bims-midmar 2022-01-09 papers

bims-midmar

Biomed News

on Mitochondrial DNA maintenance and replication

Issue of 2022–01–09
twelve papers selected by
Flavia Söllner, Ludwig-Maximilians University

Rational Designs at the Forefront of Mitochondria-Targeted Gene Delivery: Recent Progress and Future Perspectives.
MPV17 Gene Variant Mutation Presenting as Leucoencephalopathy with Peripheral Neuropathy.
Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients.
The frequency of the known mitochondrial variants associated with drug-induced toxicity in a Korean population.
Peripheral Blood Mitochondrial DNA Levels Were Modulated by SARS-CoV-2 Infection Severity and Its Lessening Was Associated With Mortality Among Hospitalized Patients With COVID-19.
mtIF3 is locally translated in axons and regulates mitochondrial translation for axonal growth.
Mitochondrial dysfunction and Parkinson's disease.
DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53.
Targeting Mitochondrial Metabolism and RNA Polymerase POLRMT to Overcome Multidrug Resistance in Cancer.
Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA.
Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy.
Mitochondrial DNA copy number is associated with treatment response and cognitive function in euthymic bipolar patients receiving valproate.

ACS Biomater Sci Eng. 2022 Jan 03.

Rational Designs at the Forefront of Mitochondria-Targeted Gene Delivery: Recent Progress and Future Perspectives.

Naoto Yoshinaga, Keiji Numata.

  Mitochondria play an essential role in cellular metabolism and generate energy in cells. To support these functions, several proteins are encoded in the mitochondrial DNA (mtDNA). The mutation of mtDNA causes mitochondrial dysfunction and ultimately results in a variety of inherited diseases. To date, gene delivery systems targeting mitochondria have been developed to ameliorate mtDNA mutations. However, applications of these strategies in mitochondrial gene therapy are still being explored and optimized. Thus, from this perspective, we herein highlight recent mitochondria-targeting strategies for gene therapy and discuss future directions for effective mitochondria-targeted gene delivery.

Keywords:  gene therapy; mitochondria; mitochondria-targeting peptides; organelle targeting

DOI:  https://doi.org/10.1021/acsbiomaterials.1c01114
Neurol India. 2021 Nov-Dec;69(6):69(6): 1817-1819

MPV17 Gene Variant Mutation Presenting as Leucoencephalopathy with Peripheral Neuropathy.

Ravindranadh Chowdary Mundlamuri, Pradeep Divate, Parthasarthy Satishchandra.

  Mitochondrial DNA depletion syndromes (MDS) are rare mitochondrial disorders with evolving broad genotype and phenotype. This is a first case report from India about MPV 17, a mitochondrial inner membrane protein gene variant mutation, presenting with neuropathy, leucoencephalopathy and subclinical hepatic dysfunction with detailed clinical and imaging description.

Keywords:  MPV17 gene; Mitochondrial depletion syndromes; neuropathy and leukoencephalopathy

DOI:  https://doi.org/10.4103/0028-3886.333468
Mol Neurobiol. 2022 Jan 03.

Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients.

Maria Isabel Alvarez-Mora, Petar Podlesniy, Teresa Riazuelo, Laura Molina-Porcel, Ellen Gelpi, Laia Rodriguez-Revenga.

  Hexanucleotide repeat expansion in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Loss of C9ORF72 protein function and a toxic gain-of-function directly by the RNA or RAN translation have been proposed as triggering pathological mechanisms, along with the accumulation of TDP-43 protein. In addition, mitochondrial defects have been described to be a major driver of disease initiation. Mitochondrial DNA copy number has been proposed as a useful biomarker of mitochondrial dysfunction. The aim of our study was to determine the presence of mtDNA copy number alterations in C9ALS/FTD patients. Therefore, we assessed mtDNA copy number in postmortem prefrontal cortex from 18 C9ORF72 brain donors and 9 controls using digital droplet PCR. A statistically significant decrease of 50% was obtained when comparing C9ORF72 samples and controls. This decrease was independent of age and sex. The reduction of mtDNA copy number was found to be higher in patients' samples presenting abundant TDP-43 protein inclusions. A growing number of studies demonstrated the influence of mtDNA copy number reduction on neurodegeneration. Our results provide new insights into the role of mitochondrial dysfunction in the pathogenesis of C9ALS/FTD.

Keywords:  C9ALS/FTD; C9ORF72; Neurodegeneration; ddPCR; mtDNA copy number

DOI:  https://doi.org/10.1007/s12035-021-02673-7
BMC Med Genomics. 2022 Jan 03. 15(1): 3

The frequency of the known mitochondrial variants associated with drug-induced toxicity in a Korean population.

Vinh Hoa Pham, Van Lam Nguyen, Hye-Eun Jung, Yong-Soon Cho, Jae-Gook Shin.

   BACKGROUND: Few studies have annotated the whole mitochondrial DNA (mtDNA) genome associated with drug responses in Asian populations. This study aimed to characterize mtDNA genetic profiles, especially the distribution and frequency of well-known genetic biomarkers associated with diseases and drug-induced toxicity in a Korean population.
METHOD: Whole mitochondrial genome was sequenced for 118 Korean subjects by using a next-generation sequencing approach. The bioinformatic pipeline was constructed for variant calling, haplogroup classification and annotation of mitochondrial mutation.
RESULTS: A total of 681 variants was identified among all subjects. The MT-TRNP gene and displacement loop showed the highest numbers of variants (113 and 74 variants, respectively). The m.16189T > C allele, which is known to reduce the mtDNA copy number in human cells was detected in 25.4% of subjects. The variants (m.2706A > G, m.3010A > G, and m.1095T > C), which are associated with drug-induced toxicity, were observed with the frequency of 99.15%, 30.51%, and 0.08%, respectively. The m.2150T > A, a genotype associated with highly disruptive effects on mitochondrial ribosomes, was identified in five subjects. The D and M groups were the most dominant groups with the frequency of 34.74% and 16.1%, respectively.
CONCLUSIONS: Our finding was consistent with Korean Genome Project and well reflected the unique profile of mitochondrial haplogroup distribution. It was the first study to annotate the whole mitochondrial genome with drug-induced toxicity to predict the ADRs event in clinical implementation for Korean subjects. This approach could be extended for further study for validation of the potential ethnic-specific mitochondrial genetic biomarkers in the Korean population.

Keywords:  Drug-induced toxicity; Korean population; Mitochondria; Polymorphism

DOI:  https://doi.org/10.1186/s12920-021-01153-0
Front Cell Infect Microbiol. 2021 ;11 754708

Peripheral Blood Mitochondrial DNA Levels Were Modulated by SARS-CoV-2 Infection Severity and Its Lessening Was Associated With Mortality Among Hospitalized Patients With COVID-19.

José J Valdés-Aguayo, Idalia Garza-Veloz, José R Vargas-Rodríguez, María C Martinez-Vazquez, Lorena Avila-Carrasco, Sofia Bernal-Silva, Carolina González-Fuentes, Andreu Comas-García, Diana E Alvarado-Hernández, Alba S H Centeno-Ramirez, Iram P Rodriguez-Sánchez, Ivan Delgado-Enciso, Margarita L Martinez-Fierro.

   Introduction: During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus hijacks the mitochondria causing damage of its membrane and release of mt-DNA into the circulation which can trigger innate immunity and generate an inflammatory state. In this study, we explored the importance of peripheral blood mt-DNA as an early predictor of evolution in patients with COVID-19 and to evaluate the association between the concentration of mt-DNA and the severity of the disease and the patient's outcome.
Methods: A total 102 patients (51 COVID-19 cases and 51 controls) were included in the study. mt-DNA obtained from peripheral blood was quantified by qRT-PCR using the NADH mitochondrial gene.
Results: There were differences in peripheral blood mt-DNA between patients with COVID-19 (4.25 ng/μl ± 0.30) and controls (3.3 ng/μl ± 0.16) (p = 0.007). Lower mt-DNA concentrations were observed in patients with severe COVID-19 when compared with mild (p= 0.005) and moderate (p= 0.011) cases of COVID-19. In comparison with patients with severe COVID-19 who survived (3.74 ± 0.26 ng/μl) decreased levels of mt-DNA in patients with severe COVID-19 who died (2.4 ± 0.65 ng/μl) were also observed (p = 0.037).
Conclusion: High levels of mt-DNA were associated with COVID-19 and its decrease could be used as a potential biomarker to establish a prognosis of severity and mortality of patients with COVID-19.

Keywords:  COVID-19; SARS-CoV-2; mitochondria; mitochondrial DNA; severity

DOI:  https://doi.org/10.3389/fcimb.2021.754708
BMC Biol. 2022 Jan 07. 20(1): 12

mtIF3 is locally translated in axons and regulates mitochondrial translation for axonal growth.

Soyeon Lee, Dongkeun Park, Chunghun Lim, Jae-Ick Kim, Kyung-Tai Min.

   BACKGROUND: The establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites. In particular, mitochondria are transported to axons and support local energy production to maintain energy-demanding neuronal processes including axon branching, growth, and regeneration. Additionally, local protein synthesis is required for structural and functional changes in axons, with nuclear-encoded mitochondrial mRNAs having been found localized in axons. However, it remains unclear whether these mRNAs are locally translated and whether the potential translated mitochondrial proteins are involved in the regulation of mitochondrial functions in axons. Here, we aim to further understand the purpose of such compartmentalization by focusing on the role of mitochondrial initiation factor 3 (mtIF3), whose nuclear-encoded transcripts have been shown to be present in axonal growth cones.
RESULTS: We demonstrate that brain-derived neurotrophic factor (BDNF) induces local translation of mtIF3 mRNA in axonal growth cones. Subsequently, mtIF3 protein is translocated into axonal mitochondria and promotes mitochondrial translation as assessed by our newly developed bimolecular fluorescence complementation sensor for the assembly of mitochondrial ribosomes. We further show that BDNF-induced axonal growth requires mtIF3-dependent mitochondrial translation in distal axons.
CONCLUSION: We describe a previously unknown function of mitochondrial initiation factor 3 (mtIF3) in axonal protein synthesis and development. These findings provide insight into the way neurons adaptively control mitochondrial physiology and axonal development via local mtIF3 translation.

Keywords:  Axon development; Bimolecular fluorescence complementation; Local translation; Mitochondria; Mitochondrial translation

DOI:  https://doi.org/10.1186/s12915-021-01215-w
Nat Neurosci. 2022 Jan;25(1): 2

Mitochondrial dysfunction and Parkinson's disease.

Rebecca Wright.

DOI: https://doi.org/10.1038/s41593-021-00989-0
Int J Biol Sci. 2022 ;18(1): 409-425

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53.

Pengbo Wang, Boquan Wu, Shilong You, Saien Lu, Shengjun Xiong, Yuanming Zou, Pengyu Jia, Xiaofan Guo, Ying Zhang, Liu Cao, Yingxian Sun, Naijin Zhang.

  DNA polymerase gamma (PolG) is the major polymerase of mitochondrial DNA (mtDNA) and essential for stabilizing mitochondrial function. Vascular calcification (VC) is common senescence related degenerative pathology phenomenon in the end-stage of multiple chronic diseases. Mitochondrial dysfunction was often observed in calcified vessels, but the function and mechanism of PolG in the calcification process was still unknown. The present study found PolGD257A/D257A mice presented more severe calcification of aortas than wild type (WT) mice with vitamin D3 (Vit D3) treatment, and this phenomenon was also confirmed in vitro. Mechanistically, PolG could enhance the recruitment and interaction of p53 in calcification condition to recover mitochondrial function and eventually to resist calcification. Meanwhile, we found the mutant PolG (D257A) failed to achieve the same rescue effects, suggesting the 3'-5' exonuclease activity guarantee the enhanced interaction of p53 and PolG in response to calcification stimulation. Thus, we believed that it was PolG, not mutant PolG, could maintain mitochondrial function and attenuate calcification in vitro and in vivo. And PolG could be a novel potential therapeutic target against calcification, providing a novel insight to clinical treatment.

Keywords:  DNA polymerase gamma; calcification; mitochondria; p53

DOI:  https://doi.org/10.7150/ijbs.65030
Front Chem. 2021 ;9 775226

Targeting Mitochondrial Metabolism and RNA Polymerase POLRMT to Overcome Multidrug Resistance in Cancer.

Hui-Jing Yu, Guan-Li Xiao, Yu-Ying Zhao, Xin-Xin Wang, Rongfeng Lan.

  Clinically, the prognosis of tumor therapy is fundamentally affected by multidrug resistance (MDR), which is primarily a result of enhanced drug efflux mediated by channels in the membrane that reduce drug accumulation in tumor cells. How to restore the sensitivity of tumor cells to chemotherapy is an ongoing and pressing clinical issue. There is a prevailing view that tumor cells turn to glycolysis for energy supply due to hypoxia. However, studies have shown that mitochondria also play crucial roles, such as providing intermediates for biosynthesis through the tricarboxylic acid (TCA) cycle and a plenty of ATP to fuel cells through the complete breakdown of organic matter by oxidative phosphorylation (OXPHOS). High OXPHOS have been found in some tumors, particularly in cancer stem cells (CSCs), which possess increased mitochondria mass and may be depends on OXPHOS for energy supply. Therefore, they are sensitive to inhibitors of mitochondrial metabolism. In view of this, we should consider mitochondrial metabolism when developing drugs to overcome MDR, where mitochondrial RNA polymerase (POLRMT) would be the focus, as it is responsible for mitochondrial gene expression. Inhibition of POLRMT could disrupt mitochondrial metabolism at its source, causing an energy crisis and ultimately eradicating tumor cells. In addition, it may restore the energy supply of MDR cells to glycolysis and re-sensitize them to conventional chemotherapy. Furthermore, we discuss the rationale and strategies for designing new therapeutic molecules for MDR cancers by targeting POLRMT.

Keywords:  OxPhos; POLRMT; RNA polymerase; cancer stem cell; multidrug resisitance

DOI:  https://doi.org/10.3389/fchem.2021.775226
Mol Brain. 2022 Jan 06. 15(1): 9

Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA.

Hiroko Sugawara, Miki Bundo, Takaoki Kasahara, Yutaka Nakachi, Junko Ueda, Mie Kubota-Sakashita, Kazuya Iwamoto, Tadafumi Kato.

  Bipolar disorder (BD) is a severe psychiatric disorder characterized by repeated conflicting manic and depressive states. In addition to genetic factors, complex gene-environment interactions, which alter the epigenetic status in the brain, contribute to the etiology and pathophysiology of BD. Here, we performed a promoter-wide DNA methylation analysis of neurons and nonneurons derived from the frontal cortices of mutant Polg1 transgenic (n = 6) and wild-type mice (n = 6). The mutant mice expressed a proofreading-deficient mitochondrial DNA (mtDNA) polymerase under the neuron-specific CamK2a promoter and showed BD-like behavioral abnormalities, such as activity changes and altered circadian rhythms. We identified a total of 469 differentially methylated regions (DMRs), consisting of 267 neuronal and 202 nonneuronal DMRs. Gene ontology analysis of DMR-associated genes showed that cell cycle-, cell division-, and inhibition of peptide activity-related genes were enriched in neurons, whereas synapse- and GABA-related genes were enriched in nonneurons. Among the DMR-associated genes, Trim2 and Lrpprc showed an inverse relationship between DNA methylation and gene expression status. In addition, we observed that mutant Polg1 transgenic mice shared several features of DNA methylation changes in postmortem brains of patients with BD, such as dominant hypomethylation changes in neurons, which include hypomethylation of the molecular motor gene and altered DNA methylation of synapse-related genes in nonneurons. Taken together, the DMRs identified in this study will contribute to understanding the pathophysiology of BD from an epigenetic perspective.

Keywords:  Bipolar disorder; DNA methylation; Mitochondrial dysfunction; Neuron; Nonneuron; Schizophrenia

DOI:  https://doi.org/10.1186/s13041-021-00894-4
Hum Hered. 2022 Jan 06.

Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy.

Yujuan Qi, Zhenhua Wu, Yaobang Bai, Yan Jiao, Peijun Li.

OBJECTIVES: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study is to analysis the association between mitochondrial tRNA (mt-tRNA) mutations and DCM.
MATERIAL AND METHODS: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP and ROS were analyzed.
RESULTS: 7 possible pathogenic mutations: MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G and MT-TT 15927G>A were identified in DCM group but absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs, and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number, whereas a markedly increased in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM.
CONCLUSIONS: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which shaded novel insight into the pathophysiology of DCM that was manifestated by mitochondrial dysfunction.

DOI: https://doi.org/10.1159/000521615
Int J Neuropsychopharmacol. 2022 Jan 03. pii: pyab095. [Epub ahead of print]

Mitochondrial DNA copy number is associated with treatment response and cognitive function in euthymic bipolar patients receiving valproate.

Cheng-Chen Chang, Po See Chen, Jhih-Rong Lin, Yi-An Chen, Chin-San Liu, Ta-Tsung Lin, Hui Hua Chang.

   BACKGROUND: Bipolar disorder (BD) is associated with cognitive impairment and mitochondrial dysfunction. However, the associations among mitochondrial DNA copy number (MCN), treatment response, and cognitive function remain elusive in BD patients.
METHODS: Sixty euthymic BD patients receiving valproate (VPA) and 66 healthy controls from the community were recruited. The indices of metabolic syndrome (MetS) were measured. Quantitative polymerase chain reaction analysis of blood leukocytes was used to measure the MCN. Cognitive function was measured by calculating perseverative errors and completed categories on the Wisconsin Card Sorting Test (WCST). The VPA treatment response was measured using the Alda scale.
RESULTS: BD patients had significantly higher MCN, triglyceride and C-reactive protein (CRP) levels, waist circumference, and worse performance on the WCST than the controls. Regression models showed that BD itself and the VPA concentration exerted significant effects on increased MCN levels. Moreover, the receiver operating characteristic curve analysis showed that an MCN of 2.05 distinguished VPA responders from nonresponders with an area under the curve of 0.705 and a sensitivity and specificity of 0.529 and 0.816, respectively. An MCN level greater than 2.05 was associated with a 5.39 higher odds of being a VPA responder (p= 0.006). BD patients who were stratified into the high MCN group had a higher VPA response rate, better WCST performance, lower CRP level, and less MetS.
CONCLUSIONS: The study suggests a link between the peripheral MCN and cognitive function in BD patients. As an inflammatory status, MetS might modulate this association.

Keywords:  bipolar disorder; cognitive function; metabolic syndrome; mitochondrial DNA copy number; valproate

DOI:  https://doi.org/10.1093/ijnp/pyab095