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Parchwani D, Singh R, Patel D. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance. World J Methodol 2025; 15:102709. [DOI: 10.5662/wjm.v15.i3.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 03/06/2025] Open
Abstract
The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
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Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Digisha Patel
- Department of Physiology, Shantabaa Medical College and General Hospital Amreli, Amreli 365601, Gujarāt, India
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2
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Peeri NC, Teer JK, Thompson ZJ, Nabors LB, Brooks M, Sologon CM, Williams SL, Egan KM. Glioma grade and mortality in relation to sequence variation in the mitochondrial genome. Cancer Genet 2025; 294-295:171-180. [PMID: 40382795 DOI: 10.1016/j.cancergen.2025.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/06/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
PURPOSE Glioma arises from glial cells and comprises ∼80 % of malignant adult brain tumors. The polymorphic mitochondrial genome plays a key role in maintaining redox homeostasis and generation of reactive oxygen species (ROS). ROS have a well-established role in glial tumors. We investigated associations between germline mtDNA variants and haplogroups with glioma grade and glioblastoma (GBM) survival. METHODS We conducted germline mtDNA sequencing for 388 patients (300 Caucasians, 88 African Americans [AA]) with incident glioma (105 non-GBM, 283 GBM). Across all patients we identified 1431 homoplasmic mtDNA variants, including 692 variants observed only in Caucasians, 474 only in AAs, and 265 in both groups. We estimated Odds Ratios (OR) and 95 % Confidence Intervals (CI) for mtDNA common variants, haplogroups, and gene variant burden in relation to glioma grade and tertiles of survival in GBM patients. Bonferroni and Benjamini-Hochberg correction were applied for multiple comparisons. RESULTS No mtDNA haplogroup was associated with glioma grade or patient survival in GBM. Common variants m.3010G>A, m.195T>C, and m.16189T>C were linked to lower-grade glioma risk. For GBM survival, m.1719G>A, m.14766T>C, m.16129G>A, and m.204T>C were associated with a poorer prognosis while variant m.73A>G was associated with an improved prognosis. A higher variant burden in MT-ND1 and MT-ND5 was associated with a better prognosis. No results remained statistically significant after correction. CONCLUSION This is the first comprehensive study of germline mtDNA sequence variation in relation to glioma grade at diagnosis and gliobastoma patient survival. Results warrant further study in larger populations and investigation of biologic mechanisms linking mtDNA polymorphism to these endpoints.
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Affiliation(s)
- Noah C Peeri
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, NY, NY, 10017, USA.
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA
| | - Zachary J Thompson
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA
| | - L Burt Nabors
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Marisa Brooks
- Department of Neurology, University of Miami, Miami, FL, 33136, USA
| | | | - Sion L Williams
- Department of Neurology, University of Miami, Miami, FL, 33136, USA
| | - Kathleen M Egan
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA
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3
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Wernhart S, Rassaf T. Exercise, cancer, and the cardiovascular system: clinical effects and mechanistic insights. Basic Res Cardiol 2025; 120:35-55. [PMID: 38353711 PMCID: PMC11790717 DOI: 10.1007/s00395-024-01034-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/21/2024] [Accepted: 01/21/2024] [Indexed: 03/05/2024]
Abstract
Cardiovascular diseases and cancer are the leading causes of death in the Western world and share common risk factors. Reduced cardiorespiratory fitness (CRF) is a major determinant of cardiovascular morbidity and cancer survival. In this review we discuss cancer- induced disturbances of parenchymal, cellular, and mitochondrial function, which limit CRF and may be antagonized and attenuated through exercise training. We show the impact of CRF on cancer survival and its attenuating effects on cardiotoxicity of cancer-related treatment. Tailored exercise programs are not yet available for each tumor entity as several trials were performed in heterogeneous populations without adequate cardiopulmonary exercise testing (CPET) prior to exercise prescription and with a wide variation of exercise modalities. There is emerging evidence that exercise may be a crucial pillar in cancer treatment and a tool to mitigate cardiotoxic treatment effects. We discuss modalities of aerobic exercise and resistance training and their potential to improve CRF in cancer patients and provide an example of a periodization model for exercise training in cancer.
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Affiliation(s)
- Simon Wernhart
- West German Heart- and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | - Tienush Rassaf
- West German Heart- and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany
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Murillo Carrasco AG, Chammas R, Furuya TK. Mitochondrial DNA alterations in precision oncology: Emerging roles in diagnostics and therapeutics. Clinics (Sao Paulo) 2025; 80:100570. [PMID: 39884256 PMCID: PMC11830334 DOI: 10.1016/j.clinsp.2024.100570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 12/25/2024] [Indexed: 02/01/2025] Open
Abstract
Mitochondria are dynamic organelles essential for vital cellular functions, including ATP production, apoptosis regulation, and calcium homeostasis. Increasing research has highlighted the significance of mitochondrial DNA (mtDNA) content and alterations in the development and progression of various diseases, including cancer. The high mutation rate and vulnerability of mtDNA to damage make these alterations valuable biomarkers for cancer diagnosis, monitoring disease progression, detecting metastasis, and predicting treatment resistance across different tumor types. This review explores the emerging roles of mtDNA alterations in precision oncology, emphasizing their potential in theranostics. The authors explore the mechanisms by which mtDNA mutations contribute to tumorigenesis and therapy resistance, the impact of heteroplasmy in cancer biology, and the integration of mtDNA-based diagnostics with current therapeutic strategies. Additionally, the authors highlight the experimental tools and models currently used to investigate mtDNA alterations in cancer, including advanced sequencing technologies and animal models.
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Affiliation(s)
- Alexis Germán Murillo Carrasco
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil; Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil.
| | - Roger Chammas
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil; Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil.
| | - Tatiane Katsue Furuya
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil; Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil.
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5
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Chen F, Xue Y, Zhang W, Zhou H, Zhou Z, Chen T, YinWang E, Li H, Ye Z, Gao J, Wang S. The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy. Cancer Metastasis Rev 2024; 43:1419-1443. [PMID: 39307891 PMCID: PMC11554835 DOI: 10.1007/s10555-024-10211-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/08/2024] [Indexed: 11/05/2024]
Abstract
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.
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Affiliation(s)
- Fanglu Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yucheng Xue
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenkan Zhang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hao Zhou
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhiyi Zhou
- The First People's Hospital of Yuhang District, Hangzhou, Zhejiang, China
| | - Tao Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Eloy YinWang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hengyuan Li
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhaoming Ye
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Shengdong Wang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
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O’Halloran K, Hakimjavadi H, Bootwalla M, Ostrow D, Kerawala R, Cotter JA, Yellapantula V, Kaneva K, Wadhwani NR, Treece A, Foreman NK, Alexandrescu S, Vega JV, Biegel JA, Gai X. Pediatric Chordoma: A Tale of Two Genomes. Mol Cancer Res 2024; 22:721-729. [PMID: 38691518 PMCID: PMC11296893 DOI: 10.1158/1541-7786.mcr-23-0741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 02/23/2024] [Accepted: 04/26/2024] [Indexed: 05/03/2024]
Abstract
Little is known about the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with the rest of the mtDNA genes (P = 0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (P < 0.0001). Furthermore, a progressive increase in heteroplasmy of nonsynonymous mtDNA mutations was noted in patients with multiple tumors (P = 0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that in the adult cohort (P = 0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (P < 5.9e-07 and P < 0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations seem important for chordoma genesis, especially in pediatric chordoma.
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Affiliation(s)
- Katrina O’Halloran
- Department of Hematology, Oncology and Blood & Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Hesamedin Hakimjavadi
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Moiz Bootwalla
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Dejerianne Ostrow
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Rhea Kerawala
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Jennifer A. Cotter
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Venkata Yellapantula
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Nitin R Wadhwani
- Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
| | - Amy Treece
- Division of Pathology, Children’s Hospital Colorado, Denver, CO, USA
| | - Nicholas K. Foreman
- Division of Hematology, Oncology, Children’s Hospital Colorado, Denver, CO, USA
| | | | | | - Jaclyn A. Biegel
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Xiaowu Gai
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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7
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An J, Nam CH, Kim R, Lee Y, Won H, Park S, Lee WH, Park H, Yoon CJ, An Y, Kim JH, Jun JK, Bae JM, Shin EC, Kim B, Cha YJ, Kwon HW, Oh JW, Park JY, Kim MJ, Ju YS. Mitochondrial DNA mosaicism in normal human somatic cells. Nat Genet 2024; 56:1665-1677. [PMID: 39039280 PMCID: PMC11319206 DOI: 10.1038/s41588-024-01838-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 06/21/2024] [Indexed: 07/24/2024]
Abstract
Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.
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Affiliation(s)
- Jisong An
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Chang Hyun Nam
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Ryul Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Inocras Inc, Daejeon, Republic of Korea
| | - Yunah Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Hyein Won
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Seongyeol Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Inocras Inc, Daejeon, Republic of Korea
| | - Won Hee Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Hansol Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Inocras Inc, Daejeon, Republic of Korea
| | - Christopher J Yoon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Yohan An
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Jie-Hyun Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong Kwan Jun
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Bun Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - Yong Jun Cha
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - Hyun Woo Kwon
- Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ji Won Oh
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jee Yoon Park
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Jung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Seok Ju
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
- Inocras Inc, Daejeon, Republic of Korea.
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Guo Y, Yan S, Zhang W. Translatomics to explore dynamic differences in immunocytes in the tumor microenvironment. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 34:102037. [PMID: 37808922 PMCID: PMC10551571 DOI: 10.1016/j.omtn.2023.102037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Protein is an essential component of all living organisms and is primarily responsible for life activities; furthermore, its synthesis depends on a highly complex and accurate translation system. For proteins, the regulation at the translation level exceeds the sum of that during transcription, mRNA degradation, and protein degradation. Therefore, it is necessary to study regulation at the translation level. Imbalance in the translation process may change the cellular landscape, which not only leads to the occurrence, maintenance, progression, invasion, and metastasis of cancer but also affects the function of immune cells and changes the tumor microenvironment. Detailed analysis of transcriptional and protein atlases is needed to better understand how gene translation occurs. However, a more rigorous direct correlation between mRNA and protein levels is needed, which somewhat limits further studies. Translatomics is a technique for capturing and sequencing ribosome-related mRNAs that can effectively identify translation changes caused by ribosome stagnation and local translation abnormalities during cancer occurrence to further understand the changes in the translation landscape of cancer cells themselves and immune cells in the tumor microenvironment, which can provide new strategies and directions for tumor treatment.
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Affiliation(s)
- Yilin Guo
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Shiqi Yan
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
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Wang SF, Tseng LM, Lee HC. Role of mitochondrial alterations in human cancer progression and cancer immunity. J Biomed Sci 2023; 30:61. [PMID: 37525297 PMCID: PMC10392014 DOI: 10.1186/s12929-023-00956-w] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/11/2023] [Indexed: 08/02/2023] Open
Abstract
Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as energy production, cellular metabolism, apoptosis, and calcium and redox homeostasis. Although the "Warburg effect," in which cancer cells prefer aerobic glycolysis even under normal oxygen circumstances, was proposed a century ago, how mitochondrial dysfunction contributes to cancer progression is still unclear. This review discusses recent progress in the alterations of mitochondrial DNA (mtDNA) and mitochondrial dynamics in cancer malignant progression. Moreover, we integrate the possible regulatory mechanism of mitochondrial dysfunction-mediated mitochondrial retrograde signaling pathways, including mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mitochondrial unfolded protein response and integrated stress response) in cancer progression and provide the possible therapeutic targets. Furthermore, we discuss recent findings on the role of mitochondria in the immune regulatory function of immune cells and reveal the impact of the tumor microenvironment and metabolism remodeling on cancer immunity. Targeting the mitochondria and metabolism might improve cancer immunotherapy. These findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients and provide precise and personalized medicine against cancer.
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Affiliation(s)
- Sheng-Fan Wang
- Department of Pharmacy, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 112, Taiwan
- School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei, 112, Taiwan
| | - Ling-Ming Tseng
- Division of General Surgery, Department of Surgery, Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 112, Taiwan
- Department of Surgery, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei, 112, Taiwan
| | - Hsin-Chen Lee
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei, 112, Taiwan.
- Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei, 112, Taiwan.
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Ding H, Zhao Y, Jiang Z, Zhou D, Zhu R. Analysis of Mitochondrial Transfer RNA Mutations in Breast Cancer. Balkan J Med Genet 2023; 25:15-22. [PMID: 37265965 PMCID: PMC10230833 DOI: 10.2478/bjmg-2022-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
Damage of mitochondrial functions caused by mitochondrial DNA (mtDNA) pathogenic mutations had long been proposed to be involved in breast carcinogenesis. However, the detailed pathological mechanism remained deeply undetermined. In this case-control study, we screened the frequencies of mitochondrial tRNA (mt-tRNA) mutations in 80 breast cancer tissues and matched normal adjacent tissues. PCR and Sanger sequence revealed five possible pathogenic mutations: tRNAVal G1606A, tRNAIle A4300G, tRNASer(UCN) T7505C, tRNAGlu A14693G and tRNAThr G15927A. We noticed that these mutations resided at extremely conserved positions of tRNAs and would affect tRNAs transcription or modifications. Furthermore, functional analysis suggested that patients with these mt-tRNA mutations exhibited much lower levels of mtDNA copy number and ATP, as compared with controls (p<0.05). Therefore, it can be speculated that these mutations may impair mitochondrial protein synthesis and oxidative phosphorylation (OXPHOS) complexes, which caused mitochondrial dysfunctions that were involved in the breast carcinogenesis. Taken together, our data indicated that mutations in mt-tRNA were the important contributors to breast cancer, and mutational analyses of mt-tRNA genes were critical for prevention of breast cancer.
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Affiliation(s)
- H.J. Ding
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Y.P. Zhao
- Department of Pharmacy, Shaoxing Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Shaoxing, China
| | - Z.C. Jiang
- Department of Pathology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - D.T. Zhou
- Department of Pharmacy, The First People’s Hospital of Kaili, Kaili, China
| | - R. Zhu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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11
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Ren D, Mo Y, Yang M, Wang D, Wang Y, Yan Q, Guo C, Xiong W, Wang F, Zeng Z. Emerging roles of tRNA in cancer. Cancer Lett 2023; 563:216170. [PMID: 37054943 DOI: 10.1016/j.canlet.2023.216170] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/01/2023] [Accepted: 04/05/2023] [Indexed: 04/15/2023]
Abstract
Transfer RNAs (tRNAs) play pivotal roles in the transmission of genetic information, and abnormality of tRNAs directly leads to translation disorders and causes diseases, including cancer. The complex modifications enable tRNA to execute its delicate biological function. Alteration of appropriate modifications may affect the stability of tRNA, impair its ability to carry amino acids, and disrupt the pairing between anticodons and codons. Studies confirmed that dysregulation of tRNA modifications plays an important role in carcinogenesis. Furthermore, when the stability of tRNA is impaired, tRNAs are cleaved into small tRNA fragments (tRFs) by specific RNases. Though tRFs have been found to play vital regulatory roles in tumorigenesis, its formation process is far from clear. Understanding improper tRNA modifications and abnormal formation of tRFs in cancer is conducive to uncovering the role of metabolic process of tRNA under pathological conditions, which may open up new avenues for cancer prevention and treatment.
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Affiliation(s)
- Daixi Ren
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.
| | - Yongzhen Mo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Mei Yang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Dan Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Yumin Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qijia Yan
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Fuyan Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.
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12
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Giannikou K, Martin KR, Abdel-Azim AG, Pamir KJ, Hougard TR, Bagwe S, Tang Y, MacKeigan JP, Kwiatkowski DJ, Henske EP, Lam HC. Spectrum of germline and somatic mitochondrial DNA variants in Tuberous Sclerosis Complex. Front Genet 2023; 13:917993. [PMID: 36793390 PMCID: PMC9923026 DOI: 10.3389/fgene.2022.917993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/23/2022] [Indexed: 02/03/2023] Open
Abstract
Tuberous Sclerosis Complex (TSC) is caused by loss of function variants in either TSC1 or TSC2 and is characterized by broad phenotypic heterogeneity. Currently, there is limited knowledge regarding the role of the mitochondrial genome (mtDNA) in TSC pathogenesis. In this study, we aimed to determine the prevalence and spectrum of germline and somatic mtDNA variants in TSC and identify potential disease modifiers. Analysis of mtDNA amplicon massively parallel sequencing (aMPS) data, off-target mtDNA from whole-exome sequencing (WES), and/or qPCR, revealed mtDNA alterations in 270 diverse tissues (139 TSC-associated tumors and 131 normal tissue samples) from 199 patients and six healthy individuals. Correlation of clinical features to mtDNA variants and haplogroup analysis was done in 102 buccal swabs (age: 20-71 years). No correlation was found between clinical features and either mtDNA variants or haplogroups. No pathogenic variants were identified in the buccal swab samples. Using in silico analysis, we identified three predicted pathogenic variants in tumor samples: MT-ND4 (m.11742G>A, p. Cys328Tyr, VAF: 43%, kidney angiomyolipoma), MT-CYB (m.14775T>C, p. Leu10Pro, VAF: 43%, LAM abdominal tumor) and MT-CYB (m.15555C>T, p. Pro270Leu, VAF: 7%, renal cell carcinoma). Large deletions of the mitochondrial genome were not detected. Analysis of tumors from 23 patients with corresponding normal tissue did not reveal any recurrent tumor-associated somatic variants. The mtDNA/gDNA ratio between tumors and corresponding normal tissue was also unchanged. Overall, our findings demonstrate that the mitochondrial genome is highly stable across tissues and within TSC-associated tumors.
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Affiliation(s)
- Krinio Giannikou
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Katie R. Martin
- Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - Ahmad G. Abdel-Azim
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Kaila J. Pamir
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Thomas R. Hougard
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Shefali Bagwe
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Yan Tang
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Jeffrey P. MacKeigan
- Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - David J. Kwiatkowski
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Elizabeth P. Henske
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Hilaire C. Lam
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
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13
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Welch DR, Foster C, Rigoutsos I. Roles of mitochondrial genetics in cancer metastasis. Trends Cancer 2022; 8:1002-1018. [PMID: 35915015 PMCID: PMC9884503 DOI: 10.1016/j.trecan.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/27/2022] [Accepted: 07/07/2022] [Indexed: 01/31/2023]
Abstract
The contributions of mitochondria to cancer have been recognized for decades. However, the focus on the metabolic role of mitochondria and the diminutive size of the mitochondrial genome compared to the nuclear genome have hindered discovery of the roles of mitochondrial genetics in cancer. This review summarizes recent data demonstrating the contributions of mitochondrial DNA (mtDNA) copy-number variants (CNVs), somatic mutations, and germline polymorphisms to cancer initiation, progression, and metastasis. The goal is to summarize accumulating data to establish a framework for exploring the contributions of mtDNA to neoplasia and metastasis.
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Affiliation(s)
- Danny R Welch
- Department of Cancer Biology, The Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; Department of Internal Medicine (Hematology/Oncology), The Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; Department of Molecular and Integrative Physiology, The Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; Department of Pathology, The Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; The University of Kansas Comprehensive Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
| | - Christian Foster
- Department of Cancer Biology, The Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Isidore Rigoutsos
- Computational Medicine Center, Sidney Kimmel College of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite M81, Philadelphia, PA 19107, USA
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14
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Kim M, Mahmood M, Reznik E, Gammage PA. Mitochondrial DNA is a major source of driver mutations in cancer. Trends Cancer 2022; 8:1046-1059. [PMID: 36041967 PMCID: PMC9671861 DOI: 10.1016/j.trecan.2022.08.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022]
Abstract
Mitochondrial DNA (mtDNA) mutations are among the most common genetic events in all tumors and directly impact metabolic homeostasis. Despite the central role mitochondria play in energy metabolism and cellular physiology, the role of mutations in the mitochondrial genomes of tumors has been contentious. Until recently, genomic and functional studies of mtDNA variants were impeded by a lack of adequate tumor mtDNA sequencing data and available methods for mitochondrial genome engineering. These barriers and a conceptual fog surrounding the functional impact of mtDNA mutations in tumors have begun to lift, revealing a path to understanding the role of this essential metabolic genome in cancer initiation and progression. Here we discuss the history, recent developments, and challenges that remain for mitochondrial oncogenetics as the impact of a major new class of cancer-associated mutations is unveiled.
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Affiliation(s)
- Minsoo Kim
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Ed Reznik
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Payam A Gammage
- CRUK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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15
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Chiaratti MR, Chinnery PF. Modulating mitochondrial DNA mutations: factors shaping heteroplasmy in the germ line and somatic cells. Pharmacol Res 2022; 185:106466. [PMID: 36174964 DOI: 10.1016/j.phrs.2022.106466] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/30/2022]
Abstract
Until recently it was thought that most humans only harbor one type of mitochondrial DNA (mtDNA), however, deep sequencing and single-cell analysis has shown the converse - that mixed populations of mtDNA (heteroplasmy) are the norm. This is important because heteroplasmy levels can change dramatically during transmission in the female germ line, leading to high levels causing severe mitochondrial diseases. There is also emerging evidence that low level mtDNA mutations contribute to common late onset diseases such as neurodegenerative disorders and cardiometabolic diseases because the inherited mutation levels can change within developing organs and non-dividing cells over time. Initial predictions suggested that the segregation of mtDNA heteroplasmy was largely stochastic, with an equal tendency for levels to increase or decrease. However, transgenic animal work and single-cell analysis have shown this not to be the case during germ-line transmission and in somatic tissues during life. Mutation levels in specific mtDNA regions can increase or decrease in different contexts and the underlying molecular mechanisms are starting to be unraveled. In this review we provide a synthesis of recent literature on the mechanisms of selection for and against mtDNA variants. We identify the most pertinent gaps in our understanding and suggest ways these could be addressed using state of the art techniques.
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Affiliation(s)
- Marcos R Chiaratti
- Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, Brazil.
| | - Patrick F Chinnery
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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16
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Keraite I, Becker P, Canevazzi D, Frias-López C, Dabad M, Tonda-Hernandez R, Paramonov I, Ingham MJ, Brun-Heath I, Leno J, Abulí A, Garcia-Arumí E, Heath SC, Gut M, Gut IG. A method for multiplexed full-length single-molecule sequencing of the human mitochondrial genome. Nat Commun 2022; 13:5902. [PMID: 36202811 PMCID: PMC9537161 DOI: 10.1038/s41467-022-33530-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 09/21/2022] [Indexed: 11/09/2022] Open
Abstract
Methods to reconstruct the mitochondrial DNA (mtDNA) sequence using short-read sequencing come with an inherent bias due to amplification and mapping. They can fail to determine the phase of variants, to capture multiple deletions and to cover the mitochondrial genome evenly. Here we describe a method to target, multiplex and sequence at high coverage full-length human mitochondrial genomes as native single-molecules, utilizing the RNA-guided DNA endonuclease Cas9. Combining Cas9 induced breaks, that define the mtDNA beginning and end of the sequencing reads, as barcodes, we achieve high demultiplexing specificity and delineation of the full-length of the mtDNA, regardless of the structural variant pattern. The long-read sequencing data is analysed with a pipeline where our custom-developed software, baldur, efficiently detects single nucleotide heteroplasmy to below 1%, physically determines phase and can accurately disentangle complex deletions. Our workflow is a tool for studying mtDNA variation and will accelerate mitochondrial research.
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Affiliation(s)
- Ieva Keraite
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Philipp Becker
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Qiagen, Hilden, Germany
| | - Davide Canevazzi
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Cristina Frias-López
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Marc Dabad
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Raúl Tonda-Hernandez
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Ida Paramonov
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Matthew John Ingham
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Isabelle Brun-Heath
- Institute for Research in Biomedicine (IRB Barcelona) - The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Joint IRB-BSC Program in Computational Biology, Barcelona, Spain
| | - Jordi Leno
- Department of Clinical and Molecular Genetics and Rare Disease, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Medicine Genetics Group, VHIR, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Anna Abulí
- Department of Clinical and Molecular Genetics and Rare Disease, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Medicine Genetics Group, VHIR, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Elena Garcia-Arumí
- Department of Clinical and Molecular Genetics and Rare Disease, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Research Group on Neuromuscular and Mitochondrial Disorders, VHIR, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Simon Charles Heath
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Marta Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
- Universitat Pompeu Fabra, Barcelona, Spain.
| | - Ivo Glynne Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
- Universitat Pompeu Fabra, Barcelona, Spain.
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17
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Agnoletto C, Volinia S. Mitochondria dysfunction in circulating tumor cells. Front Oncol 2022; 12:947479. [PMID: 35992829 PMCID: PMC9386562 DOI: 10.3389/fonc.2022.947479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/11/2022] [Indexed: 12/16/2022] Open
Abstract
Circulating tumor cells (CTCs) represent a subset of heterogeneous cells, which, once released from a tumor site, have the potential to give rise to metastasis in secondary sites. Recent research focused on the attempt to detect and characterize these rare cells in the circulation, and advancements in defining their molecular profile have been reported in diverse tumor species, with potential implications for clinical applications. Of note, metabolic alterations, involving mitochondria, have been implicated in the metastatic process, as key determinants in the transition of tumor cells to a mesenchymal or stemness-like phenotype, in drug resistance, and in induction of apoptosis. This review aimed to briefly analyse the most recent knowledge relative to mitochondria dysfunction in CTCs, and to envision implications of altered mitochondria in CTCs for a potential utility in clinics.
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Affiliation(s)
- Chiara Agnoletto
- Rete Oncologica Veneta (ROV), Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Stefano Volinia
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Biological and Chemical Research Centre (CNBCh UW), University of Warsaw, Warsaw, Poland
- Center of New Technologies, University of Warsaw, Warsaw, Poland
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18
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Chen K, Lu P, Beeraka NM, Sukocheva OA, Madhunapantula SV, Liu J, Sinelnikov MY, Nikolenko VN, Bulygin KV, Mikhaleva LM, Reshetov IV, Gu Y, Zhang J, Cao Y, Somasundaram SG, Kirkland CE, Fan R, Aliev G. Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers. Semin Cancer Biol 2022; 83:556-569. [PMID: 33035656 DOI: 10.1016/j.semcancer.2020.09.012] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 09/28/2020] [Accepted: 09/28/2020] [Indexed: 02/08/2023]
Abstract
Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.
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Affiliation(s)
- Kuo Chen
- The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Street, Zhengzhou, 450052, China; Institue for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia
| | - Pengwei Lu
- The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Street, Zhengzhou, 450052, China
| | - Narasimha M Beeraka
- Center of Excellence in Regenerative Medicine and Molecular Biology (CEMR), Department of Biochemistry, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, Karnataka, India
| | - Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - SubbaRao V Madhunapantula
- Center of Excellence in Regenerative Medicine and Molecular Biology (CEMR), Department of Biochemistry, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, Karnataka, India
| | - Junqi Liu
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Str., Zhengzhou, 450052, China
| | - Mikhail Y Sinelnikov
- Institue for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia
| | - Vladimir N Nikolenko
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia; Department of Normal and Topographic Anatomy, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University (MSU), 31-5 Lomonosovsky Prospect, 117192, Moscow, Russia
| | - Kirill V Bulygin
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia; Department of Normal and Topographic Anatomy, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University (MSU), 31-5 Lomonosovsky Prospect, 117192, Moscow, Russia
| | - Liudmila M Mikhaleva
- Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russian Federation
| | - Igor V Reshetov
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia
| | - Yuanting Gu
- The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Street, Zhengzhou, 450052, China
| | - Jin Zhang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia
| | - Yu Cao
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia
| | - Siva G Somasundaram
- Department of Biological Sciences, Salem University, 223 West Main Street Salem, WV, 26426, USA
| | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, 223 West Main Street Salem, WV, 26426, USA
| | - Ruitai Fan
- The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Street, Zhengzhou, 450052, China.
| | - Gjumrakch Aliev
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Street, Moscow, 119991, Russia; Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russian Federation; Institute of Physiologically Active Compounds of Russian Academy of Sciences, Severny pr. 1, Chernogolovka, Moscow Region, 142432, Russia; GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA
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19
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Wagner A, Kosnacova H, Chovanec M, Jurkovicova D. Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential. Int J Mol Sci 2022; 23:ijms23147897. [PMID: 35887244 PMCID: PMC9321253 DOI: 10.3390/ijms23147897] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 02/01/2023] Open
Abstract
Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increasing evidence suggests that mtDNA mutations, mtDNA epigenetics and miRNA regulations dynamically modify signalling pathways in an altered microenvironment, resulting in cancer initiation and progression and aberrant therapy response. In this review, we discuss mitochondria as organelles importantly involved in tumorigenesis and anti-cancer therapy response. Tumour treatment unresponsiveness still represents a serious drawback in current drug therapies. Therefore, studying aspects related to genetic and epigenetic control of mitochondria can open a new field for understanding cancer therapy response. The urgency of finding new therapeutic regimens with better treatment outcomes underlines the targeting of mitochondria as a suitable candidate with new therapeutic potential. Understanding the role of mitochondria and their regulation in cancer development, progression and treatment is essential for the development of new safe and effective mitochondria-based therapeutic regimens.
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Affiliation(s)
- Alexandra Wagner
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Department of Simulation and Virtual Medical Education, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Helena Kosnacova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Department of Simulation and Virtual Medical Education, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Miroslav Chovanec
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
| | - Dana Jurkovicova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Correspondence:
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20
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Smith ALM, Whitehall JC, Greaves LC. Mitochondrial
DNA
mutations in aging and cancer. Mol Oncol 2022; 16:3276-3294. [PMID: 35842901 PMCID: PMC9490137 DOI: 10.1002/1878-0261.13291] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/18/2022] [Accepted: 07/15/2022] [Indexed: 11/09/2022] Open
Abstract
Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age‐related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.
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Affiliation(s)
- Anna LM Smith
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
| | - Julia C Whitehall
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
| | - Laura C Greaves
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
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21
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El-Gammal Z, Nasr MA, Elmehrath AO, Salah RA, Saad SM, El-Badri N. Regulation of mitochondrial temperature in health and disease. Pflugers Arch 2022; 474:1043-1051. [PMID: 35780250 PMCID: PMC9492600 DOI: 10.1007/s00424-022-02719-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/15/2022] [Indexed: 11/30/2022]
Abstract
Mitochondrial temperature is produced by various metabolic processes inside the mitochondria, particularly oxidative phosphorylation. It was recently reported that mitochondria could normally operate at high temperatures that can reach 50℃. The aim of this review is to identify mitochondrial temperature differences between normal cells and cancer cells. Herein, we discussed the different types of mitochondrial thermosensors and their advantages and disadvantages. We reviewed the studies assessing the mitochondrial temperature in cancer cells and normal cells. We shed the light on the factors involved in maintaining the mitochondrial temperature of normal cells compared to cancer cells.
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Affiliation(s)
- Zaynab El-Gammal
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt.,Egypt Center for Research and Regenerative Medicine, Cairo, Egypt
| | - Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt
| | - Ahmed O Elmehrath
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt.,Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Radwa A Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt
| | - Shams M Saad
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, Egypt.
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22
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Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation. Mitochondrion 2022; 65:176-183. [PMID: 35787470 DOI: 10.1016/j.mito.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/11/2022] [Accepted: 06/19/2022] [Indexed: 11/21/2022]
Abstract
The mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.
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23
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Ji X, Guo W, Gu X, Guo S, Zhou K, Su L, Yuan Q, Liu Y, Guo X, Huang Q, Xing J. Mutational profiling of mtDNA control region reveals tumor-specific evolutionary selection involved in mitochondrial dysfunction. EBioMedicine 2022; 80:104058. [PMID: 35594659 PMCID: PMC9121266 DOI: 10.1016/j.ebiom.2022.104058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/06/2022] [Accepted: 04/28/2022] [Indexed: 11/05/2022] Open
Abstract
Background Mitochondrial DNA (mtDNA) mutations alter mitochondrial function in oxidative metabolism and play an important role in tumorigenesis. A series of studies have demonstrated that the mtDNA control region (mtCTR), which is essential for mtDNA replication and transcription, represents a mutational hotspot in human tumors. However, a comprehensive pan-cancer evolutionary pattern analysis of mtCTR mutations is urgently needed. Methods We generated a comprehensive combined dataset containing 10026 mtDNA somatic mutations from 4664 patients, covering 20 tumor types based on public and private next-generation sequencing data. Findings Our results demonstrated a significantly higher and much more variable mutation rate in mtCTR than in the coding region across different tumor types. Moreover, our data showed a remarkable distributional bias of tumor somatic mutations between the hypervariable segment (HVS) and non-HVS, with a significantly higher mutation density and average mutation sites in HVS. Importantly, the tumor-specific mutational pattern between mtCTR HVS and non-HVS was identified, which was classified into three evolutionary selection types (relaxed, moderate, and strict constraint types). Analysis of substitution patterns revealed that the prevalence of CH > TH in non-HVS greatly contributed to the mutational selection pattern of mtCTR across different tumor types. Furthermore, we found that the mutational pattern of mtCTR in the four tumor types was clearly associated with mitochondrial biogenesis, mitochondrial oxidative metabolism, and the overall survival of patients. Interpretation Our results suggest that somatic mutations in mtCTR may be shaped by tumor-specific selective pressure and are involved in tumorigenesis. Fundings National Natural Science Foundation of China [grants 82020108023, 81830070, 81872302], and Autonomous Project of State Key Laboratory of Cancer Biology, China [grants CBSKL2019ZZ06, CBSKL2019ZZ27].
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24
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Young MJ, Sachidanandam R, Hales DB, Brard L, Robinson K, Rahman MM, Khadka P, Groesch K, Young CKJ. Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients. Life (Basel) 2022; 12:life12040562. [PMID: 35455053 PMCID: PMC9030153 DOI: 10.3390/life12040562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/30/2022] [Accepted: 04/08/2022] [Indexed: 12/30/2022] Open
Abstract
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.
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Affiliation(s)
- Matthew J. Young
- Department of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; (D.B.H.); (M.M.R.); (P.K.); (C.K.J.Y.)
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA; (L.B.); (K.R.)
- Correspondence: ; Tel.: +1-618-453-6437
| | - Ravi Sachidanandam
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Dale B. Hales
- Department of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; (D.B.H.); (M.M.R.); (P.K.); (C.K.J.Y.)
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA; (L.B.); (K.R.)
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA
| | - Laurent Brard
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA; (L.B.); (K.R.)
- Department of Obstetrics & Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
| | - Kathy Robinson
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA; (L.B.); (K.R.)
- Division of Hematology/Oncology, Department of Internal Medicine, Southern Illinois University, Springfield, IL 62702, USA
| | - Md. Mostafijur Rahman
- Department of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; (D.B.H.); (M.M.R.); (P.K.); (C.K.J.Y.)
| | - Pabitra Khadka
- Department of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; (D.B.H.); (M.M.R.); (P.K.); (C.K.J.Y.)
| | - Kathleen Groesch
- Department of Obstetrics & Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
- Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Carolyn K. J. Young
- Department of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; (D.B.H.); (M.M.R.); (P.K.); (C.K.J.Y.)
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25
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Wu Q, Tsai HI, Zhu H, Wang D. The Entanglement between Mitochondrial DNA and Tumor Metastasis. Cancers (Basel) 2022; 14:cancers14081862. [PMID: 35454769 PMCID: PMC9028275 DOI: 10.3390/cancers14081862] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Mitochondrial dysfunction is one of the main features of cancer cells. As genetic material in mitochondria, mitochondrial DNA (mtDNA) variations and dysregulation of mitochondria-encoded genes have been shown to correlate with survival outcomes in cancer patients. Cancer metastasis is often a major cause of treatment failure, which is a multi-step cascade process. With the development of gene sequencing and in vivo modeling technology, the role of mtDNA in cancer metastasis has been continuously explored. Our review systematically provides a summary of the multiple roles of mtDNA in cancer metastasis and presents the broad prospects for mtDNA in cancer prediction and therapy. Abstract 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.
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Affiliation(s)
- Qiwei Wu
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China;
| | - Hsiang-i Tsai
- Laboratory of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China;
| | - Haitao Zhu
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China;
- Laboratory of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China;
- Correspondence: (H.Z.); (D.W.); Tel.: +86-138-6139-0259 (D.W.)
| | - Dongqing Wang
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China;
- Correspondence: (H.Z.); (D.W.); Tel.: +86-138-6139-0259 (D.W.)
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26
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Miranda M, Bonekamp NA, Kühl I. Starting the engine of the powerhouse: mitochondrial transcription and beyond. Biol Chem 2022; 403:779-805. [PMID: 35355496 DOI: 10.1515/hsz-2021-0416] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/09/2022] [Indexed: 12/25/2022]
Abstract
Mitochondria are central hubs for cellular metabolism, coordinating a variety of metabolic reactions crucial for human health. Mitochondria provide most of the cellular energy via their oxidative phosphorylation (OXPHOS) system, which requires the coordinated expression of genes encoded by both the nuclear (nDNA) and mitochondrial genomes (mtDNA). Transcription of mtDNA is not only essential for the biogenesis of the OXPHOS system, but also generates RNA primers necessary to initiate mtDNA replication. Like the prokaryotic system, mitochondria have no membrane-based compartmentalization to separate the different steps of mtDNA maintenance and expression and depend entirely on nDNA-encoded factors imported into the organelle. Our understanding of mitochondrial transcription in mammalian cells has largely progressed, but the mechanisms regulating mtDNA gene expression are still poorly understood despite their profound importance for human disease. Here, we review mechanisms of mitochondrial gene expression with a focus on the recent findings in the field of mammalian mtDNA transcription and disease phenotypes caused by defects in proteins involved in this process.
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Affiliation(s)
- Maria Miranda
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, D-50931, Germany
| | - Nina A Bonekamp
- Department of Neuroanatomy, Mannheim Center for Translational Neurosciences (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, D-68167, Germany
| | - Inge Kühl
- Department of Cell Biology, Institute of Integrative Biology of the Cell (I2BC), UMR9198, CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette, F-91190, France
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27
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Mitochondrial Proteins as Source of Cancer Neoantigens. Int J Mol Sci 2022; 23:ijms23052627. [PMID: 35269772 PMCID: PMC8909979 DOI: 10.3390/ijms23052627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 01/27/2023] Open
Abstract
In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions.
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28
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Wang X, Shelton SD, Bordieanu B, Frank AR, Yi Y, Venigalla SSK, Gu Z, Lenser NP, Glogauer M, Chandel NS, Zhao H, Zhao Z, McFadden DG, Mishra P. Scinderin promotes fusion of electron transport chain dysfunctional muscle stem cells with myofibers. NATURE AGING 2022; 2:155-169. [PMID: 35342888 PMCID: PMC8954567 DOI: 10.1038/s43587-021-00164-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 12/08/2021] [Indexed: 06/14/2023]
Abstract
Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS). The source of these changes, and how MuSCs respond to mitochondrial dysfunction, is unknown. We report here that in response to mitochondrial ROS, murine MuSCs directly fuse with neighboring myofibers; this phenomenon removes ETC-dysfunctional MuSCs from the stem cell compartment. MuSC-myofiber fusion is dependent on the induction of Scinderin, which promotes formation of actin-dependent protrusions required for membrane fusion. During aging, we find that the declining MuSC population accumulates mutations in the mitochondrial genome, but selects against dysfunctional variants. In the absence of clearance by Scinderin, the decline in MuSC numbers during aging is repressed; however, ETC-dysfunctional MuSCs are retained and can regenerate dysfunctional myofibers. We propose a model in which ETC-dysfunctional MuSCs are removed from the stem cell compartment by fusing with differentiated tissue.
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Affiliation(s)
- Xun Wang
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Spencer D Shelton
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bogdan Bordieanu
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Present Address: Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425 USA
| | - Anderson R Frank
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Internal Medicine, Division of Endocrinology, Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Yating Yi
- Department of Comprehensive Dentistry, College of Dentistry, Texas A&M University, Dallas, TX 75246, USA
- Present address: State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Siva Sai Krishna Venigalla
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhimin Gu
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Nicholas P Lenser
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Present address: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael Glogauer
- Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
| | - Navdeep S Chandel
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Hu Zhao
- Department of Comprehensive Dentistry, College of Dentistry, Texas A&M University, Dallas, TX 75246, USA
- Present address: The Chinese Institute for Brain Research, Beijing, China
| | - Zhiyu Zhao
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - David G McFadden
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Internal Medicine, Division of Endocrinology, Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Prashant Mishra
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390
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29
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Li CH, Haider S, Boutros PC. Age influences on the molecular presentation of tumours. Nat Commun 2022; 13:208. [PMID: 35017538 PMCID: PMC8752853 DOI: 10.1038/s41467-021-27889-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/17/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer is often called a disease of aging. There are numerous ways in which cancer epidemiology and behaviour change with the age of the patient. The molecular bases for these relationships remain largely underexplored. To characterise them, we analyse age-associations in the nuclear and mitochondrial somatic mutational landscape of 20,033 tumours across 35 tumour-types. Age influences both the number of mutations in a tumour (0.077 mutations per megabase per year) and their evolutionary timing. Specific mutational signatures are associated with age, reflecting differences in exogenous and endogenous oncogenic processes such as a greater influence of tobacco use in the tumours of younger patients, but higher activity of DNA damage repair signatures in those of older patients. We find that known cancer driver genes such as CDKN2A and CREBBP are mutated in age-associated frequencies, and these alter the transcriptome and predict for clinical outcomes. These effects are most striking in brain cancers where alterations like SUFU loss and ATRX mutation are age-dependent prognostic biomarkers. Using three cancer datasets, we show that age shapes the somatic mutational landscape of cancer, with clinical implications.
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Affiliation(s)
- Constance H Li
- Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Department of Human Genetics, University of California, Los Angeles, CA, USA
- Department of Urology, University of California, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
- Institute for Precision Health, University of California, Los Angeles, CA, USA
| | - Syed Haider
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Paul C Boutros
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Department of Human Genetics, University of California, Los Angeles, CA, USA.
- Department of Urology, University of California, Los Angeles, CA, USA.
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
- Institute for Precision Health, University of California, Los Angeles, CA, USA.
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
- Vector Institute for Artificial Intelligence, Toronto, ON, Canada.
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30
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Mennuni M, Filograna R, Felser A, Bonekamp NA, Giavalisco P, Lytovchenko O, Larsson N. Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen. EMBO Rep 2022; 23:e53054. [PMID: 34779571 PMCID: PMC8728608 DOI: 10.15252/embr.202153054] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
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Affiliation(s)
- Mara Mennuni
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Roberta Filograna
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Andrea Felser
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
- University Institute of Clinical ChemistryBern University HospitalBernSwitzerland
| | - Nina A Bonekamp
- Mitochondrial Biology GroupMax Planck Institute for Biology of AgeingCologneGermany
- Department of NeuroanatomyMannheim Center for Translational Neuroscience (MCTN)Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Patrick Giavalisco
- Metabolomics Core FacilityMax Planck Institute for Biology of AgeingCologneGermany
| | - Oleksandr Lytovchenko
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Nils‐Göran Larsson
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
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31
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Gonçalves AC, Richiardone E, Jorge J, Polónia B, Xavier CPR, Salaroglio IC, Riganti C, Vasconcelos MH, Corbet C, Sarmento-Ribeiro AB. Impact of cancer metabolism on therapy resistance - Clinical implications. Drug Resist Updat 2021; 59:100797. [PMID: 34955385 DOI: 10.1016/j.drup.2021.100797] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.
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Affiliation(s)
- Ana Cristina Gonçalves
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Elena Richiardone
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Belgium
| | - Joana Jorge
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Bárbara Polónia
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Cristina P R Xavier
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | | | - Chiara Riganti
- Department of Oncology, School of Medicine, University of Torino, Italy
| | - M Helena Vasconcelos
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy of the University of Porto, Porto, Portugal
| | - Cyril Corbet
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Belgium.
| | - Ana Bela Sarmento-Ribeiro
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; Hematology Service, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
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32
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Kowal K, Tkaczyk-Wlizło A, Pierzchała M, Gawor J, Ślaska B. Molecular differences in mitochondrial DNA genomes of dogs with malignant mammary tumours. Vet Comp Oncol 2021; 20:256-264. [PMID: 34554638 DOI: 10.1111/vco.12772] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 07/01/2021] [Accepted: 09/20/2021] [Indexed: 11/30/2022]
Abstract
The aim of this study was to determine molecular defects in mitochondrial DNA (mtDNA) with the use of large-scale genome analysis in malignant canine mammary gland tumours and indicate whether these changes were linked with the carcinogenesis process. With the use of the NGS technology, we sequenced 27 samples of mtDNA isolated from blood and tumours obtained from 13 dogs with mammary gland tumours. The total number of mutations and polymorphisms in the analysed mitochondrial genomes was 557. We identified 383 single nucleotide polymorphisms (SNP), 32 indels (or length polymorphisms), 4 mutations, 137 heteroplasmic positions and 1 indel mutation. The highest variability (132 changes) was observed in the variable number of tandem repeats (VNTR) region. The heteroplasmy rate in VNTR varied among individuals and even between two tumours in one organism. Our previous study resulted in determination of a probable CpG island in this region, thus it is not excluded that these changes might alter mtDNA methylation. Only the ATP8 gene was not affected by any polymorphisms or mutations, whereas the COX1 gene had the highest number of polymorphisms from all protein-coding genes. One change m.13594G>A was detected in a region spanning two genes: ND5 and ND6, from which a deleterious effect was observed for the ND5 protein. Molecular changes were frequently observed in the TΨC loop, which is thought to interact with ribosomal RNA.
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Affiliation(s)
- Krzysztof Kowal
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, Lublin, Poland
| | - Angelika Tkaczyk-Wlizło
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, Lublin, Poland
| | - Mariusz Pierzchała
- Department of Genomics and Biodiversity, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzębiec, Poland
| | - Jan Gawor
- DNA Sequencing and Synthesis Facility, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Brygida Ślaska
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, Lublin, Poland
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33
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Shaukat AN, Kaliatsi EG, Stamatopoulou V, Stathopoulos C. Mitochondrial tRNA-Derived Fragments and Their Contribution to Gene Expression Regulation. Front Physiol 2021; 12:729452. [PMID: 34539450 PMCID: PMC8446549 DOI: 10.3389/fphys.2021.729452] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/09/2021] [Indexed: 01/14/2023] Open
Abstract
Mutations in human mitochondrial tRNAs (mt-tRNAs) are responsible for several and sometimes severe clinical phenotypes, classified among mitochondrial diseases. In addition, post-transcriptional modifications of mt-tRNAs in correlation with several stress signals can affect their stability similarly to what has been described for their nuclear-encoded counterparts. Many of the perturbations related to either point mutations or aberrant modifications of mt-tRNAs can lead to specific cleavage and the production of mitochondrial tRNA-derived fragments (mt-tRFs). Although mt-tRFs have been detected in several studies, the exact biogenesis steps and biological role remain, to a great extent, unexplored. Several mt-tRFs are produced because of the excessive oxidative stress which predominantly affects mitochondrial DNA integrity. In addition, mt-tRFs have been detected in various diseases with possible detrimental consequences, but also their production may represent a response mechanism to external stimuli, including infections from pathogens. Finally, specific point mutations on mt-tRNAs have been reported to impact the pool of the produced mt-tRFs and there is growing evidence suggesting that mt-tRFs can be exported and act in the cytoplasm. In this review, we summarize current knowledge on mitochondrial tRNA-deriving fragments and their possible contribution to gene expression regulation.
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Affiliation(s)
| | - Eleni G Kaliatsi
- Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece
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34
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Nagase H, Watanabe T, Koshikawa N, Yamamoto S, Takenaga K, Lin J. Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer. Cancer Sci 2021; 112:4834-4843. [PMID: 34533888 PMCID: PMC8645765 DOI: 10.1111/cas.15143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/21/2022] Open
Abstract
As the energy factory for the cell, the mitochondrion, through its role of adenosine triphosphate production by oxidative phosphorylation, can be regarded as the guardian of well regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria are often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression, and metastasis of tumor cells. Such pathogenic mtDNA aberrations are likely to increase and occasionally be homoplasmic in cancer cells and, intriguingly, in normal cells in the proximity of tumor microenvironments as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. Here we discuss a promising novel therapeutic strategy, using the sequence‐specific properties of pyrrole‐imidazole polyamide‐triphenylphosphonium conjugates, against cancer for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance.
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Affiliation(s)
- Hiroki Nagase
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Takayoshi Watanabe
- Division of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Nobuko Koshikawa
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Seigi Yamamoto
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Keizo Takenaga
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Jason Lin
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
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35
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Wei W, Gaffney DJ, Chinnery PF. Cell reprogramming shapes the mitochondrial DNA landscape. Nat Commun 2021; 12:5241. [PMID: 34475388 PMCID: PMC8413449 DOI: 10.1038/s41467-021-25482-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/14/2021] [Indexed: 12/25/2022] Open
Abstract
Individual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10-5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy.
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Affiliation(s)
- Wei Wei
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
- Medical Research Council Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Daniel J Gaffney
- Human Induced Pluripotent Stem Cell Initiative, Wellcome Genome Campus, Hinxton, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Patrick F Chinnery
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
- Medical Research Council Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
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36
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Mohd Khair SZN, Abd Radzak SM, Mohamed Yusoff AA. The Uprising of Mitochondrial DNA Biomarker in Cancer. DISEASE MARKERS 2021; 2021:7675269. [PMID: 34326906 PMCID: PMC8302403 DOI: 10.1155/2021/7675269] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022]
Abstract
Cancer is a heterogeneous group of diseases, the progression of which demands an accumulation of genetic mutations and epigenetic alterations of the human nuclear genome or possibly in the mitochondrial genome as well. Despite modern diagnostic and therapeutic approaches to battle cancer, there are still serious concerns about the increase in death from cancer globally. Recently, a growing number of researchers have extensively focused on the burgeoning area of biomarkers development research, especially in noninvasive early cancer detection. Intergenomic cross talk has triggered researchers to expand their studies from nuclear genome-based cancer researches, shifting into the mitochondria-mediated associations with carcinogenesis. Thus, it leads to the discoveries of established and potential mitochondrial biomarkers with high specificity and sensitivity. The research field of mitochondrial DNA (mtDNA) biomarkers has the great potential to confer vast benefits for cancer therapeutics and patients in the future. This review seeks to summarize the comprehensive insights of nuclear genome cancer biomarkers and their usage in clinical practices, the intergenomic cross talk researches that linked mitochondrial dysfunction to carcinogenesis, and the current progress of mitochondrial cancer biomarker studies and development.
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Affiliation(s)
- Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
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37
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Pérez-Amado CJ, Bazan-Cordoba A, Hidalgo-Miranda A, Jiménez-Morales S. Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression. Int J Mol Sci 2021; 22:7369. [PMID: 34298989 PMCID: PMC8304746 DOI: 10.3390/ijms22147369] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.
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Affiliation(s)
- Carlos Jhovani Pérez-Amado
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
- Programa de Maestría y Doctorado, Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Amellalli Bazan-Cordoba
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
- Programa de Maestría y Doctorado, Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
| | - Silvia Jiménez-Morales
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
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38
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Kaneva K, O’Halloran K, Triska P, Liu X, Merkurjev D, Bootwalla M, Ryutov A, Cotter JA, Ostrow D, Biegel JA, Gai X. The spectrum of mitochondrial DNA (mtDNA) mutations in pediatric CNS tumors. Neurooncol Adv 2021; 3:vdab074. [PMID: 34337412 PMCID: PMC8320689 DOI: 10.1093/noajnl/vdab074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND We previously established the landscape of mitochondrial DNA (mtDNA) mutations in 23 subtypes of pediatric malignancies, characterized mtDNA mutation profiles among these subtypes, and provided statistically significant evidence for a contributory role of mtDNA mutations to pediatric malignancies. METHODS To further delineate the spectrum of mtDNA mutations in pediatric central nervous system (CNS) tumors, we analyzed 545 tumor-normal paired whole-genome sequencing datasets from the Children's Brain Tumor Tissue Consortium. RESULTS Germline mtDNA variants were used to determine the haplogroup, and maternal ancestry, which was not significantly different among tumor types. Among 166 (30.5%) tumors we detected 220 somatic mtDNA mutations, primarily missense mutations (36.8%), as well as 22 loss-of-function mutations. Different pediatric CNS tumor subtypes had distinct mtDNA mutation profiles. The number of mtDNA mutations per tumor ranged from 0.20 (dysembryoplastic neuroepithelial tumor [DNET]) to 0.75 (meningiomas). The average heteroplasmy was 10.7%, ranging from 4.6% in atypical teratoid/rhabdoid tumor (AT/RT) to 26% in diffuse intrinsic pontine glioma. High-grade gliomas had a significant higher number of mtDNA mutations per sample than low-grade gliomas (0.6 vs 0.27) (P = .004), with almost twice as many missense mtDNA mutations per sample (0.24 vs 0.11), and higher average heteroplasmy levels (16% vs 10%). Recurrent mtDNA mutations may represent hotspots which may serve as biologic markers of disease. CONCLUSIONS Our findings demonstrate varying contributions of mtDNA mutations in different subtypes of CNS tumors. Sequencing the mtDNA genome may ultimately be used to characterize CNS tumors at diagnosis and monitor disease progression.
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Affiliation(s)
- Kristiyana Kaneva
- Division of Hematology-Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA,Present address: Tempus Labs, Inc., Chicago, Illinois, USA
| | - Katrina O’Halloran
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Petr Triska
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine of Charles University, Prague, Czech Republic
| | - Xiyu Liu
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Daria Merkurjev
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Moiz Bootwalla
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Alex Ryutov
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Jennifer A Cotter
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Dejerianne Ostrow
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Jaclyn A Biegel
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Xiaowu Gai
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA,Corresponding Author: Xiaowu Gai, PhD, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Mailstop #173, Los Angeles, CA 90027, USA ()
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39
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Leão Barros MB, Pinheiro DDR, Borges BDN. Mitochondrial DNA Alterations in Glioblastoma (GBM). Int J Mol Sci 2021; 22:ijms22115855. [PMID: 34072607 PMCID: PMC8199454 DOI: 10.3390/ijms22115855] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 01/12/2023] Open
Abstract
Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.
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Affiliation(s)
- Mariceli Baia Leão Barros
- Molecular Biology Laboratory, Biological Sciences Institute, Federal University of Para, Belém, PA 66075, Brazil;
| | | | - Bárbara do Nascimento Borges
- Molecular Biology Laboratory, Biological Sciences Institute, Federal University of Para, Belém, PA 66075, Brazil;
- Correspondence:
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40
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Haumann S, Boix J, Knuever J, Bieling A, Vila Sanjurjo A, Elson JL, Blakely EL, Taylor RW, Riet N, Abken H, Kashkar H, Hornig-Do HT, Wiesner RJ. Mitochondrial DNA mutations induce mitochondrial biogenesis and increase the tumorigenic potential of Hodgkin and Reed-Sternberg cells. Carcinogenesis 2021; 41:1735-1745. [PMID: 32255484 DOI: 10.1093/carcin/bgaa032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 03/17/2020] [Accepted: 04/06/2020] [Indexed: 11/14/2022] Open
Abstract
Functioning mitochondria are crucial for cancer metabolism, but aerobic glycolysis is still considered to be an important pathway for energy production in many tumor cells. Here we show that two well established, classic Hodgkin lymphoma (cHL) cell lines harbor deleterious variants within mitochondrial DNA (mtDNA) and thus exhibit reduced steady-state levels of respiratory chain complexes. However, instead of resulting in the expected bioenergetic defect, these mtDNA variants evoke a retrograde signaling response that induces mitochondrial biogenesis and ultimately results in increased mitochondrial mass as well as function and enhances proliferation in vitro as well as tumor growth in mice in vivo. When complex I assembly was impaired by knockdown of one of its subunits, this led to further increased mitochondrial mass and function and, consequently, further accelerated tumor growth in vivo. In contrast, inhibition of mitochondrial respiration in vivo by the mitochondrial complex I inhibitor metformin efficiently slowed down growth. We conclude that, as a new mechanism, mildly deleterious mtDNA variants in cHL cancer cells cause an increase of mitochondrial mass and enhanced function as a compensatory effect using a retrograde signaling pathway, which provides an obvious advantage for tumor growth.
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Affiliation(s)
- Sophie Haumann
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany.,Department of Pediatrics, Medical Faculty and University Hospital of Cologne, Cologne, Germany
| | - Julia Boix
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Jana Knuever
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany.,Department of Dermatology, Medical Faculty and University Hospital of Cologne, Cologne, Germany
| | - Angela Bieling
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Anton Vila Sanjurjo
- Grupo GIBE, Departamento de Bioloxía Celular e Molecular, Facultade de Ciencias, Universidade de A Coruña (UDC), A Coruña, Spain
| | - Joanna L Elson
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.,Human Metabolomics, North-West University, Potchefstroom, South Africa
| | - Emma L Blakely
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne UK
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne UK
| | - Nicole Riet
- Department I for Internal Medicine, Medical Faculty and University of Cologne, 50931 Cologne, Germany
| | - Hinrich Abken
- Department I for Internal Medicine, Medical Faculty and University of Cologne, 50931 Cologne, Germany.,Center for Molecular Medicine Cologne, 50931 Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.,RCI, Regensburg Center for Interventional Immunology, Chair Gene-Immunotherapy, University Hospital Regensburg, Regensburg, Germany
| | - Hamid Kashkar
- Center for Molecular Medicine Cologne, 50931 Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.,Institute of Medical Microbiology, Immunology and Hygiene, Medical Faculty and University Hospital of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Hue-Tran Hornig-Do
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Rudolf J Wiesner
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, 50931 Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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41
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Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab 2021; 3:558-570. [PMID: 33833465 PMCID: PMC9304985 DOI: 10.1038/s42255-021-00378-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/03/2021] [Indexed: 12/21/2022]
Abstract
Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development.
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Affiliation(s)
- Alexander N Gorelick
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Minsoo Kim
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Walid K Chatila
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Konnor La
- Laboratory of Metabolic Regulation and Genetics, Rockefeller University, New York, NY, USA
| | - A Ari Hakimi
- Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael F Berger
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Barry S Taylor
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Payam A Gammage
- CRUK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
| | - Ed Reznik
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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42
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González MDM, Santos C, Alarcón C, Ramos A, Cos M, Catalano G, Acebes JJ, Aluja MP. Mitochondrial DNA haplogroups J and T increase the risk of glioma. Mitochondrion 2021; 58:95-101. [PMID: 33675980 DOI: 10.1016/j.mito.2021.02.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 12/21/2022]
Abstract
The presence of different sets of mitochondrial polymorphisms generated by the accumulation of mutations in different maternal lineages has allowed differentiating mitochondrial haplogroups in human populations. These polymorphisms, in turn, may have effects at the phenotypic level, considering a possible contribution of these germinal mutations to the development of certain diseases such as cancer. The main goal of the present study is to establish a possible association between mitochondrial haplogroups and the risk of suffering glioma. Blood samples were obtained from 32 patients from Catalonia (Spain) diagnosed with different grades of glioma (II, III and IV), according to the World Health Organization. The mitochondrial genome was amplified and sequenced using MiSeq 2000 (Illumina). The HaploGrep tool implemented in mtDNA-Server v.1.0.5 was used for the identification of mitochondrial haplogroups. Data obtained in the present study was further pooled with data from previous European studies including glioma patients from Galicia (Spain) and Italy. Results for the Catalonian samples showed an association between individuals with haplogroup J and the increased risk of suffering glioma, with a significant increase of the frequency of individuals with this haplogroup (25%) regarding the general population (7%). Combining different sets of patients with European origin, it appears that individuals with haplogroups J and T have a significantly higher risk of suffering glioma (p < 0.001; OR: 2.407 and p = 0.007; OR: 1.82, respectively). This is the first study that establishes an association between different mitochondrial haplogroups and the risk of suffering glioma, highlighting the role of mitochondrial variants in this disease.
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Affiliation(s)
- María Del Mar González
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Cristina Santos
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Carlos Alarcón
- Servicio de Neurocirugía, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain; Servicio de Neurocirugía, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Amanda Ramos
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Mònica Cos
- Sección de Neurorradiología, Institut de Diagnòstic per la Imatge, Centre Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Giulio Catalano
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Palermo, Italy
| | - Juan José Acebes
- Servicio de Neurocirugía, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Pilar Aluja
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
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43
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Stewart JB, Chinnery PF. Extreme heterogeneity of human mitochondrial DNA from organelles to populations. Nat Rev Genet 2021; 22:106-118. [PMID: 32989265 DOI: 10.1038/s41576-020-00284-x] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Contrary to the long-held view that most humans harbour only identical mitochondrial genomes, deep resequencing has uncovered unanticipated extreme genetic variation within mitochondrial DNA (mtDNA). Most, if not all, humans contain multiple mtDNA genotypes (heteroplasmy); specific patterns of variants accumulate in different tissues, including cancers, over time; and some variants are preferentially passed down or suppressed in the maternal germ line. These findings cast light on the origin and spread of mtDNA mutations at multiple scales, from the organelle to the human population, and challenge the conventional view that high percentages of a mutation are required before a new variant has functional consequences.
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Affiliation(s)
- James B Stewart
- Max Planck Institute for Biology of Ageing, Cologne, Germany
- Wellcome Centre for Mitochondrial Research, Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Patrick F Chinnery
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
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44
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Isokallio MA, Stewart JB. High-Throughput Detection of mtDNA Mutations Leading to tRNA Processing Errors. Methods Mol Biol 2021; 2192:117-132. [PMID: 33230770 DOI: 10.1007/978-1-0716-0834-0_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Some mutations in the tRNA genes of mitochondrial DNA (mtDNA) have been demonstrated to affect the processing of the mitochondrial transcriptome in human patients with mitochondrial disease. A recent analysis of mtDNA mutations in 527 human tumors revealed that approximately a quarter of the somatic mt-tRNA gene mutations lead to aberrant processing of the mitochondrial transcriptome in these tumors. Here, we describe a method, based on mtDNA mutations induced by the mtDNA mutator mouse, to map the sites that lead to transcript processing abnormalities. Mutations in the mtDNA are identified and quantified by amplicon-based mtDNA sequencing, and compared to the allelic ratios observed in matched RNASeq data. Strong deviation in the variant allele frequencies between the amplicon and RNASeq data suggests that such mutations lead to disruptions in mitochondrial transcript processing.
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45
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Filograna R, Mennuni M, Alsina D, Larsson NG. Mitochondrial DNA copy number in human disease: the more the better? FEBS Lett 2020; 595:976-1002. [PMID: 33314045 PMCID: PMC8247411 DOI: 10.1002/1873-3468.14021] [Citation(s) in RCA: 265] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/26/2020] [Indexed: 12/19/2022]
Abstract
Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.
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Affiliation(s)
- Roberta Filograna
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - Mara Mennuni
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - David Alsina
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - Nils-Göran Larsson
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
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46
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Affiliation(s)
- Hiran A Prag
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Michael P Murphy
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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47
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Tasdogan A, McFadden DG, Mishra P. Mitochondrial DNA Haplotypes as Genetic Modifiers of Cancer. Trends Cancer 2020; 6:1044-1058. [PMID: 32980320 DOI: 10.1016/j.trecan.2020.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/05/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria play an essential role in cellular metabolism, generation of reactive oxygen species (ROS), and the initiation of apoptosis. These properties enable mitochondria to be crucial integrators in the pathways of tumorigenesis. An open question is to what extent variation in the mitochondrial genome (mtDNA) contributes to the biological heterogeneity observed in human tumors. In this review, we summarize our current understanding of the role of mtDNA genetics in relation to human cancers.
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Affiliation(s)
- Alpaslan Tasdogan
- Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - David G McFadden
- Department of Internal Medicine, Department of Biochemistry, Simmons Comprehensive Cancer Center, Division of Endocrinology, Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Prashant Mishra
- Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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48
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Karakaidos P, Rampias T. Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity. Life (Basel) 2020; 10:life10090173. [PMID: 32878185 PMCID: PMC7555762 DOI: 10.3390/life10090173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/28/2020] [Indexed: 12/27/2022] Open
Abstract
In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.
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49
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Wu H, Zhang K, Chen Y, Li J, Strout MP, Gu X. Optimized high-fidelity 3DPCR to assess potential mitochondrial targeting by activation-induced cytidine deaminase. FEBS Open Bio 2020; 10:1782-1792. [PMID: 32633086 PMCID: PMC7459399 DOI: 10.1002/2211-5463.12927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/10/2020] [Accepted: 06/03/2020] [Indexed: 11/09/2022] Open
Abstract
Activation‐induced cytidine deaminase (AID) initiates somatic hypermutation and class switch recombination of immunoglobulin genes in B cells, whereas off‐targeted AID activity contributes to oncogenic mutations and chromosomal translocations associated with B cell malignancies. Paradoxically, only a minority of AID is allowed to access the nuclear genome, but the majority of AID is retained in the cytoplasm. It is unknown whether cytoplasmic AID can access and target the mitochondrial genome [mitochondrial DNA (mtDNA)]. To address this issue, we developed high‐fidelity differential DNA denaturation PCR, which allowed the enrichment of genuine mtDNA mutations and therefore the identification of endogenous mtDNA mutation signatures in vitro. With this approach, we showed that AID targeting to mtDNA is a rare event in AID‐expressing lymphoma lines. Further biochemical and microscopic analysis revealed that a fraction of cytosol AID is associated with the outer membrane of mitochondria but unable to access the mitochondrial matrix. Together, our data suggested that the mitochondrial genome is protected from AID‐mediated mutagenesis by physical segregation of AID from accessing mtDNA within the mitochondrial matrix.
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Affiliation(s)
- Haiyan Wu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, China.,Department of Oral and Maxillofacial Surgery, Xi'an Jiaotong University College of Stomatology, Xi'an, China
| | - Kaili Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, China.,Department of Periodontology and Oral Medicine, Xi'an Jiaotong University College of Stomatology, Xi'an, China
| | - Yue Chen
- Department of Periodontology and Oral Medicine, Xi'an Jiaotong University College of Stomatology, Xi'an, China
| | - Jinfeng Li
- Department of Oral and Maxillofacial Surgery, Xi'an Jiaotong University College of Stomatology, Xi'an, China
| | - Matthew P Strout
- Section of Hematology, Yale University School of Medicine, New Haven, CT, USA
| | - Xiwen Gu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, China
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50
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Nguyen H, LaFramboise T. Complexities and pitfalls in analyzing and interpreting mitochondrial DNA content in human cancer. J Genet Genomics 2020; 47:349-359. [PMID: 33004308 DOI: 10.1016/j.jgg.2020.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 04/01/2020] [Accepted: 04/20/2020] [Indexed: 11/29/2022]
Abstract
Mutations in the human mitochondrial genome have been observed in all types of human cancer, indicating that mutations might contribute to tumorigenesis, metastasis, recurrence, or drug response. This possibility is appealing because of the known shift from oxidative metabolism to glycolysis, known as the Warburg effect, that occurs in malignancy. Mitochondrial DNA (mtDNA) mutations could either be maternally inherited and predispose to cancer (germ line mutations) or occur sporadically in the mtDNA of specific tissues (tissue- or tumor-specific somatic mutations) and contribute to the tumor initiation and progression process. High-throughput sequencing technologies now enable comprehensive detection of mtDNA variation in tissues and bodily fluids, with the potential to be used as an early detection tool that may impact the treatment of cancer. Here, we discuss insights into the roles of mtDNA mutations in carcinogenesis, highlighting the complexities involved in the analysis and interpretation of mitochondrial genomic content, technical challenges in studying their contribution to pathogenesis, and the value of mtDNA mutations in developing early detection, diagnosis, prognosis, and therapeutic strategies for cancer.
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Affiliation(s)
- Hieu Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology (VRSIG), 458 Minh Khai, Vinh Tuy, Hai Ba Trung, Hanoi, Viet Nam; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Thomas LaFramboise
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
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