Oncometabolic role of mitochondrial sirtuins in glioma patients

PLOS ONE RESEARCH ARTICLE Oncometabolic role of mitochondrial sirtuins in glioma patients Maria Fazal Ul Haq1☯, Muhammad Zahid Hussain2, Ishrat Mahjabeen ID1☯*, Zertashia Akram1, Nadia Saeed1, Rabia Shafique1, Sumaira Fida Abbasi1, Mahmood Akhtar Kayani ID1 1 Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan, 2 Department of Rheumatology, Military hospital, Rawalpindi, Pakistan a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Haq MFU, Hussain MZ, Mahjabeen I, Akram Z, Saeed N, Shafique R, et al. (2023) Oncometabolic role of mitochondrial sirtuins in glioma patients. PLoS ONE 18(2): e0281840. https://doi.org/10.1371/journal.pone.0281840 Editor: Erika Di Zazzo, University of Molise Department of Medicine and Health Sciences “Vincenzo Tiberio”: Universita degli Studi del Molise Dipartimento di Medicina e Scienze della Salute Vincenzo Tiberio, ITALY Received: September 19, 2022 Accepted: January 31, 2023 Published: February 21, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0281840 Copyright: © 2023 Haq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript. ☯ These authors contributed equally to this work. * Abstract Mitochondrial sirtuins have diverse role specifically in aging, metabolism and cancer. In cancer, these sirtuins play dichotomous role as tumor suppressor and promoter. Previous studies have reported the involvement of sirtuins in different cancers. However, till now no study has been published with respect to mitochondrial sirtuins and glioma risks. Present study was purposed to figure out the expression level of mitochondrial sirtuins (SIRT3, SIRT4, SIRT5) and related genes (GDH, OGG1-2α, SOD1, SOD2, HIF1α and PARP1) in 153 glioma tissue samples and 200 brain tissue samples from epilepsy patients (taken as controls). To understand the role of selected situins in gliomagenesis, DNA damage was measured using the comet assay and oncometabolic role (oxidative stress level, ATP level and NAD level) was measured using the ELISA and quantitative PCR. Results analysis showed significant down-regulation of SIRT4 (p = 0.0337), SIRT5 (p<0.0001), GDH (p = 0.0305), OGG1-2α (p = 0.0001), SOD1 (p<0.0001) and SOD2 (p<0.0001) in glioma patients compared to controls. In case of SIRT3 (p = 0.0322), HIF1α (p = 0.0385) and PARP1 (p = 0.0203), significant up-regulation was observed. ROC curve analysis and cox regression analysis showed the good diagnostic and prognostic value of mitochondrial sirtuins in glioma patients. Oncometabolic rate assessment analysis showed significant increased ATP level (p<0.0001), NAD+ level [(NMNAT1 (p<0.0001), NMNAT3 (p<0.0001) and NAMPT (p<0.04)] and glutathione level (p<0.0001) in glioma patients compared to controls. Significant increased level of damage ((p<0.04) and decrease level of antioxidant enzymes include superoxide dismutase (SOD, p<0.0001), catalase (CAT, p<0.0001) and glutathione peroxidase (GPx, p<0.0001) was observed in patients compared to controls. Present study data suggest that variation in expression pattern of mitochondrial sirtuins and increased metabolic rate may have diagnostic and prognostic significance in glioma patients. Introduction Gliomas are among the most common type of CNS tumors and epidemiological studies have stated that gliomas are 40% of all CNS and brain tumors [1–4]. On the basis of molecular and PLOS ONE | https://doi.org/10.1371/journal.pone.0281840 February 21, 2023 1 / 24 PLOS ONE Funding: The author(s) received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Mitochondrial sirtuins and Glioma histopathological features, gliomas are classified into low grade gliomas (LGG) and high-grade gliomas (HGG). Risk factors of gliomas are environmental factors, epigenetic and genetic factors. Genetic factors include the genetic variations/polymorphisms in metabolic/repairing pathway genes, apoptosis, and necroptosis [5, 6]. Most of the data published on genetic factors is present on mutations in nuclear region while the involvement of mitochondrial genes in glioma is lacking [5]. Mitochondria is very important organelle for cellular processes like energy production by oxidative phosphorylation, apoptosis, cell cycle proliferation etc. Reactive oxygen species (ROS) are highly produced in mitochondria and when this ROS levels are high, they can be harmful to cell, damages proteins, lipids and DNA hence results in mitochondrial dysfunction and carcinogenesis [7]. Brain and CNS consume a high percentage of energy and neurons are more susceptible to oxidative damage and ROS and has been found to be involved in neurodegenerative diseases [8]. Rate of mutation has been reported higher in mitochondrial DNA as it lacks the protective histone proteins and inefficient DNA repair mechanisms [9]. Furthermore, in glioma patients, another mitochondrial mechanism actively involved is necroptosis, which controlled the deep dyregulation of apoptosis signals. This dyregulation of programmed cell death ultimately results in gliomagenesis and tumor aggressiveness [6, 10]. Mitochondrial variations have also been found to link with carcinogenesis by deregulation of number of important mechanisms [11]. Among these pathways, variations of mitochondrial sirtuins genes have been suggested. Sirtuins, a family of orthologues of yeast silent information regulator 3 (SIRT3), 4 (SIRT4) and 5 (SIRT5) are important tumor suppressor genes located in mitochondria [12, 13]. Among these proteins, SIRT3 is considered as guardian of mitochondria due to its role in deacetylation and metabolism [14]. Its deacetylation results in activation of proteins essential to control the oxidative stress and DNA damage/repair [15]. SIRT4, second mitochondrial sirtuin, has been reported to control the generation of reactive oxygen species (ROS) in mitochondria. Furthermore, it is actively involved in an NAD+ dependent protein ADP-ribosly transferase activity [16]. SIRT5, third mitochondrial sirtuin, has been reported as a mitochondrial NAD+ dependent deacetylase and involved in ROS detoxification and TCA cycle [17]. Previous studies have reported the involvement of mitochondrial sirtuins in regulation of important mitochondrial pathways such as ROS detoxification, repair, apoptosis/necroptosis and energy metabolism [18–20]. Mitochondrial sirtuins show (...truncated)