bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022–04–24
sixteen papers selected by
Flavia Söllner, Ludwig-Maximilians University
  1. The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
  2. Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.
  3. The Entanglement between Mitochondrial DNA and Tumor Metastasis.
  4. Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy.
  5. Organization and expression of the mammalian mitochondrial genome.
  6. Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNA Gly (MT-TG) Variant.
  7. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
  8. Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
  9. Mitochondrial Genetics Reinforces Multiple Layers of Interaction in Alzheimer's Disease.
  10. Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy.
  11. Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
  12. NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia.
  13. Radiological clues to a mitochondrial problem.
  14. Long-Term Progression and Rapid Decline in Hearing Loss in Patients with a Point Mutation at Nucleotide 3243 of the Mitochondrial DNA.
  15. The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions.
  16. Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.
  1. Nat Cell Biol. 2022 Apr 21.
    The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
    Yi Liu, Zhe Chen, Zong-Heng Wang, Katherine M Delaney, Juanjie Tang, Mehdi Pirooznia, Duck-Yeon Lee, Ilker Tunc, Yuesheng Li, Hong Xu.
      Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial RNA polymerase (PolrMT) has 3'-to-5' exoribonuclease activity, which is indispensable for PolrMT to synthesize short RNA oligonucleotides and prime DNA replication in vitro. An exoribonuclease-deficient mutant, PolrMTE423P, partially restores mitochondrial transcription but fails to support mtDNA replication when expressed in PolrMT-mutant flies, indicating that the exoribonuclease activity is necessary for mtDNA replication. In addition, overexpression of PolrMTE423P in adult flies leads to severe neuromuscular defects and a marked increase in mtDNA transcript errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription.
    DOI:  https://doi.org/10.1038/s41556-022-00887-y
  2. Life (Basel). 2022 Apr 09. pii: 562. [Epub ahead of print]12(4):
    Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.
    Matthew J Young, Ravi Sachidanandam, Dale B Hales, Laurent Brard, Kathy Robinson, Md Mostafijur Rahman, Pabitra Khadka, Kathleen Groesch, Carolyn K J Young.
      Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.
    Keywords:  endometrial cancer; heteroplasmy; homoplasmy; human mitochondrial DNA (mtDNA) maintenance; mtDNA content; mtDNA copy number; mtDNA topoisomers; next-generation sequencing (NGS); somatic mutations; uterine cancer
    DOI:  https://doi.org/10.3390/life12040562
  3. Cancers (Basel). 2022 Apr 07. pii: 1862. [Epub ahead of print]14(8):
    The Entanglement between Mitochondrial DNA and Tumor Metastasis.
    Qiwei Wu, Hsiang-I Tsai, Haitao Zhu, Dongqing Wang.
      Mitochondrial DNA, the genetic material in mitochondria, encodes essential oxidative phosphorylation proteins and plays an important role in mitochondrial respiration and energy transfer. With the development of genome sequencing and the emergence of novel in vivo modeling techniques, the role of mtDNA in cancer biology is gaining more attention. Abnormalities of mtDNA result in not only mitochondrial dysfunction of the the cancer cells and malignant behaviors, but regulation of the tumor microenvironment, which becomes more aggressive. Here, we review the recent progress in the regulation of cancer metastasis using mtDNA and the underlying mechanisms, which may identify opportunities for finding novel cancer prediction and therapeutic targets.
    Keywords:  immune escape; metastasis; mitochondrial DNA; tumor progression
    DOI:  https://doi.org/10.3390/cancers14081862
  4. Pharmaceutics. 2022 Mar 31. pii: 757. [Epub ahead of print]14(4):
    Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy.
    Rúben Faria, Milan Paul, Swati Biswas, Eric Vivès, Prisca Boisguérin, Ângela Sousa, Diana Costa.
      Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine-dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation.
    Keywords:  PEI-based complexes; cell-penetrating peptides; mitochondria targeting; mitochondrial DNA diseases; mitochondrial gene therapy; nanodelivery systems
    DOI:  https://doi.org/10.3390/pharmaceutics14040757
  5. Nat Rev Genet. 2022 Apr 22.
    Organization and expression of the mammalian mitochondrial genome.
    Oliver Rackham, Aleksandra Filipovska.
      The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.
    DOI:  https://doi.org/10.1038/s41576-022-00480-x
  6. Front Neurol. 2022 ;13 795060
    Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNA Gly (MT-TG) Variant.
    Haiyan Yang, Victor Wei Zhang, Liang Ai, Siyi Gan, Liwen Wu.
       Background: Mitochondrial diseases are clinically heterogeneous, can occur at any age, and can manifest with a wide range of clinical symptoms. They can involve any organ or tissue, characteristically involve multiple systems, typically affecting organs that are highly dependent on aerobic metabolism, and making a definitive molecular diagnosis of a mitochondrial disorder is challenging.
    Methods: Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that were performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis.
    Results: In this study, we reported a childhood-onset mitochondrial phenotype in a 13-year-old patient. Analysis of the next-generation sequencing data of the nuclear genome and the full-length sequencing of the mitochondrial genome revealed the rare m.10000G>A variant in MT-TG that was present at variable heteroplasmy levels across tissue types: 32.7% in the blood, 56.15% in urinary epithelial cells, and 27.3% in oral mucosa cells. No variant was found in the peripheral blood of his mother and sister. No pathogenic mutation of nDNA was found.
    Conclusion: Our results added evidence that the de novo m.10000G>A variation in the highly conserved sequence of MT-TG appears to suggest a childhood-onset mitochondrial phenotype in the 13-year-old patient, thus broadening the genotypic interpretation of mitochondrial DNA-related diseases.
    Keywords:  children; m.10000G>A; mitochondrial disease; mitochondrial tRNA Gly; neurology—clinical
    DOI:  https://doi.org/10.3389/fneur.2022.795060
  7. Mov Disord. 2022 Apr 23.
    Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
    Kobi Wasner, Semra Smajic, Jenny Ghelfi, Sylvie Delcambre, Cesar A Prada-Medina, Evelyn Knappe, Giuseppe Arena, Patrycja Mulica, Gideon Agyeah, Aleksandar Rakovic, Ibrahim Boussaad, Katja Badanjak, Jochen Ohnmacht, Jean-Jacques Gérardy, Masashi Takanashi, Joanne Trinh, Michel Mittelbronn, Nobutaka Hattori, Christine Klein, Paul Antony, Philip Seibler, Malte Spielmann, Sandro L Pereira, Anne Grünewald.
       BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons.
    OBJECTIVES: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level.
    METHODS: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures.
    RESULTS: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS.
    CONCLUSIONS: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Parkinson's disease; induced pluripotent stem cells; mitochondrial DNA; parkin; neuroinflammation
    DOI:  https://doi.org/10.1002/mds.29025
  8. Front Cell Dev Biol. 2022 ;10 874596
    Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
    Irene H Flønes, Charalampos Tzoulis.
      Parkinson's disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of α -synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.
    Keywords:  Parkinson's disease; mitochondria; mitochondrial complex I; neurodegeneration; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fcell.2022.874596
  9. Biomedicines. 2022 Apr 12. pii: 880. [Epub ahead of print]10(4):
    Mitochondrial Genetics Reinforces Multiple Layers of Interaction in Alzheimer's Disease.
    Giovanna Chaves Cavalcante, Leonardo Miranda Brito, Ana Paula Schaan, Ândrea Ribeiro-Dos-Santos, Gilderlanio Santana de Araújo, On Behalf Of Alzheimer's Disease Neuroimaging Initiative.
      Nuclear DNA has been the main source of genome-wide loci association in neurodegenerative diseases, only partially accounting for the heritability of Alzheimer's Disease (AD). In this context, mitochondrial DNA (mtDNA) is gaining more attention. Here, we investigated mitochondrial genes and genetic variants that may influence mild cognitive impairment and AD, through an integrative analysis including differential gene expression and mitochondrial genome-wide epistasis. We assessed the expression of mitochondrial genes in different brain tissues from two public RNA-Seq databases (GEO and GTEx). Then, we analyzed mtDNA from the ADNI Cohort and investigated epistasis regarding mitochondrial variants and levels of Aβ1-42, TAU, and Phosphorylated TAU (PTAU) from cognitively healthy controls, and both mild cognitive impairment (MCI) and AD cases. We identified multiple differentially expressed mitochondrial genes in the comparisons between cognitively healthy individuals and AD patients. We also found increased protein levels in MCI and AD patients when compared to healthy controls, as well as novel candidate networks of mtDNA epistasis, which included variants in all mitochondrially-encoded oxidative phosphorylation complexes, 12S rRNA and MT-DLOOP. Our results highlight layers of potential interactions involving mitochondrial genetics and suggest specific molecular alterations as potential biomarkers for AD.
    Keywords:  Alzheimer’s Disease; PTAU; TAU; cerebrospinal fluid; differential expression; epistasis; mtDNA
    DOI:  https://doi.org/10.3390/biomedicines10040880
  10. Nat Biomed Eng. 2022 Apr 18.
    Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy.
    Xiao-Yan Fan, Lei Guo, Lei-Ning Chen, Shen Yin, Jiarong Wen, Sen Li, Jun-Yu Ma, Tao Jing, Man-Xi Jiang, Xiao-Hong Sun, Meilan Chen, Feng Wang, Zhen-Bo Wang, Chang-Fa Zhang, Xing-Hua Wang, Zhao-Jia Ge, Chun Hu, Lizhang Zeng, Wei Shen, Qing-Yuan Sun, Xiang-Hong Ou, Shi-Ming Luo.
      Mitochondrial replacement therapy (MRT) has been used to prevent maternal transmission of disease-causing mutations in mitochondrial DNA (mtDNA). However, because MRT requires nuclear transfer, it carries the risk of mtDNA carryover and hence of the reversion of mtDNA to pathogenic levels owing to selective replication and genetic drift. Here we show in HeLa cells, mouse embryos and human embryos that mtDNA heteroplasmy can be reduced by pre-labelling the mitochondrial outer membrane of a donor zygote via microinjection with an mRNA coding for a transmembrane peptide fused to an autophagy receptor, to induce the degradation of the labelled mitochondria via forced mitophagy. Forced mitophagy reduced mtDNA carryover in newly reconstructed embryos after MRT, and had negligible effects on the growth curve, reproduction, exercise capacity and other behavioural characteristics of the offspring mice. The induction of forced mitophagy to degrade undesired donor mtDNA may increase the clinical feasibility of MRT and could be extended to other nuclear transfer techniques.
    DOI:  https://doi.org/10.1038/s41551-022-00881-7
  11. Semin Cell Dev Biol. 2022 Apr 18. pii: S1084-9521(22)00122-7. [Epub ahead of print]
    Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
    Helin Hocaoglu, Matthew Sieber.
      Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration. Mitochondrial metabolism dynamically changes as tissues transition through distinct phases of development. These organelles support the energetic and biosynthetic demands of developing cells and function as key structures that coordinate the nutrient status of the organism with developmental progression. This review will examine the mechanisms that link mitochondria to developmental processes. We will also examine the process of mitochondrial respiratory quiescence (MRQ), a novel mechanism for regulating cellular metabolism through the biochemical and physiological remodeling of mitochondria. Lastly, we will examine MRQ as a system to discover the mechanisms that drive mitochondrial remodeling during development.
    Keywords:  Cancer; Drosophila; Metabolism; Mitochondria; Oocytes; Quiescence; Reprogramming; Stem cells
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.040
  12. Antioxidants (Basel). 2022 Apr 11. pii: 760. [Epub ahead of print]11(4):
    NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia.
    Heather L Vellers, Hye-Youn Cho, Wesley Gladwell, Kevin Gerrish, Janine H Santos, Gaston Ofman, Laura Miller-DeGraff, T Beth Mahler, Steven R Kleeberger.
      Approximately 1 in 10 newborns are born preterm and require supplemental oxygen (O2) in an extrauterine environment following birth. Supplemental O2 can induce oxidative stress that can impair mitochondrial function, resulting in lung injury and increased risk in early life pulmonary diseases. The nuclear factor-erythroid 2 related factor 2 (NRF2) protects the cells from oxidative stress by regulating the expression of genes containing antioxidant response elements and many mitochondrial-associated genes. In this study, we compared Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) mice to define the role of NRF2 in lung mitochondrial genomic features in late embryonic development in mice (embryonic days, E13.5 and E18.5) versus birth (postnatal day 0, PND0). We also determined whether NRF2 protects lung mitochondrial genome parameters in postnatal mice exposed to a 72 h hyperoxia environment. We found Nrf2-/- embryonic lungs were characterized by decreases in mtDNA copies from E13.5 to E18.5. Interestingly, Nrf2-/- heteroplasmy frequency was significantly higher than Nrf2+/+ at E18.5, though this effect reversed at PND0. In postnatal mice exposed to hyperoxia, we identified three- to four-fold increases in mitochondria-encoded mitochondrial genes, which regulate oxidative phosphorylation. Overall, our findings demonstrate a potentially critical role of NRF2 in mediating long-term effects of hyperoxia on mitochondrial function.
    Keywords:  DNA lesions; NRF2; heteroplasmy; mitochondrial function; mitochondrial sequencing; mtDNA copy number
    DOI:  https://doi.org/10.3390/antiox11040760
  13. Pract Neurol. 2022 Apr 21. pii: practneurol-2022-003356. [Epub ahead of print]
    Radiological clues to a mitochondrial problem.
    Jonathan Hawken, Paul Tobin, Mo Hu, Marc Edwards, Srinivasa Abburu, William Owen Pickrell.
      
    Keywords:  mitochondrial disorders; neuroradiology
    DOI:  https://doi.org/10.1136/practneurol-2022-003356
  14. Life (Basel). 2022 Apr 06. pii: 543. [Epub ahead of print]12(4):
    Long-Term Progression and Rapid Decline in Hearing Loss in Patients with a Point Mutation at Nucleotide 3243 of the Mitochondrial DNA.
    Aki Sakata, Akinori Kashio, Hajime Koyama, Tsukasa Uranaka, Shinichi Iwasaki, Chisato Fujimoto, Makoto Kinoshita, Tatsuya Yamasoba.
      Patients with m.3243A>G mutation of mitochondrial DNA develop bilaterally symmetric sensorineural hearing loss. However, it is unclear how fast their hearing loss progresses over time, and whether they experience rapid progression of hearing loss. In the present study, we conducted a long-term hearing evaluation in patients with MELAS or MIDD who harbored the m.3243A>G mutation of mitochondrial DNA. A retrospective chart review was performed on 15 patients with this mutation who underwent pure-tone audiometry at least once a year for more than two years. The mean follow-up period was 12.8 years. The mean progression rate of hearing loss was 5.5 dB per year. Hearing loss progressed rapidly to be profoundly deaf in seven patients during the observation period. Heteroplasmy and age-corrected heteroplasmy levels correlated with the age of onset of hearing loss. These results indicate that patients with m.3243A>G mutation have a gradual progression of hearing loss in the early stages and rapid decline in hearing to be profoundly deaf in approximately half of the patients. Although it is possible to predict the age of onset of hearing loss from heteroplasmy and age-corrected heteroplasmy levels, it is difficult to predict whether and when the rapid hearing loss will occur.
    Keywords:  diabetes; disequilibrium; dizziness; hearing loss; mitochondrial gene mutations
    DOI:  https://doi.org/10.3390/life12040543
  15. Mol Biol Rep. 2022 Apr 20.
    The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions.
    Mounica Soma, Satya Kumar Lalam.
      Biosynthesis and regulation of nicotinamide adenine dinucleotide (NAD+) has recently gained a lot of attention. A systemic decline in NAD+ across many tissues is associated with all the hallmarks of aging. NAD+ can affect a variety of cellular processes, including metabolic pathways, DNA repair, and immune cell activity, both directly and indirectly. These cellular processes play a vital role in maintaining homeostasis, but as people get older, their tissue and cellular NAD+ levels decrease, and this drop in NAD+ levels has been connected to a number of age-related disorders. By restoring NAD+ levels, several of these age-related disorders can be delayed or even reversed. Some of the new studies conducted in mice and humans have targeted the NAD+ metabolism with NAD+ intermediates. Of these, nicotinamide mononucleotide (NMN) has been shown to offer great therapeutic potential with promising results in age-related chronic conditions such as diabetes, cardiovascular issues, cognitive impairment, and many others. Further, human interventions are required to study the long-term effects of supplementing NMN with varying doses. The paper focuses on reviewing the importance of NAD+ on human aging and survival, biosynthesis of NAD+ from its precursors, key clinical trial findings, and the role of NMN on various health conditions.
    Keywords:  Age-related disorders; Anti-aging; NAD+; NMN; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Therapeutic potential
    DOI:  https://doi.org/10.1007/s11033-022-07459-1
  16. Am J Respir Cell Mol Biol. 2022 Apr 20.
    Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.
    Brydie R Huckestein, John F Alcorn.
      
    DOI:  https://doi.org/10.1165/rcmb.2022-0096ED
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