Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Shamim I. Ahmad in 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.
Introduction to Mitochondria Biology
Sara C. Zapico in Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Each mitochondrion contains between two to ten copies of the mtDNA. Human mtDNA is a double-stranded negatively supercoiled circular molecule (Fig. 3). It is organized into protein-DNA complexes, nucleoids, within the mitochondrial matrix (Gilkerson 2009). There is evidence that some of the genes from the ancestral bacteria have been transferred to the nuclear DNA; however, 16,569 base pairs remain within the mitochondrion. It contains 37 genes, which in turn code for the synthesis of 12S and 16S rRNAs, 22 tRNAs and 13 proteins that are structural subunits of OXPHOS enzyme complexes, seven of Complex I; three of Complex IV; two of Complex V and one of Complex III (Andrews et al. 1999, Anderson et al. 1981). Apart from that, nuclear genes encode approximately 1,500 mitochondrial proteins, the majority of mitochondrial respiratory chain polypeptides, including all four subunits of complex II, replication proteins such as the mitochondrial DNA polymerase γ (DNA pol γ), the mitochondria RNA polymerase components, the mtTFA, the mitochondrial ribosomal proteins and elongation factors and the mitochondrial metabolic enzymes (Chinnery and Schon 2003, Wallace 2005, Schatz 1996, Shoubridge 2001).
A Diagnostic Approach to Pneumocystis jiroveci Pneumonia
Johan A. Maertens, Kieren A. Marr in Diagnosis of Fungal Infections, 2007
While differences in patient population, PCR technique, and study design make comparing the data from varied clinical studies difficult, protocols targeting the major surface glycoprotein (MSG) gene (105), a gene which belongs to a multi-copy gene family, have been the most sensitive. (More so than those that use the mitochondrial ribosomal RNA gene, another multi-copy target.) Furthermore, at least for diagnostic purposes, single-round touchdown PCR (TD-PCR) seems to be superior to nested PCR (106). Although they have not been compared head-to-head, given that nested PCR requires at least two rounds of amplification, an inherently greater risk of contamination and false positive results is to be expected.
Time-course effect of ultrasmall superparamagnetic iron oxide nanoparticles on intracellular iron metabolism and ferroptosis activation
Published in Nanotoxicology, 2021
Jinling Gao, Huige Zhou, Yanjie Zhao, Lin Lu, Jianzhong Zhang, Wenting Cheng, Xuxia Song, Yuxin Zheng, Chunying Chen, Jinglong Tang
Ferroptosis is an iron-based cell death caused by excessive lipid peroxidation (Yang and Stockwell 2016). It can be prevented by lipophilic antioxidants and iron chelators (Lu et al. 2018). In the current study, human breast cancer cell lines MDA-MB-231 were exposed to USPIO for 24 h and the cell viability assay shows the subtle suppression effect. Importantly, Fer-1 and Lip-1 as specific ferroptosis inhibitors effectively affected USPIO-induced cell death. Similarly, DFO as an iron ion chelator also significantly inhibited the USPIO-induced cell death. In addition, the co-incubation of Z-VAD-FMK with Fer-1 treatment revealed similar effects of improving cell viability compared with either Z-VAD-FMK or Fer-1 alone, indicating that ferroptosis may share some common pathway with apoptosis. TIMM8B is involved in the import of some multi-pass transmembrane proteins into the mitochondrial inner membrane, which is associated with mitochondrial biogenesis and translation. Mitochondrial ribosomal proteins (MRPs) including MRPL18 and TIMM8B, were significantly upregulated in breast cancer cells (Del Puerto-Nevado et al. 2019). The upregulation of TIMM8B could be induced by pretreatment Z-VAD-FMK and Fer-1 inhibitors, which revealed novel insight TIMM8B may be as crosstalk of ferroptosis and apoptosis. Studies have revealed the crosstalk between autophagy and ferroptosis (Zhou et al. 2019). Hou et al. (2016) identified that autophagy promotes ferroptosis by the degradation of ferritin in cancer cells (Hou et al. 2016).
Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases
Published in Expert Opinion on Therapeutic Targets, 2019
Camila Florencia Zuccato, Antonela Sofia Asad, Alejandro Javier Nicola Candia, María Florencia Gottardo, Mariela Alejandra Moreno Ayala, María Susana Theas, Adriana Seilicovich, Marianela Candolfi
HN is a 24-amino acid peptide originally isolated from a cDNA library during the search for survival factors in an unaffected brain section of a patient with Alzheimer’s disease (AD) [1]. HN is transcribed by a portion of the polycistronic mitochondrial MT-RNR2 gene that encodes the large 16S mitochondrial ribosomal RNA (rRNA) [2]. HN cDNA is polyadenylated, which may be involved in exporting the HN transcript from the mitochondria to the cytoplasm before translation. When HN mRNA is translated within the mitochondria, it yields a 21-amino acid peptide and when it is translated in the cytoplasm, it results in a 24-amino acid peptide; however, both are functional and successfully inhibit the mitochondrial apoptotic pathway [3]. HN has been detected in tissues and plasma [4–6]. Circulating levels of HN have been shown to fluctuate with age and have been proposed as biomarkers for several pathological conditions, as we describe below.
ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease
Published in Expert Opinion on Investigational Drugs, 2020
Based on hypotheses regarding the off-target toxicities of traditional aminoglycoside antibiotics like gentamicin and G418, ELX-02 was initially synthesized in a campaign aimed at reducing affinity toward ribosomes from either prokaryotes or from eukaryotic mitochondria while maintaining or increasing affinity toward eukaryotic ribosomes in the cytosol [20,21–22]. This selectivity profile Figure 3 was hypothesized to improve nonsense mutation read-through while mitigating drug-induced tolerability attributed to binding to the mitochondrial ribosome. Optimization led to ELX-02 and other similar molecules showing greater read-through activity in a plasmid-based dual-luciferase assay and restoration of full length, functional protein by ELX-02 in cellular assays while simultaneously demonstrating improved cellular tolerability [20,23,24].
Related Knowledge Centers
- Cytoplasm
- Inner Mitochondrial Membrane
- Mitochondrial DNA
- Ribosomal Protein
- Ribosome
- Messenger Rna
- Cell Nucleus
- Mitochondrion
- Protein Complex
- Translation