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Mitochondrial DNA Mutations and Mitochondrial Diseases
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
These patients often present the following symptoms: stroke-like episodes, causing subacute brain dysfunction and changes in brain structure, lactic acidosis and/or RRFS. Seizures are frequent in these patients associated with the episode or as an isolated phenomena. Other symptoms include intermittent episodes of encephalopathy, headaches, deafness, dementia and diabetes. Over 80% of patients with MELAS have the 3243A > G mutation in the MT-TL1 gene. Other mutations in this mt-tRNA gene (e.g., 3271T > C), other mt-tRNA genes (e.g., 1642G > A, MT-TV gene) and protein-encoding genes (e.g., 9957T > C in the MT-CO3 gene, several MT-ND5 mutations (12770A > G, 13045A > C, 13513G > A and 13514A > G), and MT-ND1 mutations) may also cause MELAS (Goto et al. 1991, 1990, Taylor et al. 1996, Manfredi et al. 1995, Santorelli et al. 1997, Shanske et al. 2008, Corona et al. 2001, Liolitsa et al. 2003, Kirby et al. 2004).
The Effects of Resveratrol on the Brain Mitochondria
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Naia et al. (2017) have reported that RES (1–5 µM for 96 h) rescued mitochondria regarding loss of MMP in primary cortical and striatal neurons obtained from the embryos of YAC128 mice (which are an experimental model of Huntington’s disease – HD) [73]. Interestingly, RES did not modulate the acetylation of H3 protein, indicating that RES did not alter SIRT1 activity in that experimental model (SIRT1 is a deacetylase and H3 is a well-known target of SIRT1). The authors also tested whether RES would be able to modulate genes related with mitochondrial biogenesis in an in vivo experimental model using YAC 128 mice. RES (1 mg/kg.day-1 for 28 days, subcutaneous route) decreased the levels of acetylated H3 in both cerebral cortex and striatum of the wild type animals and only in the striatum of the YAC128 animals. The authors next examined whether RES would modulate the expression of genes related with mitochondrial function in the cerebral cortex of mice. It was observed that RES upregulated the expression of MT-ND5 (mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 5) and MT-CO1 (mitochondrially encoded cytochrome c oxidase I) genes in the cerebral cortex of YAC128 mice. Interestingly, RES can downregulate the expression of those genes in the cerebral cortex of wild type mice. Other analyses were performed by the authors and reinforced the hypothesis that RES induced mitochondrial biogenesis, ameliorating mitochondrial function in the neurons of cerebral areas affected in HD. The biochemical alterations promoted by RES were accompanied by benefits in the animal behavior in that experimental model. It was previously shown that mutant huntingtin interacts with mitochondrial membranes, causing loss of MMP, bioenergetics decline, and increased production of ROS by the organelles [74,75]. Thus, RES would be an interesting choice to be used as an alternative drug in the treatment of HD. However, safety of this treatment should be better studied in further research.
Application of next-generation sequencing in the diagnosis of gastric cancer
Published in Scandinavian Journal of Gastroenterology, 2022
Narges Moradi, Solmaz Ohadian Moghadam, Siamak Heidarzadeh
WGS includes the analysis of non-coding mitochondrial genome which is known for the higher chances of alteration occurrence compared to nuclear DNA [35–37]. Mitochondrial dysfunction, heteroplasmy and subsequently cellular deregulation, can originate from the mentioned cancer-related alterations. A recent NGS-based study has compared the whole mt-Genome in GC-dealing patients and healthy individuals revealing that GC tumors presented variations in MT-DLOOP2, MT-DLOOP1, MT-RNR1, MT-ND2, MT-ND4, MT-ND5 and MT-CO1 regions [35]. Using WGS, Broad analysis of H. pylori genome is useful in diagnosing and treating the infection [38]. As a virus that have been linked to gastric adenocarcinoma, EBV genome can be detected by NGS platforms including WGS providing a more accurate alternative for traditional detection techniques such as in Situ Hybridization (ISH) [39].
Mitochondrial delivery of microRNA mimic let-7b to NSCLC cells by PAMAM-based nanoparticles
Published in Journal of Drug Targeting, 2020
Niloufar Maghsoudnia, Reza Baradaran Eftekhari, Alireza Naderi Sohi, Parisa Norouzi, Hamid Akbari, Mohammad Hossein Ghahremani, Masoud Soleimani, Mohsen Amini, Hamed Samadi, Farid Abedin Dorkoosh
A variety of biological mechanisms within the cancer cells have shown that mitochondria is a key regulator of many important cellular mechanisms including energy metabolism, cell viability and death [1]. Many cancerous cells such as non-small cell lung cancer (NSCLC) cells rely heavily on mitochondrial respiration for their growth and survival [2]. Inhibition of mitochondrial oxidative phosphorylation (OXPHOS) function can affect growth and metastasis processes by production of reactive oxygen species (ROS) higher than normal levels leading to mtDNA damage and mitochondrial dysfunction [2,3]. Recently, it has been studied that miRNAs are surprisingly localised in mitochondria in addition to the cell cytoplasm referring as mitomiRs [4–10]. It is reported that mitomiRs play a significant role in regulation of mitochondrial-encoded genes involved in respiratory chain function [5]. Let-7b is one of the members of a tumour suppressor microRNA family (let-7) that is downregulated apparently in a variety of human cancer cells particularly in NSCLC cells [11]. This microRNA regulates the expression of different oncogenes such as KRAS (Kirsten rat sarcoma viral oncogene homolog), MYC (Myelocytomatosis) and HMGA2 (High-mobility group AT-hook 2), as well as other cell cycle progression genes [11,12]. Let-7b has been also revealed to be localised in mitochondria targeting a number of mitochondrial-encoded genes involved in oxidative phosphorylation including MT-ATP6 (Mitochondrially Encoded ATP Synthase Membrane Subunit 6), MT-ATP8 (Mitochondrially Encoded ATP Synthase Membrane Subunit 8), COX2 (Cytochrome c oxidase subunit 2 also known as Mitochondrially Encoded Cytochrome C Oxidase II (MT-CO2)), COX1(Cytochrome c oxidase I also known as Mitochondrially Encoded Cytochrome C Oxidase I (MT-CO1)) and MT-ND5 (Mitochondrially Encoded NADH Dehydrogenase Subunit 5) [4–6,13]. In this research, delivery of miRNA let-7b to mitochondria is suggested to inhibit NSCLC cells growth [14].
Bacterial TLR4 and NOD2 signaling linked to reduced mitochondrial energy function in active inflammatory bowel disease
Published in Gut Microbes, 2020
Emmanuelle Ruiz, Harrison M. Penrose, Sandra Heller, Hani Nakhoul, Melody Baddoo, Erik F. Flemington, Emad Kandil, Suzana D. Savkovic
Currently, we showed that in inflamed IBD the IC Mito-0 signature significantly correlated with active bacterial TLR4 and NOD2 signaling. The effect of gut bacteria triggered signaling on IC mitochondrial function and possible roles in intestinal homeostasis and disease development is understudied.29 Gut pathogens are capable of destabilizing host cell mitochondrial functions related to calcium signaling for their survival and transmission.30 Similarly, under normal circumstances select gut pathobionts tend to control mitochondrial activity in favor of infection and inflammation through the production of hydrogen sulfide (H2S) and nitrogen oxide (NO).27 Also, gut commensal bacteria metabolites, including short-chain fatty acids (SCFA) and secondary bile acids, could affect host IC mitochondrial energy functions in homeostasis and during inflammation.31 Furthermore, bacterial LPS along with induced inflammatory TNF and IL-6 also have been shown to impair mitochondria ATP production.32 On the other hand, mitochondrial functions might modify the gut microbiota composition due to alterations in mitochondrial innate immune responses. For example, polymorphisms in mt-ND5 and mt-CYTB have been shown to induce specific gut microbiota compositions, which could play a role in inducing inflammation.33 Also, altered mitochondria function could influence intestinal immune cells, which in turn can affect gut microbiota composition.28 We demonstrated before that reduced mitochondrial energy function leads to increased inflammatory mediators and elevated TLRs signaling.16 Additionally, recent work has demonstrated that loss of barrier function to commensal bacteria triggered by dysfunctional mitochondrial activity included aberrant NOD2 function, suggesting an important role for mitochondrial-NOD2 regulation in maintaining IC homeostasis and restricting inflammatory processes.34 Nevertheless, our findings reveal that in human inflamed IBD reduced mitochondrial energy function is strongly linked not only to TNF signaling,16 but also to signaling triggered by bacterial components, highlighting a direct role for mitochondria in sensitizing the intestine to commensal bacteria and exacerbating inflammation.