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Mitochondrial DNA Mutations and Mitochondrial Diseases
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Although 72 of the 85 subunits that form the respiratory chain complexes are encoded in the nucleus, mutations in such genes are rare. This might be a reflection of the highly deleterious nature of these mutations, which would result in lethality during embryogenesis. To date, mutations have been described in subunits of complex I (NDUFS 1, 2, 3, 4, 7 and 8, NDUFV1 and 2, and NDUFA1 and 11), associated with Leigh syndrome, encephalomyopathy, leukodystrophy and the four subunits of complex II (SDHA, B, C and D) associated with Leigh syndrome and ataxia in the case of the A subunit, and more rarely paraganglioma and feocromocitoma in the case of subunits B, C, and D. Mutations have also been described in complex III subunits UQCRB and UQCRQ associated with hypoglycemia, lactic acidosis and severe psychomotor delay with extra pyramidal signs, as well as a mutation in the complex IV (COX6B1) associated with childhood encephalomyopathy (Zhu et al. 2009).
Single-cell analysis reveals immune modulation and metabolic switch in tumor-draining lymph nodes
Published in OncoImmunology, 2020
Yen-Liang Li, Chung-Hsing Chen, Jing-Yi Chen, You-Syuan Lai, Shao-Chun Wang, Shih-Sheng Jiang, Wen-Chun Hung
To confirm the metabolic change in FRCs found in our study, we downloaded two public datasets to evaluate the genes which were differentially expressed in FRCs. The first dataset used single-cell RNA-seq to examine the stromal compartment in murine TDLNs harvested at different time points after injection of B16 melanoma cells.54 We found that the expression of genes related to OXPHOS and mitochondria dysfunction was elevated in the TDLNs at day 11 when compared to that of normal lymph nodes and day 4 TDLNs and three of the genes (Cox6b1, Cox7b and Cox10) identified in our MMTV-PyMT mice were significantly increased (Supplementary Figure 4A). The second dataset (E-MTAB-7427) published recently consisted raw sequencing data for the melanoma model.56 We analyzed the 5 genes altered in FRCs in our study and found that four of them were statistically elevated during tumor progression (Supplementary Figure 4B). Thus, results of these two studies support out findings that metabolic reprogramming occurred in the FRCs of TDLNs.
Molecular tissue profiling by MALDI imaging: recent progress and applications in cancer research
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Pey Yee Lee, Yeelon Yeoh, Nursyazwani Omar, Yuh-Fen Pung, Lay Cheng Lim, Teck Yew Low
MALDI imaging allows the study of drug candidates in great detail by enabling the visualization of drug uptake, distribution, accumulation, and elimination in a spatio-temporal manner. By using MALDI imaging to evaluate the localization of anticancer agents in different cancer models with distinct morphology and drug sensitivity, heterogeneous drug penetration in the tumor tissue microenvironments can be characterized. This information is important for understanding drug action mechanisms and efficacy [109–111]. A MALDI imaging study on the spatial penetration of perifosine in a 3D spheroid of colorectal carcinoma revealed heterogeneous drug distribution that could be linked to drug resistance and disease relapse [112]. A notable advantage of this technique is that it can be used for simultaneous mapping and quantitation of the parent compounds and their metabolites without the use of labeling [113]. In one study, Buck et al. [114] applied MALDI imaging to monitor and quantify the distribution of irinotecan and its active metabolite, SN-38, in mouse sections to evaluate drug uptake into targeted tissues and its toxicity in other tissue sites. It can be employed to determine the expression of drug target ligands [115] and drug-target engagement [116] to correlate with drug response. It can also be used to assess response to therapeutic drugs. Aichler et al. [117] showed that MALDI imaging profiles discriminated response to cisplatin-based neoadjuvant chemotherapy in pretherapeutic esophageal adenocarcinoma patients and identified defects in specific mitochondrial respiratory chain proteins such as COX7A2, COX6B1, and COX6C as predictive markers for treatment response. A study by Mascini et al. [118] reported that its use in combination with principal component linear discriminant analysis enabled the identification of a proteomic signature that could predict treatment response in patient-derived xenograft models of triple-negative breast cancer. As well, Patterson et al. [100] investigated the lipidome of colorectal cancer liver metastasis specimens using MALDI imaging and discovered distinct lipid signatures associated with the response to chemotherapy that may be useful to predict clinical response.