN and IGFBP3 (146732). An 18-amino acid heparin-binding domain of IGFBP3 and phe6 (F6) of HN were required for the interaction. HN did not compete with IGF1 (147440) for binding to IGFBP3. HN, but not F6A mutant HN, inhibited IGFBP3-induced apoptosis in human A172 glioblastoma cells, but not in human SH-SY5Y neuroblastoma or mouse cortical primary neurons. In primary neurons, IGFBP3 potentiated HN rescue from A-beta(1-43) toxicity.
Ying et al. (2004) examined the activity of synthetic HN on various cell lines and found that HN induced chemotaxis of monocytes by competing with amyloid beta-42 for FPRL1 (136538). HN reduced aggregation and fibrillary formation by suppressing the effect of amyloid beta-42 on mononuclear phagocytes. In neuroblast cells, both HN and amyloid beta-42 activated FPRL1; however, only amyloid beta-42 caused apoptotic death, and HN blocked the cytopathic effect of amyloid beta-42. Ying et al. (2004) concluded that HN shares FPRL1 with amyloid beta-42 and may exert its neuroprotective effects by competitively inhibiting access of FPRL1 to amyloid beta-42.
Kin et al. (2006) investigated the expression of HN in muscles from 4 patients who had chronic progressive external ophthalmoplegia (KSS; 530000) with different mitochondrial mutations and from 2 patients with Leigh syndrome (256000) who had L156R mutations in the MTATP6 gene (516060.0001). HN was strongly positive in all ragged-red fibers (RRFs) and mildly positive in some non-RRFs of all patients examined. Kin et al. (2006) suggested that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities.
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; 540000) is commonly caused by mutation in mitochondrial DNA that results in defective ATP synthesis. By immunohistochemical analysis, Kariya et al. (2005) found that HN expression was upregulated in MELAS muscle biopsies, predominantly in RRFs. Expression of HN in TE671 rhabdomyosarcoma cells, or exposure of TE671 cells to exogenous HN, elevated ATP/ADP ratio in the absence of elevated pyruvate or lactate, suggesting that the induced ATP was derived from mitochondria rather than from cytoplasmic glycolysis.
By continuous introcerebroventricular infusion in rats, Muzumdar et al. (2009) found that HN improved insulin sensitivity, which was associated with activation of hypothalamic Stat3 (102582) signaling. Single treatment with mutant HN that does not bind IGFBP3 (HNGF6A) significantly lowered blood glucose in Zucker diabetic fatty rats. Inhibition of hypothalamic Stat3 completely negated the effect of intravenous HNGF6A on liver glucose production. Using ELISA, Muzumdar et al. (2009) also found that circulating levels of HN decreased with age in humans and mice. Rn content decreased with age in rat skeletal muscle and tended to decrease with age in hypothalamus.
Bachar et al. (2010) found that exposure of HAECs to exogenous HN reduced oxidized low density lipoprotein-induced formation of reactive oxygen species, apoptosis, and formation of ceramide, a lipid second messenger involved in the apoptotic signaling cascade.
Rossini et al. (2011) identified VSTM2L (616537) as an endogenous antagonist of HN neuroprotective activity. Domain analysis revealed that the N-terminal signal sequence was required for VSTM2L secretion and that its central IgG-like domain bound HN. Secretion of VSTM2L was required for inhibition of HN neuroprotective activity.
See Blanc et al. (1981) and Kearsey and Craig (1981).
See Blanc et al. (1981).
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