bims-nadaut Biomed News
on NAD and autophagy
Issue of 2023–07–30
eleven papers selected by
Niall Wilson, Newcastle University
  1. Rev1 deficiency induces a metabolic shift in MEFs that can be manipulated by the NAD+ precursor nicotinamide riboside.
  2. Promotion of mitochondrial fragmentation suppresses the formation of mitochondrial spherical compartmentation in PINK1B9Drosophila melanogaster.
  3. Ionizing radiation triggers mitophagy to enhance DNA damage in cancer cells.
  4. Mitochondrial dysfunction: roles in skeletal muscle atrophy.
  5. Cisplatin triggers oxidative stress, apoptosis and pro-inflammatory responses by inhibiting the SIRT1-mediated Nrf2 pathway in chondrocytes.
  6. Methadone Potentiates the Cytotoxicity of Temozolomide by Impairing Calcium Homeostasis and Dysregulation of PARP in Glioblastoma Cells.
  7. NAD+, Axonal Maintenance, and Neurological Disease.
  8. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.
  9. SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.
  10. Manoalide Induces Intrinsic Apoptosis by Oxidative Stress and Mitochondrial Dysfunction in Human Osteosarcoma Cells.
  11. SIRT5 alleviates liver ischemia/reperfusion injury by regulating mitochondrial succinylation and oxidative stress.
  1. Heliyon. 2023 Jun;9(6): e17392
    Rev1 deficiency induces a metabolic shift in MEFs that can be manipulated by the NAD+ precursor nicotinamide riboside.
    Sharath Anugula, Zhiquan Li, Yuan Li, Alexander Hendriksen, Peter Bjarn Christensen, Lin Wang, Jonathan M Monk, Niels de Wind, Vilhelm A Bohr, Claus Desler, Robert K Naviaux, Lene Juel Rasmussen.
      Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD + supplementation. Autophagy decreases in Rev1-/- mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD+ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1-/- MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.
    Keywords:  Autophagy; Healthspan; Mitochondria; NAD+; Nicotinamide riboside; Replication stress; Rev1
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e17392
  2. Biochem Biophys Res Commun. 2023 Jul 14. pii: S0006-291X(23)00879-3. [Epub ahead of print]676 48-57
    Promotion of mitochondrial fragmentation suppresses the formation of mitochondrial spherical compartmentation in PINK1B9Drosophila melanogaster.
    Yi Li, Wen Chen, Danling Wang.
      Mitochondria undergo structural changes reflective of functional statuses. Ultrastructural characterizing of mitochondria is valuable for understanding mitochondrial dysfunction in various pathological conditions. PINK1, a Parkinson's disease (PD) associated gene, plays key roles in maintaining mitochondrial function and integrity. In Drosophila melanogaster, deficiency of PINK1 results in PD-like pathologies due to mitochondrial abnormalities. Here, we report the existence of a new type of mitochondrial-membrane deformity, mitochondrial spherical compartmentation (MSC), caused by PINK1 deficiency in Drosophila. The MSC is a three-dimensional spheroid-like mitochondrial membrane structure encompassing nonselective contents. Upregulation of dDrp1, downregulation of dMarf, and upregulation of dArgK1-A-all resulting in mitochondrial fragmentation-were able to suppress the formation of MSC. Furthermore, arginine kinase, only when localizing to the vicinity of mitochondria, induced mitochondrial fragmentation and reversed the MSC phenotype. In summary, this study demonstrates that loss of dPINK1 leads to the formation of mitochondrial-membrane deformity MSC, which responds to mitochondrial dynamics. In addition, our data suggest a new perspective of how phosphagen energy-buffer system might regulate mitochondrial dynamics.
    Keywords:  Arginine kinase; Mitochondrial spherical compartmentation; Mitochondrial-membrane deformity; PINK1; Transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.bbrc.2023.07.022
  3. Cell Death Discov. 2023 Jul 28. 9(1): 267
    Ionizing radiation triggers mitophagy to enhance DNA damage in cancer cells.
    Yanxian Ren, Pengfei Yang, Chenghao Li, Wen-An Wang, Tianyi Zhang, Jin Li, Haining Li, Chunlu Dong, Wenbo Meng, Heng Zhou.
      Radiotherapy is an important cancer treatment strategy that causes DNA damage in tumor cells either directly or indirectly. Autophagy is a physiological process linked to DNA damage. Mitophagy is a form of autophagy, which specifically targets and eliminates impaired mitochondria, thereby upholding cellular homeostasis. However, the connection between DNA damage and mitophagy has yet to be fully elucidated. We found that mitophagy, as an upstream signal, increases ionizing radiation-induced DNA damage by downregulating or overexpressing key mitophagy proteins Parkin and BNIP3. Enhancing the basal level of mitophagy in conjunction with X-ray irradiation can potentially diminish cell cycle arrest at the G2/M phase, substantially elevate the accumulation of γ-H2AX, 53BP1, and PARP1 foci within the nucleus, augment DNA damage, and facilitate the demise of tumor cells. Consequently, this approach prolongs the survival of melanoma-bearing mice. The findings of this study are anticipated to offer a therapeutic approach for enhancing the therapeutic effectiveness of radiotherapy.
    DOI:  https://doi.org/10.1038/s41420-023-01573-0
  4. J Transl Med. 2023 07 26. 21(1): 503
    Mitochondrial dysfunction: roles in skeletal muscle atrophy.
    Xin Chen, Yanan Ji, Ruiqi Liu, Xucheng Zhu, Kexin Wang, Xiaoming Yang, Boya Liu, Zihui Gao, Yan Huang, Yuntian Shen, Hua Liu, Hualin Sun.
      Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.
    Keywords:  Antioxidants; Mitochondrial dysfunction; Muscle atrophy; Therapy
    DOI:  https://doi.org/10.1186/s12967-023-04369-z
  5. Environ Toxicol. 2023 Jul 27.
    Cisplatin triggers oxidative stress, apoptosis and pro-inflammatory responses by inhibiting the SIRT1-mediated Nrf2 pathway in chondrocytes.
    Pei-Ling Hsieh, Kun-Ling Tsai, Wan-Ching Chou, Chin-Hsien Wu, I-Ming Jou, Yuan-Kun Tu, Ching-Hou Ma.
      Although the height of the proliferating layer that was suppressed in the growth plate has been recognized as an adverse effect of cisplatin in pediatric cancer survivors, the detailed pathological mechanism has not been elucidated. Sirtuin-1 (SIRT1) has been reported as an essential modulator of cartilage homeostasis, but its role in cisplatin-induced damage of chondrocytes remains unclear. In this study, we examined how cisplatin affected the expression of SIRT1 and cell viability. Next, we showed downregulation of SIRT1 after cisplatin treatment resulted in suppression of Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), leading to inhibition of Nrf2 nuclear translocation and subsequently decreased Heme oxygenase-1(HO-1) and NAD(P)H Quinone Dehydrogenase 1(NQO-1) expression. Blockage of the SIRT1/ PGC-1α axis not only increased oxidative stress with lower antioxidant SOD and GSH, but also contributed to mitochondrial dysfunction evidenced by the collapse of membrane potential and repression of mitochondrial DNA copy number and ATP. We also found that Cisplatin up-regulated the p38 phosphorylation, pro-inflammatory events and matrix metalloproteinases (MMPs) in chondrocytes through the SIRT1-modulated antioxidant manner. Collectively, our findings suggest that preservation of SIRT1 in chondrocytes may be a potential target to ameliorate growth plate dysfunction for cisplatin-receiving pediatric cancer survivors.
    Keywords:  SIRT1; chondrocytes; cisplatin; inflammation; oxidative stress
    DOI:  https://doi.org/10.1002/tox.23885
  6. Cancers (Basel). 2023 Jul 11. pii: 3567. [Epub ahead of print]15(14):
    Methadone Potentiates the Cytotoxicity of Temozolomide by Impairing Calcium Homeostasis and Dysregulation of PARP in Glioblastoma Cells.
    Ondrej Honc, Jiri Novotny.
      Methadone is commonly used as an alternative to morphine in patients with pain associated with glioblastoma and other cancers. Although concomitant administration of methadone and cytostatics is relatively common, the effect of methadone on the efficacy of cytostatic drugs has not been well studied until recently. Moreover, the mechanism behind the effect of methadone on temozolomide efficacy has not been investigated in previous studies, or this effect has been automatically attributed to opioid receptors. Our findings indicate that methadone potentiates the effect of temozolomide on rat C6 glioblastoma cells and on human U251 and T98G glioblastoma cells and increases cell mortality by approximately 50% via a mechanism of action independent of opioid receptors. Our data suggest that methadone acts by affecting mitochondrial potential, the level of oxidative stress, intracellular Ca2+ concentration and possibly intracellular ATP levels. Significant effects were also observed on DNA integrity and on cleavage and expression of the DNA repair protein PARP-1. None of these effects were attributed to the activation of opioid receptors and Toll-like receptor 4. Our results provide an alternative perspective on the mechanism of action of methadone in combination with temozolomide and a potential strategy for the treatment of glioblastoma cell resistance to temozolomide.
    Keywords:  apoptosis; glioblastoma; methadone; oxidative stress; temozolomide
    DOI:  https://doi.org/10.3390/cancers15143567
  7. Antioxid Redox Signal. 2023 Jul 28.
    NAD+, Axonal Maintenance, and Neurological Disease.
    Athanasios Alexandris, Vassilis E Koliatsos.
       SIGNIFICANCE: The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance . Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks NAD+ metabolism for axonal self-destruction, the complex roles of NAD+ in axonal viability and disease have become research priority.
    RECENT ADVANCES: The discoveries of the protective WldS and of SARM1 activation as the main instructive signal for WD have shed new light on the regulatory role of NAD+ in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD+ hydrolase and sensor of NAD+ metabolism. The discovery of regulators of NMNAT2 proteostasis in axons, the allosteric regulation of SARM1 by NAD+ andNMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD+ metabolism.
    CRITICAL ISSUES: Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD+ metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic.
    FUTURE DIRECTIONS: There is need for clarification of the distinct roles of NAD+ metabolism in axonal maintenance as contrasted to WD. There is also need to better understand the role of NAD+ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of CNS neurodegenerative diseases.
    DOI:  https://doi.org/10.1089/ars.2023.0350
  8. Front Mol Neurosci. 2023 ;16 1224964
    Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.
    Ying Yuan, Yuan Tian, Hui Jiang, Luo-Yang Cai, Jie Song, Rui Peng, Xiao-Ming Zhang.
      Cerebral ischemia-reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia-reperfusion injury.
    Keywords:  PGC-1α; apoptosis; cerebral ischemia–reperfusion injury; mitochondria; mitochondrial biogenesis
    DOI:  https://doi.org/10.3389/fnmol.2023.1224964
  9. J Transl Med. 2023 07 22. 21(1): 494
    SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.
    Yanmin Chang, Cailin Wang, Jiahui Zhu, Siyi Zheng, Shangqi Sun, Yanqing Wu, Xingjun Jiang, Lulu Li, Rong Ma, Gang Li.
       BACKGROUND: Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown.
    METHODS: Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1-GRP75-IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs.
    RESULTS: Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1-GRP75-IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions.
    CONCLUSIONS: In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.
    Keywords:  Diabetes-associated cognitive dysfunction; Honokiol; Mitochondria-associated ER membranes; Sirtuin3; VDAC1–GRP75–IP3R complex
    DOI:  https://doi.org/10.1186/s12967-023-04246-9
  10. Antioxidants (Basel). 2023 Jul 14. pii: 1422. [Epub ahead of print]12(7):
    Manoalide Induces Intrinsic Apoptosis by Oxidative Stress and Mitochondrial Dysfunction in Human Osteosarcoma Cells.
    Zhi-Kang Yao, Yen-Hsuan Jean, Sung-Chun Lin, Yu-Cheng Lai, Nan-Fu Chen, Chung-Chih Tseng, Wu-Fu Chen, Zhi-Hong Wen, Hsiao-Mei Kuo.
      Osteosarcoma (OS) is the most common primary malignant bone tumor that produces immature osteoid. Metastatic OS has a poor prognosis with a death rate of >70%. Manoalide is a natural sesterterpenoid isolated from marine sponges. It is a phospholipase A2 inhibitor with anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to investigate the mechanism and effect of manoalide on OS cells. Our experiments showed that manoalide induced cytotoxicity in 143B and MG63 cells (human osteosarcoma). Treatment with manoalide at concentrations of 10, 20, and 40 µM for 24 and 48 h reduced MG63 cell viability to 45.13-4.40% (p < 0.01). Meanwhile, manoalide caused reactive oxygen species (ROS) overproduction and disrupted antioxidant proteins, activating the apoptotic proteins caspase-9/-3 and PARP (Poly (ADP-ribose) polymerase). Excessive levels of ROS in the mitochondria affected oxidative phosphorylation, ATP generation, and membrane potential (ΔΨm). Additionally, manoalide down-regulated mitochondrial fusion protein and up-regulated mitochondrial fission protein, resulting in mitochondrial fragmentation and impaired function. On the contrary, a pre-treatment with n-acetyl-l-cysteine ameliorated manoalide-induced apoptosis, ROS, and antioxidant proteins in OS cells. Overall, our findings show that manoalide induces oxidative stress, mitochondrial dysfunction, and apoptosis, causing the cell death of OS cells, showing potential as an innovative alternative treatment in human OS.
    Keywords:  antioxidants; apoptosis; inflammation; mitochondria; mitochondrial respiratory chain; osteosarcoma; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox12071422
  11. Antioxid Redox Signal. 2023 Jul 29.
    SIRT5 alleviates liver ischemia/reperfusion injury by regulating mitochondrial succinylation and oxidative stress.
    Jihong Yao, Yan Hu, Xinyao Tian, Yan Zhao, Zhecheng Wang, Musen Lin, Ruimin Sun, Yue Wang, Zhanyu Wang, Guiru Li, Shusen Zheng.
       AIMS: Mitochondrial dysfunction is the primary mechanism of liver ischemia/reperfusion (I/R) injury. The lysine desuccinylase sirtuin 5 (SIRT5) is a global regulator of the mitochondrial succinylome and has pivotal roles in mitochondrial metabolism and function; however, its hepatoprotective capacity in liver I/R remains unclear. Here, we established liver I/R model in SIRT5-silenced and SIRT5-overexpressed mice to examine the role and precise mechanisms of SIRT5 in liver I/R injury.
    RESULTS: Succinylation was strongly enriched in liver mitochondria during I/R, and inhibiting mitochondrial succinylation significantly attenuated liver I/R injury. Importantly, the levels of the desuccinylase SIRT5 were notably decreased in liver transplant patients, as well as in mice subjected to I/R and in AML12 cells exposed to H/R. Furthermore, SIRT5 significantly ameliorated liver I/R-induced oxidative injury, apoptosis and inflammation by regulating mitochondrial oxidative stress and function. Intriguingly, the hepatoprotective effect of SIRT5 was mediated by PRDX3. Mechanistically, SIRT5 specifically desuccinylated PRDX3 at the K84 site, which enabled PRDX3 to alleviate mitochondrial oxidative stress during liver I/R.
    INNOVATION: This study denoted the new effect and mechanism of SIRT5 in regulating mitochondrial oxidative stress through lysine desuccinylation, thus preventing liver I/R injury.
    CONCLUSION: Our findings demonstrate for the first time that SIRT5 is a key mediator of liver I/R that regulates mitochondrial oxidative stress through the desuccinylation of PRDX3, which provides a novel strategy to prevent liver I/R injury.
    Keywords:  PRDX3 mitochondrial oxidative stress.; SIRT5; liver ischemia/reperfusion; succinylation
    DOI:  https://doi.org/10.1089/ars.2022.0137
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