bims-midmar 2021-12-19 papers

bims-midmar

Biomed News

on Mitochondrial DNA maintenance and replication

Issue of 2021‒12‒19
eight papers selected by
Flavia Söllner
Ludwig-Maximilians University

The role of mitochondrial dynamics in mtDNA maintenance.
Increased Mitochondrial DNA Copy Number and Oxidative Damage in Patients with Hashimoto's Thyroiditis.
Identification of mitochondrial RNA polymerase as a potential therapeutic target of osteosarcoma.
The mining and construction of a knowledge base for gene-disease association in mitochondrial diseases.
A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.
Suppression of metabolite shuttles for export of chloroplast and mitochondrial ATP and NADPH increases the cytosolic NADH:NAD+ ratio in tobacco leaves in the dark.
Mitochondria, pattern recognition receptors and autophagy under physiological and pathological conditions, including viral infections.

J Cell Sci. 2021 Dec 15. pii: jcs258944. [Epub ahead of print]134(24):

The role of mitochondrial dynamics in mtDNA maintenance.

Rasha Sabouny, Timothy E Shutt.

  The dynamic nature of mitochondria, which can fuse, divide and move throughout the cell, allows these critical organelles to adapt their function in response to cellular demands, and is also important for regulating mitochondrial DNA (mtDNA). While it is established that impairments in mitochondrial fusion and fission impact the mitochondrial genome and can lead to mtDNA depletion, abnormal nucleoid organization or accumulation of deletions, it is not entirely clear how or why remodeling mitochondrial network morphology affects mtDNA. Here, we focus on recent advances in our understanding of how mitochondrial dynamics contribute to the regulation of mtDNA and discuss links to human disease.

Keywords:  Fission; Fusion; Mitochondria; Mitochondrial dynamics; Mitophagy; mtDNA

DOI:  https://doi.org/10.1242/jcs.258944
Iran J Public Health. 2021 Aug;50(8): 1697-1704

Increased Mitochondrial DNA Copy Number and Oxidative Damage in Patients with Hashimoto's Thyroiditis.

Fatemeh Esfahanian, Mojgan Mirabdolhagh Hazaveh, Laya Hooshmand Garehbagh, Kowsar Falahati, Mitra Ataei, Mohammad Hossein Sanati, Zohreh Jadali.

  Background: The purpose of present study was to investigate mitochondrial DNA copy number (mtDNAcn) and mtDNA damage in peripheral blood of patients with Hashimoto's thyroiditis (HT) and healthy controls (HC).Methods: The relative mtDNAcn and oxidative DNA damage in this case-control study were measured in peripheral blood of 50 patients with Hashimoto's thyroiditis and 50 healthy controls using quantitative real-time PCR. The study was conducted in Tehran University of Medical Sciences hospital, Tehran, Iran in 2018.
Results: HT patients had significantly higher mitochondrial DNA copy number and mitochondrial oxidative damage than the comparison group.
Conclusion: These data suggest the possible involvement of mitochondria and oxidative stress in the pathophysiology of HT.

Keywords:  Autoimmunity; DNA, Mitochondrial; Hashimoto’s thyroiditis; Oxidative stress

DOI:  https://doi.org/10.18502/ijph.v50i8.6817
Cell Death Discov. 2021 Dec 14. 7(1): 393

Identification of mitochondrial RNA polymerase as a potential therapeutic target of osteosarcoma.

Qi-Cai Han, Xiang-Yang Zhang, Peng-Hui Yan, Song-Feng Chen, Fei-Fei Liu, Yun-Rong Zhu, Qing Tian.

POLRMT (RNA polymerase mitochondrial) is essential for transcription of mitochondrial genome encoding components of oxidative phosphorylation process. The current study tested POLRMT expression and its potential function in osteosarcoma (OS). The Cancer Genome Atlas (TCGA) cohorts and Gene Expression Profiling Interactive Analysis (GEPIA) database both show that POLRMT transcripts are elevated in OS tissues. In addition, POLRMT mRNA and protein levels were upregulated in local OS tissues as well as in established and primary human OS cells. In different OS cells, shRNA-induced stable knockdown of POLRMT decreased cell viability, proliferation, migration, and invasion, whiling inducing apoptosis activation. CRISPR/Cas9-induced POLRMT knockout induced potent anti-OS cell activity as well. Conversely, in primary OS cells ectopic POLRMT overexpression accelerated cell proliferation and migration. In vivo, intratumoral injection of adeno-associated virus-packed POLRMT shRNA potently inhibited U2OS xenograft growth in nude mice. Importantly, levels of mitochondrial DNA, mitochondrial transcripts and expression of respiratory chain complex subunits were significantly decreased in U2OS xenografts with POLRMT shRNA virus injection. Together, POLRMT is overexpressed in human OS, promoting cell growth in vitro and in vivo. POLRMT could be a novel therapeutic target for OS.

DOI: https://doi.org/10.1038/s41420-021-00780-x
Sci Rep. 2021 Dec 13. 11(1): 23909

The mining and construction of a knowledge base for gene-disease association in mitochondrial diseases.

Wei Wang, Junying Song, Yunhai Chuai, Fu Chen, Chunlan Song, Mingming Shu, Yayun Wang, Yunfei Li, Xinyu Zhai, Shujie Han, Shun Yao, Kexin Shen, Wei Shang, Lei Zhang.

Mitochondrial diseases are a group of heterogeneous genetic metabolic diseases caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) gene mutations. Mining the gene-disease association of mitochondrial diseases is helpful for understanding the pathogenesis of mitochondrial diseases, for carrying out early clinical diagnosis for related diseases, and for formulating better treatment strategies for mitochondrial diseases. This project researched the relationship between genes and mitochondrial diseases, combined the Malacards, Genecards, and MITOMAP disease databases to mine the knowledge on mitochondrial diseases and genes, used database integration and the sequencing method of the phenolyzer tool to integrate disease-related genes from different databases, and sorted the disease-related candidate genes. Finally, we screened 531 mitochondrial related diseases, extracted 26,723 genes directly or indirectly related to mitochondria, collected 24,602 variant sites on 1474 genes, and established a mitochondrial disease knowledge base (MitDisease) with a core of genes, diseases, and variants. This knowledge base is helpful for clinicians who want to combine the results of gene testing for diagnosis, to understand the occurrence and development of mitochondrial diseases, and to develop corresponding treatment methods.

DOI: https://doi.org/10.1038/s41598-021-03249-0
Hum Mol Genet. 2021 Dec 17. pii: ddab360. [Epub ahead of print]

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.

Ramesh Kandimalla, Maria Manczak, Jangampalli Adi Pradeepkiran, Hallie Morton, P Hemachandra Reddy.

  The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

Keywords:  Mitochondria Alzheimer’s disease Mitophagy Autophagy Dynamin-related protein 1 Oxidative stress Mitochondrial biogenesis

DOI:  https://doi.org/10.1093/hmg/ddab360
Cell Rep Methods. 2021 Nov 22. pii: 100116. [Epub ahead of print]1(7):

Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.

Qingxun Hu, Dan Wu, Matthew Walker, Pei Wang, Rong Tian, Wang Wang.

The ratio of oxidized to reduced NAD (NAD+/NADH) sets intracellular redox balance and antioxidant capacity. Intracellular NAD is compartmentalized and the mitochondrial NAD+/NADH ratio is intricately linked to cellular function. Here, we report the monitoring of the NAD+/NADH ratio in mitochondrial and cytosolic compartments in live cells by using a modified genetic biosensor (SoNar). The fluorescence signal of SoNar targeted to mitochondria (mt-SoNar) or cytosol (ct-SoNar) responded linearly to physiological NAD+/NADH ratios in situ. NAD+/NADH ratios in cytosol versus mitochondria responded rapidly, but differently, to acute metabolic perturbations, indicating distinct NAD pools. Subcellular NAD redox balance regained homeostasis via communications through malate-aspartate shuttle. Mitochondrial and cytosolic NAD+/NADH ratios are influenced by NAD+ precursor levels and are distinctly regulated under pathophysiological conditions. Compartment-targeted biosensors and real-time imaging allow assessment of subcellular NAD+/NADH redox signaling in live cells, enabling future mechanistic research of NAD redox in cell biology and disease development.

DOI: https://doi.org/10.1016/j.crmeth.2021.100116
J Plant Physiol. 2021 Nov 24. pii: S0176-1617(21)00217-0. [Epub ahead of print]268 153578

Suppression of metabolite shuttles for export of chloroplast and mitochondrial ATP and NADPH increases the cytosolic NADH:NAD+ ratio in tobacco leaves in the dark.

Beatriz Moreno-García, Patricia E López-Calcagno, Christine A Raines, Lee J Sweetlove.

  The communication between chloroplasts and mitochondria, which depends on the inter-organellar exchange of carbon skeletons, energy, and reducing equivalents, is essential for maintaining efficient respiratory metabolism and photosynthesis. We devised a multi-transgene approach to manipulate the leaf energy and redox balance in tobacco (Nicotiana tabacum) while monitoring the in vivo cytosolic redox status of NAD(H) using the biosensor c-Peredox-mCherry. Our strategy involved altering the shuttling capacity of the chloroplast by (1) increasing the chloroplast malate valve capacity by overexpression of the chloroplast malate valve transporter pOMT from Arabidopsis (AtpOMT1) while (2) reducing the activity of the chloroplast triose-phosphate/3-phosphoglycerate shuttle by knocking down the cytosolic NAD-dependent glyceraldehyde 3-phosphate dehydrogenase (NtGAPC). This was accompanied by (3) alterations to the export of reducing equivalents in the mitochondria by knocking down the mitochondrial malate dehydrogenase (NtmMDH) and (4) an increased expression of the mitochondrial fission regulator FIS1A from Arabidopsis (AtFIS1A). The multi-transgene tobacco plants were analysed in glasshouse conditions and showed significant increases in the cytosolic NADH:NAD+ in the dark when transcript levels for NtGAPC or NtmMDH were knocked down. In addition, principal component analysis and Spearman correlation analyses showed negative correlations between average transcript levels for the gene targets and parameters related to chlorophyll fluorescence and plant growth. Our results highlight the importance of the shuttling of energy and reducing equivalents from chloroplasts and mitochondria to support photosynthesis and growth and suggest an important role for the dual 2-oxoglutarate/malate and oxaloacetate/malate transporter (pOMT).

Keywords:  Energy balance; Multi-transgene transformation; Nicotiana tabacum; Organelle communication; Plant metabolic engineering; Redox metabolism

DOI:  https://doi.org/10.1016/j.jplph.2021.153578
Acta Biochim Pol. 2021 Dec 15.

Mitochondria, pattern recognition receptors and autophagy under physiological and pathological conditions, including viral infections.

Paulina Niedźwiedzka-Rystwej, Dominika Bębnowska, Roman Kołacz, Wiesław Deptuła.

Research on the health of mammals invariably shows how dynamic immunology is and how the role of many elements and immune processes of the macroorganism, developed in the process of evolution in protecting against threats, including infections, is changing. Among these elements conditioning the homeostasis of the macroorganism are mitochondria, PRR receptors (pattern recognition receptors) and the phenomenon of autophagy. In the context of physiological and pathological states in the body, mitochondria perform various functions. The primary function of these organelles is to produce energy in the cell, but on the other hand, they are heavily involved in various cellular processes, including ROS production and calcium homeostasis. They are largely involved in the activation of immune mechanisms during infectious and non-infectious conditions through mtDNA and the mitochondrial MAVS protein. Mitochondrial involvement has been also determined in PRR-related mechanisms as mtDNA has the ability to directly stimulate TLRs. On the other hand, mitochondria are also associated with apoptotic cell death and autophagy.

DOI: https://doi.org/10.18388/abp.2020_5807