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García-Barranquero P, Pérez-González S. SENS vs. the hallmarks of aging: competing visions, shared challenges. Biogerontology 2025; 26:103. [PMID: 40323495 PMCID: PMC12052809 DOI: 10.1007/s10522-025-10248-5] [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: 03/25/2025] [Accepted: 04/23/2025] [Indexed: 05/08/2025]
Abstract
Aging research is often framed within pluralistic frameworks that emphasize cellular and molecular damage processes. Among the most influential are Strategies for Engineered Negligible Senescence (SENS), which aims to counteract biological decline through targeted damage repair, and the Hallmarks of Aging (HoA), which seeks to identify fundamental mechanisms underlying this process. Both proposals, although diverse, significantly influence contemporary approaches to the challenges posed by aging. However, despite extensive discussion, we contend that key conceptual and methodological aspects remain insufficiently explored. This paper seeks to advance the debate by critically analyzing and comparing their foundational goals, theoretical premises, and research frameworks. Specifically, we examine their definitions of aging, perspectives on health and disease, approaches to scientific evidence and causal interventions, and communications strategies. In doing so, we aim to contribute to a deeper understanding and more nuanced assessment of both SENS and the HoA.
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Rupel K, Biasotto M, Vella F, Ottaviani G, Di Lenarda R, Tettamanti M, Marcon G. Influence of masticatory function on food preferences and cognitive performance in centenarians: an observational study. BDJ Open 2025; 11:28. [PMID: 40155603 PMCID: PMC11953341 DOI: 10.1038/s41405-025-00321-z] [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: 11/22/2024] [Revised: 03/11/2025] [Accepted: 03/11/2025] [Indexed: 04/01/2025] Open
Abstract
INTRODUCTION Demographic projections forecast that centenarians' population growth will continue. "CaT: Centenari a Trieste" is an ongoing study featuring the collection of demographic and anamnestic data, including the analysis of oral variables. AIMS evaluate of the possible influence of past food preferences, taste perception and masticatory function on current cognitive status in a cohort of centenarians. DESIGN Observational transversal study. MATERIALS AND METHODS 31 participants with mean age 102 ± 2 performed an examination of the oral cavity including the measurement of DMFT (Decayed Missing Filled Teeth), FTUs (functional teeth units), FOUs (functional occlusal units) and 6-n-propylthiouracil (PROP) taste perception assay. Results were correlated with dementia, subjective perception of oral health and food preferences. RESULTS Masticatory function did not correlate with dementia but had a significant impact on oral health perception. When analyzing variables affecting food preferences, PROP taste perception profile and DMFT resulted significantly correlated. Early edentulism didn't show to affect past dietary preferences. CONCLUSIONS our data suggest that in centenarians masticatory function doesn't seem to correlate to cognitive function, but influences the self-perception of oral health. Such results are an interesting addition to knowledge on the topic as they refer to a population which has never been considered before.
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Affiliation(s)
- Katia Rupel
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
- Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
| | - Matteo Biasotto
- Azienda Sanitaria Friuli Occidentale (ASFO), Pordenone, Italy
| | - Filomena Vella
- Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy
| | - Giulia Ottaviani
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
- Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy
| | - Roberto Di Lenarda
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
- Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy
| | - Mauro Tettamanti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Gabriella Marcon
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
- Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy
- Department of Medicine, University of Udine, Udine, Italy
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Kozin MS, Kulakova OG, Kiselev IS, Semina EV, Kakotkin VV, Agapov MA, Favorova OO. Mitochondrial Genome Variants and Alzheimer's Disease. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:S146-S163. [PMID: 40164157 DOI: 10.1134/s0006297924603174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/04/2024] [Accepted: 05/14/2024] [Indexed: 04/02/2025]
Abstract
Alzheimer's disease (AD), a severe neurodegenerative disease of the central nervous system, is the most common cause of cognitive impairment in people over the age of 60. The etiology and pathogenesis of Alzheimer's disease are still unclear despite decades of active research. Numerous studies have shown that neurodegenerative processes in AD are associated with the mitochondrial dysfunction. In this review, we briefly discuss the results of these studies and present the reported evidence that mitochondrial dysfunction in AD is associated with mitochondrial DNA (mtDNA) variations. The results of association analysis of mtDNA haplogroups and individual polymorphic variants, including those whose combinations define haplogroups, with AD are described in detail. These data clearly indicate the role of variations in the mitochondrial genome in the susceptibility to AD, although the problem of significance of individual mtDNA variants is far from being resolved.
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Affiliation(s)
- Maxim S Kozin
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia.
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117513, Russia
| | - Olga G Kulakova
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117513, Russia
| | - Ivan S Kiselev
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117513, Russia
| | | | - Viktor V Kakotkin
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia
| | - Mikhail A Agapov
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia
| | - Olga O Favorova
- Immanuel Kant Baltic Federal University, Kaliningrad, 236016, Russia
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117513, Russia
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Xiong W, Xu K, Sun JKL, Liu S, Zhao B, Shi J, Herrup K, Chow HM, Lu L, Li J. The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease. EMBO J 2024; 43:6001-6031. [PMID: 39424953 PMCID: PMC11612450 DOI: 10.1038/s44318-024-00270-7] [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: 10/26/2023] [Revised: 08/27/2024] [Accepted: 09/09/2024] [Indexed: 10/21/2024] Open
Abstract
Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.
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Affiliation(s)
- Wandi Xiong
- Peking-Tsinghua Center for Life Sciences, Beijing, China
- National Institute on Drug Dependence, Peking University, Beijing, China
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, China
| | - Kaiyu Xu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China
| | | | - Siling Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Baizhen Zhao
- JFK Neuroscience Institute, Hackensack Meridian Health JFK University Medical Center, Edison, NJ, USA
| | - Jie Shi
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Karl Herrup
- Department of Neurobiology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Hei-Man Chow
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Lin Lu
- Peking-Tsinghua Center for Life Sciences, Beijing, China.
- National Institute on Drug Dependence, Peking University, Beijing, China.
- Institute of Mental Health, National Clinical Research Center for Mental Disorders, Key Laboratory of Mental Health and Peking University Sixth Hospital, Peking University, Beijing, China.
| | - Jiali Li
- National Institute on Drug Dependence, Peking University, Beijing, China.
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China.
- JFK Neuroscience Institute, Hackensack Meridian Health JFK University Medical Center, Edison, NJ, USA.
- Department of Neurology, Hackensack Meridian School of Medicine, Nutley, NJ, USA.
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Feng B, Wang Z, Zhao X, Niu H, Wang Y, Wang K, Jiang K, Zhang H. Self-Internal Standard Fluorescence for Ultrasensitive Detecting of mtDNA to Evaluate Matrilineal Genetic Defect Levels. Anal Chem 2024; 96:14125-14132. [PMID: 38978161 DOI: 10.1021/acs.analchem.4c01945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Mitochondrial DNA (mtDNA) is a unique genetic material characterized by maternal inheritance. It possesses a circular structure devoid of histone protection and exhibits low cellular abundance, which poses great challenges for its sensitive and selective detection at the living cell level. Herein, we have designed three bis-naphthylimide probes with varying linker lengths (NANn-OH, n = 0, 2, 6), facilitating the formation of distinct twisted or folded molecular conformations in the free state. These probes emit the red fluorescence around 627 nm with different fluorescence quantum yields (ΦNAN0-OH = 0.0016, ΦNAN2-OH = 0.0136, and ΦNAN6-OH = 0.0125). When encountering mtDNA (0.4-3.4 μg/mL), these probes undergo conformational changes depending on the length of the attached C-strand and exhibit a gradually increasing fluorescence signal around 453 nm. The fluorescence intensity increased to 13.5-fold, 1.9-fold, and 8.2-fold, respectively. Notably, the red fluorescence intensities around 627 nm remain constant throughout this process, thus serving as an inherent correction mechanism for proportional fluorescence signal enhancement to improve selectivity and sensitivity. NAN0-OH, NAN2-OH, and NAN6-OH showed good linearity for mtDNA in the range of 0.4-3.4 μg/mL with detection limits of LODNAN0-OH = 1.04 μg/mL, LODNAN2-OH = 1.10 μg/mL, and LODNAN6-OH = 1.15 μg/mL. Cellular experiments reveal that NAN6-OH effectively monitors curcumin-induced mtDNA damage in HepG-2 cells while enabling monitoring of genetic mtDNA damage. We anticipate that this tool holds significant potential for the precise evaluation of maternal genetic defects, thereby enhancing hypersensitive assessment in clinical medicine.
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Affiliation(s)
- Beidou Feng
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
- College of the Environment, Henan Normal University, Xinxiang 453007, China
| | - Zhe Wang
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Xiaoli Zhao
- Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals; Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Xinxiang 453007, China
| | - Huiyu Niu
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Yafu Wang
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Kui Wang
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Kai Jiang
- College of the Environment, Henan Normal University, Xinxiang 453007, China
| | - Hua Zhang
- Key Laboratory of Green Chemical Media and Reactions, Ministry of Education; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
- Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals; Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Xinxiang 453007, China
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Dubie JJ, Katju V, Bergthorsson U. Dissecting the sequential evolution of a selfish mitochondrial genome in Caenorhabditis elegans. Heredity (Edinb) 2024; 133:186-197. [PMID: 38969772 PMCID: PMC11349875 DOI: 10.1038/s41437-024-00704-2] [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: 02/01/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/07/2024] Open
Abstract
Mitochondrial genomes exist in a nested hierarchy of populations where mitochondrial variants are subject to genetic drift and selection at each level of organization, sometimes engendering conflict between different levels of selection, and between the nuclear and mitochondrial genomes. Deletion mutants in the Caenorhabditis elegans mitochondrial genome can reach high intracellular frequencies despite strongly detrimental effects on fitness. During a mutation accumulation (MA) experiment in C. elegans, a 499 bp deletion in ctb-1 rose to 90% frequency within cells while significantly reducing fitness. During the experiment, the deletion-bearing mtDNA acquired three additional mutations in nd5, namely two single insertion frameshift mutations in a homopolymeric run, and a base substitution. Despite an additional fitness cost of these secondary mutations, all deletion-bearing molecules contained the nd5 mutations at the termination of the MA experiment. The presence of mutant mtDNA was associated with increased mtDNA copy-number. Variation in mtDNA copy-number was greater in the MA lines than in a wildtype nuclear background, including a severe reduction in copy-number at one generational timepoint. Evolutionary replay experiments using different generations of the MA experiment as starting points suggests that two of the secondary mutations contribute to the proliferation of the original ctb-1 deletion by unknown mechanisms.
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Affiliation(s)
- Joseph J Dubie
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
- Department of Integrative Biology, University of Texas, Austin, TX, USA
| | - Vaishali Katju
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
- Evolutionary Biology, Department of Ecology and Genetics, Uppsala University, Norbyvägen 18D, 752 36, Uppsala, Sweden.
| | - Ulfar Bergthorsson
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
- Evolutionary Biology, Department of Ecology and Genetics, Uppsala University, Norbyvägen 18D, 752 36, Uppsala, Sweden.
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7
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Ding X, Pan H, Shi P, Zhao S, Bao S, Zhong S, Dai C, Chen J, Gong L, Zhang D, Qiu X, Liao B, Huang Z. A comparative analysis of chloroplast genomes revealed the chloroplast heteroplasmy of Artemisia annua. Front Pharmacol 2024; 15:1466578. [PMID: 39206258 PMCID: PMC11349571 DOI: 10.3389/fphar.2024.1466578] [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: 07/18/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Artemisia annua L. is the main source of artemisinin, an antimalarial drug. High diversity of morphological characteristics and artemisinin contents of A. annua has affected the stable production of artemisinin while efficient discrimination method of A. annua strains is not available. The complete chloroplast (cp) genomes of 38 A. annua strains were assembled and analyzed in this study. Phylogenetic analysis of Artemisia species showed that distinct intraspecific divergence occurred in A. annua strains. A total of 38 A. annua strains were divided into two distinct lineages, one lineage containing widely-distributed strains and the other lineage only containing strains from northern China. The A. annua cp genomes ranged from 150, 953 to 150, 974 bp and contained 131 genes, and no presence or absence variation of genes was observed. The IRs and SC junctions were located in rps19 and ycf1, respectively, without IR contraction observed. Rich sequence polymorphisms were observed among A. annua strains, and a total of 60 polymorphic sites representing 14 haplotypes were identified which unfolding the cpDNA heteroplasmy of A. annua. In conclusion, this study provided valuable resource for A. annua strains identification and provided new insights into the evolutionary characteristics of A. annua.
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Affiliation(s)
- Xiaoxia Ding
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hengyu Pan
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peiqi Shi
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Siyu Zhao
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengye Bao
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shan Zhong
- College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, China
| | - Chunyan Dai
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jieting Chen
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lu Gong
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Danchun Zhang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaohui Qiu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Baosheng Liao
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhihai Huang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
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8
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Yu Y, Martins LM. Mitochondrial One-Carbon Metabolism and Alzheimer's Disease. Int J Mol Sci 2024; 25:6302. [PMID: 38928008 PMCID: PMC11203557 DOI: 10.3390/ijms25126302] [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: 03/12/2024] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024] Open
Abstract
Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.
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Affiliation(s)
- Yizhou Yu
- MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK
| | - L. Miguel Martins
- MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK
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Julián MT, Pérez-Montes de Oca A, Julve J, Alonso N. The double burden: type 1 diabetes and heart failure-a comprehensive review. Cardiovasc Diabetol 2024; 23:65. [PMID: 38347569 PMCID: PMC10863220 DOI: 10.1186/s12933-024-02136-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/15/2024] [Indexed: 02/15/2024] Open
Abstract
Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population.
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Affiliation(s)
- María Teresa Julián
- Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Alejandra Pérez-Montes de Oca
- Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Josep Julve
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
- Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Nuria Alonso
- Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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Stanev K, Yaneva A, Ivanov A, Gonovski T. The role of postoperative trimetazidine therapy in on-pump coronary artery bypass surgery. Folia Med (Plovdiv) 2023; 65:915-921. [PMID: 38351780 DOI: 10.3897/folmed.65.e102777] [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: 02/28/2023] [Accepted: 04/18/2023] [Indexed: 02/16/2024] Open
Abstract
INTRODUCTION Coronary artery bypass surgery remains the gold standard in the treatment of patients with ischemic heart disease. However, the increased oxidative stress caused by the release of free radicals during the ischemia-reperfusion time is a well-known pathophysiological process during and after coronary revascularization procedures. It may lead to reversible and irreversible myocardial injury.
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Affiliation(s)
- Kamen Stanev
- St George University Hospital, Plovdiv, Bulgaria
| | | | - Asen Ivanov
- St George University Hospital, Plovdiv, Bulgaria
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11
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Abstract
PURPOSE OF REVIEW MtDNA copy number (CN), a putative noninvasive biomarker of mitochondrial dysfunction, is associated with renal disease. The purpose of this review is to describe studies which measured human blood mtDNA-CN in the context of chronic kidney disease (CKD), and to evaluate its potential as a clinical biomarker of kidney disease. RECENT FINDINGS Following on from small scale cross-sectional studies implicating mtDNA-CN changes in diabetic kidney disease, recent large scale population studies provide compelling evidence of the association of mtDNA-CN and risk of renal disease in the general population and poor outcomes in CKD patients. SUMMARY The kidney has high bioenergetic needs, renal cells are rich in mitochondrial content containing 100s to 1000s of mtDNA molecular per cell. MtDNA has emerged as both a potential mediator, and a putative biomarker of renal disease. Damage to mtDNA can result in bioenergetic deficit, and reduced MtDNA levels in the blood have been shown to correlate with CKD. Furthermore, leakage of mtDNA outside of mitochondria into the cytosol/periphery can directly cause inflammation and is implicated in acute kidney injury (AKI). Recent large-scale population studies show the association of mtDNA-CN and renal disease and provide a strong basis for the future evaluation of circulating DNA-CN in longitudinal studies to determine its utility as a clinical biomarker for monitoring renal function.
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Affiliation(s)
- Afshan N Malik
- King's College London, Diabetes and Obesity, School of Cardiovascular Medicine and Metabolic Sciences, Guy's Campus, London, UK
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Fujiwara M, Ferdousi F, Isoda H. Investigation into Molecular Brain Aging in Senescence-Accelerated Mouse (SAM) Model Employing Whole Transcriptomic Analysis in Search of Potential Molecular Targets for Therapeutic Interventions. Int J Mol Sci 2023; 24:13867. [PMID: 37762170 PMCID: PMC10530366 DOI: 10.3390/ijms241813867] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
With the progression of an aging society, cognitive aging has emerged as a pressing concern necessitating attention. The senescence-accelerated mouse-prone 8 (SAMP8) model has proven instrumental in investigating the early stages of cognitive aging. Through an extensive examination of molecular changes in the brain cortex, utilizing integrated whole-genome transcriptomics, our principal aim was to uncover potential molecular targets with therapeutic applications and relevance to drug screening. Our investigation encompassed four distinct conditions, comparing the same strain at different time points (1 year vs. 16 weeks) and the same time point across different strains (SAMP8 vs. SAMR1), namely: physiological aging, accelerated aging, early events in accelerated aging, and late events in accelerated aging. Focusing on key functional alterations associated with aging in the brain, including neurogenesis, synapse dynamics, neurometabolism, and neuroinflammation, we identified candidate genes linked to these processes. Furthermore, employing protein-protein interaction (PPI) analysis, we identified pivotal hub genes involved in interactions within these functional domains. Additionally, gene-set perturbation analysis allowed us to uncover potential upstream genes or transcription factors that exhibited activation or inhibition across the four conditions. In summary, our comprehensive analysis of the SAMP8 mouse brain through whole-genome transcriptomics not only deepens our understanding of age-related changes but also lays the groundwork for a predictive model to facilitate drug screening for cognitive aging.
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Affiliation(s)
- Michitaka Fujiwara
- Graduate School of Environmental Science Program, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
- Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Tennodai, Tsukuba 305-8572, Japan
| | - Farhana Ferdousi
- Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan
| | - Hiroko Isoda
- Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Tennodai, Tsukuba 305-8572, Japan
- Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan
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13
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Golomb BA, Sanchez Baez R, Schilling JM, Dhanani M, Fannon MJ, Berg BK, Miller BJ, Taub PR, Patel HH. Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity. Sci Rep 2023; 13:10739. [PMID: 37438460 DOI: 10.1038/s41598-023-35896-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 05/25/2023] [Indexed: 07/14/2023] Open
Abstract
Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.
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Affiliation(s)
- Beatrice A Golomb
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive #0995, La Jolla, CA, 92093-0995, USA.
| | - Roel Sanchez Baez
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive #0995, La Jolla, CA, 92093-0995, USA
- San Ysidro Health Center, San Diego, CA, 92114, USA
| | - Jan M Schilling
- VA San Diego Healthcare System and Department of Anesthesiology, University of California, San Diego, San Diego, CA, 92161, USA
| | - Mehul Dhanani
- VA San Diego Healthcare System and Department of Anesthesiology, University of California, San Diego, San Diego, CA, 92161, USA
- Avidity Biosciences, San Diego, CA, 92121, USA
| | - McKenzie J Fannon
- VA San Diego Healthcare System and Department of Anesthesiology, University of California, San Diego, San Diego, CA, 92161, USA
| | - Brinton K Berg
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive #0995, La Jolla, CA, 92093-0995, USA
| | - Bruce J Miller
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive #0995, La Jolla, CA, 92093-0995, USA
| | - Pam R Taub
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA
| | - Hemal H Patel
- VA San Diego Healthcare System and Department of Anesthesiology, University of California, San Diego, San Diego, CA, 92161, USA
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14
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Françoso E, Zuntini AR, Ricardo PC, Araújo NS, Silva JPN, Brown MJF, Arias MC. The complete mitochondrial genome of Trigonisca nataliae (Hymenoptera, Apidae) assemblage reveals heteroplasmy in the control region. Gene 2023:147621. [PMID: 37419430 DOI: 10.1016/j.gene.2023.147621] [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: 04/25/2023] [Revised: 06/13/2023] [Accepted: 07/05/2023] [Indexed: 07/09/2023]
Abstract
The evolution of mitochondrial genomes in the stingless bees is surprisingly dynamic, making them a model system to understand mitogenome structure, function, and evolution. Out of the seven mitogenomes available in this group, five exhibit atypical characteristics, including extreme rearrangements, rapid evolution and complete mitogenome duplication. To further explore the mitogenome diversity in these bees, we utilized isolated mtDNA and Illumina sequencing to assemble the complete mitogenome of Trigonisca nataliae, a species found in Northern Brazil. The mitogenome of T. nataliae was highly conserved in gene content and structure when compared to Melipona species but diverged in the control region (CR). Using PCR amplification, cloning and Sanger sequencing, six different CR haplotypes, varying in size and content, were recovery. These findings indicate that heteroplasmy, where different mitochondrial haplotypes coexist within individuals, occurs in T. nataliae. Consequently, we argue that heteroplasmy might indeed be a common phenomenon in bees that could be associated with variations in mitogenome size and challenges encountered during the assembly process.
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Affiliation(s)
- Elaine Françoso
- Centre for Ecology, Evolution and Behaviour, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, TW20 0EX, UK; Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil.
| | | | - Paulo Cseri Ricardo
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
| | - Natália Souza Araújo
- Unit of Evolutionary Biology & Ecology, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - João Paulo Naldi Silva
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
| | - Mark J F Brown
- Centre for Ecology, Evolution and Behaviour, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, TW20 0EX, UK
| | - Maria Cristina Arias
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
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15
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Swerdlow RH. The Alzheimer's Disease Mitochondrial Cascade Hypothesis: A Current Overview. J Alzheimers Dis 2023; 92:751-768. [PMID: 36806512 DOI: 10.3233/jad-221286] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Viable Alzheimer's disease (AD) hypotheses must account for its age-dependence; commonality; association with amyloid precursor protein, tau, and apolipoprotein E biology; connection with vascular, inflammation, and insulin signaling changes; and systemic features. Mitochondria and parameters influenced by mitochondria could link these diverse characteristics. Mitochondrial biology can initiate changes in pathways tied to AD and mediate the dysfunction that produces the clinical phenotype. For these reasons, conceptualizing a mitochondrial cascade hypothesis is a straightforward process and data accumulating over decades argue the validity of its principles. Alternative AD hypotheses may yet account for its mitochondria-related phenomena, but absent this happening a primary mitochondrial cascade hypothesis will continue to evolve and attract interest.
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Affiliation(s)
- Russell H Swerdlow
- University of Kansas Alzheimer's Disease Research Center, Fairway, KS, USA.,Departments of Neurology, Molecular and Integrative Physiology, and Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS, USA
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16
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Santos AL, Sinha S. Ageing, Metabolic Dysfunction, and the Therapeutic Role of Antioxidants. Subcell Biochem 2023; 103:341-435. [PMID: 37120475 DOI: 10.1007/978-3-031-26576-1_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
The gradual ageing of the world population has been accompanied by a dramatic increase in the prevalence of obesity and metabolic diseases, especially type 2 diabetes. The adipose tissue dysfunction associated with ageing and obesity shares many common physiological features, including increased oxidative stress and inflammation. Understanding the mechanisms responsible for adipose tissue dysfunction in obesity may help elucidate the processes that contribute to the metabolic disturbances that occur with ageing. This, in turn, may help identify therapeutic targets for the treatment of obesity and age-related metabolic disorders. Because oxidative stress plays a critical role in these pathological processes, antioxidant dietary interventions could be of therapeutic value for the prevention and/or treatment of age-related diseases and obesity and their complications. In this chapter, we review the molecular and cellular mechanisms by which obesity predisposes individuals to accelerated ageing. Additionally, we critically review the potential of antioxidant dietary interventions to counteract obesity and ageing.
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Affiliation(s)
- Ana L Santos
- IdISBA - Fundación de Investigación Sanitaria de las Islas Baleares, Palma, Spain.
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17
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Miller S, Lee DA, Muhimpundu S, Maxwell CA. Developing and pilot testing a frailty-focused education and communication training workshop. PEC INNOVATION 2022; 1:100013. [PMID: 37364013 PMCID: PMC10194190 DOI: 10.1016/j.pecinn.2021.100013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 06/28/2023]
Abstract
Objective To describe development and pilot testing of a multi-modal frailty-focused education and communication training workshop for health care clinicians. Methods Pilot testing was conducted via two workshops (#1:face-to-face [2019], #2:virtual [2020]). Participants: convenience sample of clinicians and students who volunteered. Workshop #1 included registered nurses working in an acute care and one medical student (N=14); #2: nursing students enrolled in an APRN program. Design: Pre/post observational study. Data analysis: descriptive statistics, paired t-tests and Wilcoxon rank test. Results Statistically significant increases in frailty knowledge (#1: p = 0.02, d = 0.44; #2: p = 0.006, d = 0.55) and self-reported competency with older adult interactions (#1: p < 0.001, d = 0.62; #2: p = 0.001, d = 0.63) were reported for both workshops. Post course evaluations of the workshop were positive, with scores ranging from 3.5-3.9 (range: 0-4) for increased understanding of the concept of frailty, communication to support health-related behavior, and best practice empathic communication skills. Conclusion The FCOM workshop was successful. Participants gained knowledge and skills for use in working with older adults across the aging continuum from non-frail to frail. Innovation Our FCOM training workshop expands prior communication training on shared decision-making with frail individuals to a broader population of all older adults.
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Affiliation(s)
- Sally Miller
- Vanderbilt University School of Nursing, 461 21 Ave South, Nashville, TN 37240, USA
| | - Deborah A. Lee
- Middle Tennessee State University, 1301 East Main Street, Murfreesboro, TN 37132, USA
| | - Sylvie Muhimpundu
- Vanderbilt University School of Nursing, 461 21 Ave South, Nashville, TN 37240, USA
| | - Cathy A. Maxwell
- Vanderbilt University School of Nursing, 461 21 Ave South, Nashville, TN 37240, USA
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18
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Luo J, Shen S, Xia J, Wang J, Gu Z. Mitochondria as the Essence of Yang Qi in the Human Body. PHENOMICS (CHAM, SWITZERLAND) 2022; 2:336-348. [PMID: 36939762 PMCID: PMC9590506 DOI: 10.1007/s43657-022-00060-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/26/2022]
Abstract
The concept of Yang Qi in Traditional Chinese Medicine (TCM) has many similarities with mitochondria in modern medicine. Both are indispensable to human beings and closely related to life and death. This article discusses the similarities in various aspects between mitochondria and Yang Qi, including body temperature, aging, newborns, circadian rhythm, immunity, and meridian. It is well-known that Yang Qi is vital for human health. Interestingly, decreased mitochondrial function is thought to be key to the development of various diseases. Here, we further explain diseases induced by Yang Qi deficiency, such as cancer, chronic fatigue syndrome, sleep disorder, senile dementia, and metabolic diseases, from the perspective of mitochondrial function. We aim to establish similarities and connections between two important concepts, and hope our essay can stimulate further discussion and investigation on unifying important concepts in western medicine and alternative medicine, especially TCM, and provide unique holistic insights into understanding human health.
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Affiliation(s)
- Junjie Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100193 China
| | - Shiwei Shen
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, and Human Phenome Institute, Fudan University, Shanghai, 200438 China
| | - Jingjing Xia
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, and Human Phenome Institute, Fudan University, Shanghai, 200438 China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, and Human Phenome Institute, Fudan University, Shanghai, 200438 China
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853 USA
- Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou, 511458 China
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19
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Escada-Rebelo S, Cristo MI, Ramalho-Santos J, Amaral S. Mitochondria-Targeted Compounds to Assess and Improve Human Sperm Function. Antioxid Redox Signal 2022; 37:451-480. [PMID: 34847742 DOI: 10.1089/ars.2021.0238] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Currently 10%-15% of couples in reproductive age face infertility issues. More importantly, male factor contributes to 50% of these cases (either alone or in combination with female causes). Among various reasons, impaired sperm function is the main cause for male infertility. Furthermore, mitochondrial dysfunction and oxidative stress due to increased reactive oxygen species (ROS) production, particularly of mitochondrial origin, are believed to be the main contributors. Recent Advances: Mitochondrial dysfunction, particularly due to increased ROS production, has often been linked to impaired sperm function/quality. For decades, different methods and approaches have been developed to assess mitochondrial features that might correlate with sperm functionality. This connection is now completely accepted, with mitochondrial functionality assessment used more commonly as a readout of sperm functionality. More recently, mitochondria-targeted compounds are on the frontline for both assessment and therapeutic approaches. Critical Issues: In this review, we summarize the current methods for assessing key mitochondrial parameters known to reflect sperm quality as well as therapeutic strategies using mitochondria-targeted antioxidants aiming to improve sperm function in various situations, particularly after sperm cryopreservation. Future Directions: Although more systematic research is needed, mitochondria-targeted compounds definitely represent a promising tool to assess as well as to protect and improve sperm function. Antioxid. Redox Signal. 37, 451-480.
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Affiliation(s)
- Sara Escada-Rebelo
- PhD Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,IIIUC - Institute for Interdisciplinary Research, Casa Costa Alemão, University of Coimbra, Coimbra, Portugal
| | - Maria Inês Cristo
- Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - João Ramalho-Santos
- Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Sandra Amaral
- Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,IIIUC - Institute for Interdisciplinary Research, Casa Costa Alemão, University of Coimbra, Coimbra, Portugal
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20
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Gureev AP, Andrianova NV, Pevzner IB, Zorova LD, Chernyshova EV, Sadovnikova IS, Chistyakov DV, Popkov VA, Semenovich DS, Babenko VA, Silachev DN, Zorov DB, Plotnikov EY, Popov VN. Dietary restriction modulates mitochondrial DNA damage and oxylipin profile in aged rats. FEBS J 2022; 289:5697-5713. [DOI: 10.1111/febs.16451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/16/2022] [Accepted: 04/01/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Artem P. Gureev
- Department of Genetics, Cytology and Bioengineering Voronezh State University Voronezh Russia
- Laboratory of Metagenomics and Food Biotechnology Voronezh State University of Engineering Technology Voronezh Russia
| | - Nadezda V. Andrianova
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
| | - Irina B. Pevzner
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Ljubava D. Zorova
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | | | - Irina S. Sadovnikova
- Department of Genetics, Cytology and Bioengineering Voronezh State University Voronezh Russia
| | - Dmitry V. Chistyakov
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
| | - Vasily A. Popkov
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Dmitry S. Semenovich
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
| | - Valentina A. Babenko
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Denis N. Silachev
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Dmitry B. Zorov
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Egor Y. Plotnikov
- Belozersky Institute of Physico‐Chemical Biology Lomonosov Moscow State University Moscow Russia
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology Moscow Russia
| | - Vasily N. Popov
- Department of Genetics, Cytology and Bioengineering Voronezh State University Voronezh Russia
- Laboratory of Metagenomics and Food Biotechnology Voronezh State University of Engineering Technology Voronezh Russia
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21
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Castañeda V, Haro-Vinueza A, Salinas I, Caicedo A, Méndez MÁ. The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity. Mitochondrion 2022; 66:13-26. [PMID: 35817296 DOI: 10.1016/j.mito.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/20/2022] [Accepted: 06/26/2022] [Indexed: 11/26/2022]
Abstract
Mitochondrial dysfunction is a major hallmark of aging. Mitochondrial DNA (mtDNA) mutations (inherited or acquired) may cause a malfunction of the respiratory chain (RC), and thus negatively affect cell metabolism and function. In contrast, certain mtDNA single nucleotide polymorphisms (SNPs) may be beneficial to mitochondrial electron transport chain function and the extension of cellular health as well as lifespan. The goal of the MitoAging project is to detect key physiological characteristics and mechanisms that improve mitochondrial function and use them to develop therapies to increase longevity and a healthy lifespan. We chose to perform a systematic literature review (SLR) as a tool to collect key mtDNA SNPs associated with an increase in lifespan. Then validated our results by comparing them to the MitoMap database. Next, we assessed the effect of relevant SNPs on protein stability. A total of 28 SNPs were found in protein coding regions. These SNPs were reported in Japan, China, Turkey, and India. Among the studied SNPs, the C5178A mutation in the ND2 gene of Complex I of the RC was detected in all the reviewed reports except in Uygur Chinese centenarians. Then, we found that G9055A (ATP6 gene) and A10398G (ND3 gene) polymorphisms have been associated with a protective effect against Parkinson's disease (PD). Additionally, C8414T in ATP8 was significantly associated with longevity in three Japanese reports. Interestingly, using MitoMap we found that G9055A (ATP6 gene) was the only SNP promoting longevity not associated with any pathology. The identification of SNPs associated with an increase in lifespan opens the possibility to better understand individual differences regarding a decrease in illness susceptibility and find strategies that contribute to healthy aging.
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Affiliation(s)
- Verónica Castañeda
- PhD Program in Biomedicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile; Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Biología, Colegio de Ciencias Biológicas y Ambientales COCIBA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador
| | - Alissen Haro-Vinueza
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Biología, Colegio de Ciencias Biológicas y Ambientales COCIBA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador
| | - Ivonne Salinas
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Andrés Caicedo
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador.
| | - Miguel Ángel Méndez
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; Grupo de Química Computacional y Teórica, Departamento de Ingeniería Química, Colegio de Ciencias e Ingenierías, Politécnico, Universidad San Francisco de Quito, Quito, Ecuador.
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22
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Panvini AR, Gvritishvili A, Galvan H, Nashine S, Atilano SR, Kenney MC, Tombran-Tink J. Differential mitochondrial and cellular responses between H vs. J mtDNA haplogroup-containing human RPE transmitochondrial cybrid cells. Exp Eye Res 2022; 219:109013. [PMID: 35283109 PMCID: PMC9949352 DOI: 10.1016/j.exer.2022.109013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 02/02/2023]
Abstract
Mitochondrial dysfunction is associated with several retinal degenerative diseases including Age-related Macular Degeneration (AMD). Human mitochondrial DNA (mtDNA) haplogroups are inherited from a common ancestral clan and are defined by specific sets of genetic differences. The purpose of this study was to determine and compare the effects of mtDNA haplogroups H and J on transcriptome regulation and cellular resilience to oxidative stress in human RPE cytoplasmic hybrid (cybrid) cell lines in vitro. ARPE-19 cybrid cell lines containing mtDNA haplogroups H and J were created by fusing platelets obtained from normal individuals containing H and J haplogroups with mitochondria-deficient (Rho0) ARPE-19 cell lines. These cybrids were exposed to oxidative stress using 300 μM hydrogen peroxide (H2O2), following which mitochondrial structural dynamics was studied at varying time points using the mitochondrial markers - TOMM20 (Translocase of Outer Mitochondrial Membrane 20) and Mitotracker. To evaluate mitochondrial function, levels of ROS, ΔΨm and [Ca2+]m were measured using flow cytometry, and ATP levels were measured using luminescence. The H and J cybrid cell transcriptomes were compared using RNAseq to determine how changes in mtDNA regulate gene expression. Inflammatory and angiogenic markers were measured using Luminex assay to understand how these mtDNAs influenced cellular response to oxidative stress. Actin filaments' morphology was examined using confocal microscopy. Following exposure to H2O2 stress, the J cybrids showed increased mitochondrial swelling and perinuclear localization, disturbed fission and fusion, increased calcium uptake (p < 0.05), and higher secreted levels of TNF-α and VEGF (p < 0.001), compared to the H cybrids. Calcium uptake by J cybrids was reduced using an IP3R inhibitor. Thirteen genes involved in mitochondrial complex I and V function, fusion/fission events, cellular energy homeostasis, antioxidant defenses, and inflammatory responses, were significantly downregulated with log2 fold changes ranging between -1.5 and -5.1. Actin levels were also significantly reduced in stressed J cybrids (p ≤ 0.001) and disruption in actin filaments was observed. Thirty-eight genes involved in mitochondrial and cellular support functions, were upregulated with log2 fold changes of +1.5 to +5.9 in J cybrids compared to H cybrids. Our results demonstrate significant structural and functional differences between mtDNA haplogroups H vs. J -containing cybrid cells. Our study suggests that the J mtDNA haplogroup can alter the transcriptome to increase cellular susceptibility to stress and retinal degenerations.
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Affiliation(s)
- Ana Rubin Panvini
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Anzor Gvritishvili
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Hannah Galvan
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Sonali Nashine
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, 92697, USA
| | - Shari R. Atilano
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, 92697, USA
| | - M. Cristina Kenney
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, 92697, USA
| | - Joyce Tombran-Tink
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA; Department of Ophthalmology, Penn State College of Medicine, Hershey, PA, 17033, USA.
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23
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Chocron ES, Mdaki K, Jiang N, Cropper J, Pickering AM. Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function. Commun Biol 2022; 5:467. [PMID: 35577894 PMCID: PMC9110405 DOI: 10.1038/s42003-022-03405-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/23/2022] [Indexed: 11/09/2022] Open
Abstract
Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.
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Affiliation(s)
- E Sandra Chocron
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA
- Department of Radiation Oncology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Kennedy Mdaki
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Nisi Jiang
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Jodie Cropper
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Andrew M Pickering
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA.
- Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Role of Mitochondrial Dynamics in Cocaine's Neurotoxicity. Int J Mol Sci 2022; 23:ijms23105418. [PMID: 35628228 PMCID: PMC9145816 DOI: 10.3390/ijms23105418] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 01/25/2023] Open
Abstract
The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as one way it exerts its neurotoxicity, wherein the disturbances in mitochondrial dynamics have been suggested to play an essential role. In this review, we summarize the neurotoxicity of cocaine and the role of mitochondrial dynamics in cellular physiology. Subsequently, we introduce current findings that link disturbed neuronal mitochondrial dynamics with cocaine exposure. Finally, the possible role and potential therapeutic value of mitochondrial dynamics in cocaine neurotoxicity are discussed.
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25
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Yang Z, Slone J, Huang T. Next-Generation Sequencing to Characterize Mitochondrial Genomic DNA Heteroplasmy. Curr Protoc 2022; 2:e412. [PMID: 35532282 DOI: 10.1002/cpz1.412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Mitochondria play a very important role in many crucial cellular functions. Each eukaryotic cell contains hundreds of mitochondria with hundreds of mitochondrial genomes. Mutant and wild-type mitochondrial DNA (mtDNA) may co-exist as heteroplasmy and cause human disease. The purpose of the protocols in this article is to simultaneously determine the mtDNA sequence and quantify the heteroplasmy level using parallel sequencing. The protocols include mitochondrial genomic DNA PCR amplification of two full-length products using two distinct sets of PCR primers. The PCR products are mixed at an equimolar ratio, and the samples are then barcoded and sequenced with high-throughput next-generation sequencing technology. This technology is highly sensitive, specific, and accurate in determining mtDNA mutations and the degree/level of heteroplasmy. © 2022 Wiley Periodicals LLC. Basic Protocol 1: PCR amplification of mitochondrial DNA Basic Protocol 2: Analysis of next-generation sequencing of mitochondrial DNA Basic Protocol 3: Mutect2 pipeline for automated sample processing and large-scale data analysis.
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Affiliation(s)
- Zeyu Yang
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Jesse Slone
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Taosheng Huang
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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26
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Farhang-Sardroodi S, La Croix MA, Wilkie KP. Chemotherapy-induced cachexia and model-informed dosing to preserve lean mass in cancer treatment. PLoS Comput Biol 2022; 18:e1009505. [PMID: 35312676 PMCID: PMC8989307 DOI: 10.1371/journal.pcbi.1009505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 04/07/2022] [Accepted: 03/01/2022] [Indexed: 11/19/2022] Open
Abstract
Although chemotherapy is a standard treatment for cancer, it comes with significant side effects. In particular, certain agents can induce severe muscle loss, known as cachexia, worsening patient quality of life and treatment outcomes. 5-fluorouracil, an anti-cancer agent used to treat several cancers, has been shown to cause muscle loss. Experimental data indicates a non-linear dose-dependence for muscle loss in mice treated with daily or week-day schedules. We present a mathematical model of chemotherapy-induced muscle wasting that captures this non-linear dose-dependence. Area-under-the-curve metrics are proposed to quantify the treatment’s effects on lean mass and tumour control. Model simulations are used to explore alternate dosing schedules, aging effects, and morphine use in chemotherapy treatment with the aim of better protecting lean mass while actively targeting the tumour, ultimately leading to improved personalization of treatment planning and improved patient quality of life. In this paper we present a novel mathematical model for muscle loss due to cancer chemotherapy treatment. Loss of muscle mass relates to increased drug toxicity and side-effects, and to decreased patient quality of life and survival rates. With our model, we examine the therapeutic efficacy of various dosing schedules with the aim of controlling a growing tumour while also preserving lean mass. Preservation of body composition, in addition to consideration of inflammation and immune interactions, the gut microbiome, and other systemic health measures, may lead to improved patient-specific treatment plans that improve patient quality of life.
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Affiliation(s)
- Suzan Farhang-Sardroodi
- Modelling Infection, and Immunity Lab, Department of Mathematics and Statistics, York University, Toronto, Canada
- Centre for Disease Modelling (CDM), Department of Mathematics and Statistics, York University, Toronto, Canada
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27
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Hernández-Ainsa C, López-Gallardo E, García-Jiménez MC, Climent-Alcalá FJ, Rodríguez-Vigil C, García Fernández de Villalta M, Artuch R, Montoya J, Ruiz-Pesini E, Emperador S. Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome. Dis Model Mech 2022; 15:dmm049083. [PMID: 35191981 PMCID: PMC8906170 DOI: 10.1242/dmm.049083] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/06/2021] [Indexed: 01/19/2023] Open
Abstract
Pearson syndrome is a rare multisystem disease caused by single large-scale mitochondrial DNA deletions (SLSMDs). The syndrome presents early in infancy and is mainly characterised by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus the development of new models for the study of Pearson syndrome and new therapy strategies is essential. In this work, we report three different cell models carrying an SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSCs). All studied models exhibited an aberrant mitochondrial ultrastructure and defective oxidative phosphorylation system function, showing a decrease in different parameters, such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite this, iPSCs harbouring 'common deletion' were able to differentiate into three germ layers. Additionally, cybrid clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile; therefore, we consider that these three models are useful for the in vitro study of Pearson syndrome, as well as for testing new specific therapies. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Carmen Hernández-Ainsa
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Ester López-Gallardo
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | | | | | | | | | - Rafael Artuch
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Clinical Biochemistry, Genetics, Pediatric Neurology and Neonatalogy Departments, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
| | - Julio Montoya
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Eduardo Ruiz-Pesini
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Sonia Emperador
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
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28
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Mediterranean Diet a Potential Strategy against SARS-CoV-2 Infection: A Narrative Review. Medicina (B Aires) 2021; 57:medicina57121389. [PMID: 34946334 PMCID: PMC8704657 DOI: 10.3390/medicina57121389] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 01/08/2023] Open
Abstract
Mediterranean Diet represents the traditional eating habits of populations living around the Mediterranean Sea, and it is associated with a lower risk of overall mortality and cancer incidence and cardiovascular diseases. Severe acute respiratory syndrome coronavirus 2 is a new pandemic, and represents a significant and critical threat to global human health. In this study, we aimed to review the possible effects of Mediterranean Diet against the risk of the coronavirus disease 2019. Several vitamins, minerals, fatty acids, and phytochemicals with their potential anti-COVID-19 activity are presented. Different risk factors may increase or reduce the probability of contracting the disease. Mediterranean Diet has also a positive action on inflammation and immune system and could have a protective effect against severe acute respiratory syndrome coronavirus 2. Further studies are needed to corroborate the benefits of the Mediterranean Diet protective role on infection with SARS-CoV-2.
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Holt AG, Davies AM. The Effect of Mitochondrial DNA Half-Life on Deletion Mutation Proliferation in Long Lived Cells. Acta Biotheor 2021; 69:671-695. [PMID: 34131800 DOI: 10.1007/s10441-021-09417-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/07/2021] [Indexed: 01/21/2023]
Abstract
The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging and age related neurodegenerative conditions. In this study we model the effect of mtDNA half-life on mtDNA competition and selection. It has been proposed that mutation deletions ([Formula: see text]) have a replicative advantage over wild-type ([Formula: see text]) and that this is detrimental to the host cell, especially in post-mitotic cells. An individual cell can be viewed as forming a closed ecosystem containing a large population of independently replicating mtDNA. Within this enclosed environment a selfishly replicating [Formula: see text] would compete with the [Formula: see text] for space and resources to the detriment of the host cell. In this paper, we use a computer simulation to model cell survival in an environment where [Formula: see text] compete with [Formula: see text] such that the cell expires upon [Formula: see text] extinction. We focus on the survival time for long lived post-mitotic cells, such as neurons. We confirm previous observations that [Formula: see text] do have a replicative advantage over [Formula: see text]. As expected, cell survival times diminished with increased mutation probabilities, however, the relationship between survival time and mutation rate was non-linear, that is, a ten-fold increase in mutation probability only halved the survival time. The results of our model also showed that a modest increase in half-life had a profound affect on extending cell survival time, thereby, mitigating the replicative advantage of [Formula: see text]. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could significantly delay their onset.
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30
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Warnsmann V, Meisterknecht J, Wittig I, Osiewacz HD. Aging of Podospora anserina Leads to Alterations of OXPHOS and the Induction of Non-Mitochondrial Salvage Pathways. Cells 2021; 10:cells10123319. [PMID: 34943827 PMCID: PMC8699231 DOI: 10.3390/cells10123319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 01/19/2023] Open
Abstract
The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
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Affiliation(s)
- Verena Warnsmann
- Institute of Molecular Biosciences, Faculty of Biosciences, Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
| | - Jana Meisterknecht
- Functional Proteomics, Institute of Cardiovascular Physiology, Faculty of Medicine, Goethe-University, Theodor-Stein-Kai 7, 60590 Frankfurt am Main, Germany
| | - Ilka Wittig
- Functional Proteomics, Institute of Cardiovascular Physiology, Faculty of Medicine, Goethe-University, Theodor-Stein-Kai 7, 60590 Frankfurt am Main, Germany
| | - Heinz D Osiewacz
- Institute of Molecular Biosciences, Faculty of Biosciences, Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
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31
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Wilkins HM, Swerdlow RH. Mitochondrial links between brain aging and Alzheimer's disease. Transl Neurodegener 2021; 10:33. [PMID: 34465385 PMCID: PMC8408998 DOI: 10.1186/s40035-021-00261-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/21/2021] [Indexed: 02/08/2023] Open
Abstract
Advancing age is a major risk factor for Alzheimer's disease (AD). This raises the question of whether AD biology mechanistically diverges from aging biology or alternatively represents exaggerated aging. Correlative and modeling studies can inform this question, but without a firm grasp of what drives aging and AD it is difficult to definitively resolve this quandary. This review speculates over the relevance of a particular hallmark of aging, mitochondrial function, to AD, and further provides background information that is pertinent to and provides perspective on this speculation.
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Affiliation(s)
- Heather M Wilkins
- University of Kansas Alzheimer's Disease Research Center, Kansas City, KS, USA
- Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
- Departments of Biochemistry and Molecular Biology, Medical Center, University of Kansas Medical Center, Kansas City, USA
| | - Russell H Swerdlow
- University of Kansas Alzheimer's Disease Research Center, Kansas City, KS, USA.
- Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
- Departments of Biochemistry and Molecular Biology, Medical Center, University of Kansas Medical Center, Kansas City, USA.
- Departments of Molecular and Integrative Physiology, Medical Center, University of Kansas Medical Center, Kansas City, KS, USA.
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32
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Spector LG, Spellman SR, Thyagarajan B, Beckman KB, Hoffmann C, Garbe J, Hahn T, Sucheston-Campbell L, Richardson M, De For TE, Tolar J, Verneris MR. Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR. Transplant Cell Ther 2021; 27:836.e1-836.e7. [PMID: 34174468 DOI: 10.1016/j.jtct.2021.06.019] [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: 04/14/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 11/18/2022]
Abstract
Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.
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Affiliation(s)
- Logan G Spector
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Kenneth B Beckman
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Cody Hoffmann
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - John Garbe
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Theresa Hahn
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | - Michaela Richardson
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Todd E De For
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Michael R Verneris
- University of Colorado Denver, Children's Cancer and Blood Disorders, Denver, Colorado
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Stimulation of Variant Forms of the Mitochondrial DNA Helicase Twinkle by the Mitochondrial Single-Stranded DNA-Binding Protein. Methods Mol Biol 2021. [PMID: 33847968 DOI: 10.1007/978-1-0716-1290-3_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
Defects in mitochondrial DNA (mtDNA) maintenance may lead to disturbances in mitochondrial homeostasis and energy production in eukaryotic cells, causing diseases. During mtDNA replication, the mitochondrial single-stranded DNA-binding protein (mtSSB) stabilizes and protects the exposed single-stranded mtDNA from nucleolysis; perhaps more importantly, it appears to coordinate the actions of both the replicative mtDNA helicase Twinkle and DNA polymerase gamma at the replication fork. Here, we describe a helicase stimulation protocol to test in vitro the functional interaction between mtSSB and variant forms of Twinkle. We show for the first time that the C-terminal tail of Twinkle is important for such an interaction, and that it negatively regulates helicase unwinding activity in a salt-dependent manner.
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34
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Yan W, Zhang T, Kang Y, Zhang G, Ji X, Feng X, Shi G. Testosterone ameliorates age-related brain mitochondrial dysfunction. Aging (Albany NY) 2021; 13:16229-16247. [PMID: 34139672 PMCID: PMC8266321 DOI: 10.18632/aging.203153] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 05/24/2021] [Indexed: 01/07/2023]
Abstract
Brain mitochondrial dysfunction and reduced testosterone levels are common features of aging in men. Although evidence suggests that the two phenomena are interrelated, it is unclear whether testosterone supplementation ameliorates mitochondrial dysfunction in the aging male brain. Here, we show that testosterone supplementation significantly alleviates exploratory behavioral deficits and oxidative damage in the substantia nigra and hippocampus of aging male rats. These effects were consistent with improved mitochondrial function, reflected by testosterone-induced increases in mitochondrial membrane potential (MMP), antioxidant enzyme (GSH-PX, catalase, and Mn-SOD) expression/activity, and mitochondrial respiratory complex activities in both brain regions. Furthermore, elevated PGC-1α, NRF-1, and TFAM expression (suggestive of enhanced mitochondrial biogenesis), increased citrate synthase activity, mtDNA copy number, and ND1, COX1, and ATP6 expression (indicative of increased mitochondrial content), as well as increased PINK1/Parkin and decreased P62 expression (suggesting mitophagy activation), were detected in the substantial nigra and hippocampus of aged male rats after testosterone supplementation. These findings suggest that testosterone supplementation may be a viable approach to ameliorating brain mitochondrial dysfunction and thus prevent or treat cognitive-behavioral deficits and neurodegenerative conditions associated with aging.
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Affiliation(s)
- Wensheng Yan
- Department of Neurobiology, Hebei Medical University, Shijiazhuang, China
| | - Tianyun Zhang
- Department of Neurobiology, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Yunxiao Kang
- Department of Neurobiology, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Guoliang Zhang
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Xiaoming Ji
- Department of Neurobiology, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Xu Feng
- Hebei Laboratory Animal Center, Hebei Medical University, Shijiazhuang, China
| | - Geming Shi
- Department of Neurobiology, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
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35
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Alves SS, Silva-Junior RMPD, Servilha-Menezes G, Homolak J, Šalković-Petrišić M, Garcia-Cairasco N. Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses. J Alzheimers Dis 2021; 82:71-105. [PMID: 34024838 DOI: 10.3233/jad-210234] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.
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Affiliation(s)
- Suélen Santos Alves
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Rui Milton Patrício da Silva-Junior
- Department of Internal Medicine, Ribeirão Preto Medical School -University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Gabriel Servilha-Menezes
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Jan Homolak
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Melita Šalković-Petrišić
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Norberto Garcia-Cairasco
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
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Kaliszewska A, Allison J, Martini M, Arias N. Improving Age-Related Cognitive Decline through Dietary Interventions Targeting Mitochondrial Dysfunction. Int J Mol Sci 2021; 22:ijms22073574. [PMID: 33808221 PMCID: PMC8036520 DOI: 10.3390/ijms22073574] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/13/2022] Open
Abstract
Aging is inevitable and it is one of the major contributors to cognitive decline. However, the mechanisms underlying age-related cognitive decline are still the object of extensive research. At the biological level, it is unknown how the aging brain is subjected to progressive oxidative stress and neuroinflammation which determine, among others, mitochondrial dysfunction. The link between mitochondrial dysfunction and cognitive impairment is becoming ever more clear by the presence of significant neurological disturbances in human mitochondrial diseases. Possibly, the most important lifestyle factor determining mitochondrial functioning is nutrition. Therefore, with the present work, we review the latest findings disclosing a link between nutrition, mitochondrial functioning and cognition, and pave new ways to counteract cognitive decline in late adulthood through diet.
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Affiliation(s)
- Aleksandra Kaliszewska
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London SE5 8AF, UK; (A.K.); (J.A.)
| | - Joseph Allison
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London SE5 8AF, UK; (A.K.); (J.A.)
| | - Matteo Martini
- Department of Psychology, University of East London, London E154LZ, UK;
| | - Natalia Arias
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London SE5 8AF, UK; (A.K.); (J.A.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33005 Oviedo, Spain
- Correspondence:
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Warnsmann V, Marschall LM, Osiewacz HD. Impaired F 1F o-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging. Cells 2021; 10:757. [PMID: 33808173 PMCID: PMC8066942 DOI: 10.3390/cells10040757] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/22/2021] [Accepted: 03/27/2021] [Indexed: 01/11/2023] Open
Abstract
Mitochondrial F1Fo-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F1Fo-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F1Fo-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging.
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Affiliation(s)
| | | | - Heinz D. Osiewacz
- Faculty of Biosciences, Institute of Molecular Biosciences, Goethe University, 60438 Frankfurt, Germany; (V.W.); (L.-M.M.)
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Heinz D, Krotova E, Hamann A, Osiewacz HD. Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension. Front Cell Dev Biol 2021; 9:616520. [PMID: 33748105 PMCID: PMC7969656 DOI: 10.3389/fcell.2021.616520] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/27/2021] [Indexed: 12/21/2022] Open
Abstract
Organismic aging is known to be controlled by genetic and environmental traits. Pathways involved in the control of cellular metabolism play a crucial role. Previously, we identified a role of PaCLPP, a mitochondrial matrix protease, in the control of the mitochondrial energy metabolism, aging, and lifespan of the fungal aging model Podospora anserina. Most surprisingly, we made the counterintuitive observation that the ablation of this component of the mitochondrial quality control network leads to lifespan extension. In the current study, we investigated the role of energy metabolism of P. anserina. An age-dependent metabolome analysis of the wild type and a PaClpP deletion strain verified differences and changes of various metabolites in cultures of the PaClpP mutant and the wild type. Based on these data, we generated and analyzed a PaSnf1 deletion mutant and a ΔPaSnf1/ΔPaClpP double mutant. In both mutants PaSNF1, the catalytic α-subunit of AMP-activated protein kinase (AMPK) is ablated. PaSNF1 was found to be required for the development of fruiting bodies and ascospores and the progeny of sexual reproduction of this ascomycete and impact mitochondrial dynamics and autophagy. Most interestingly, while the single PaSnf1 deletion mutant is characterized by a slight lifespan increase, simultaneous deletion of PaSnf1 and PaClpP leads to a pronounced lifespan extension. This synergistic effect is strongly reinforced in the presence of the mating-type "minus"-linked allele of the rmp1 gene. Compared to the wild type, culture temperature of 35°C instead of the standard laboratory temperature of 27°C leads to a short-lived phenotype of the ΔPaSnf1/ΔPaClpP double mutant. Overall, our study provides novel evidence for complex interactions of different molecular pathways involved in mitochondrial quality control, gene expression, and energy metabolism in the control of organismic aging.
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Affiliation(s)
| | | | | | - Heinz D. Osiewacz
- Institute of Molecular Biosciences, J.W. Goethe University, Frankfurt am Main, Germany
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Ke X, Lin Z, Ye Z, Leng M, Chen B, Jiang C, Jiang X, Li G. Histone Deacetylases in the Pathogenesis of Diabetic Cardiomyopathy. Front Endocrinol (Lausanne) 2021; 12:679655. [PMID: 34367065 PMCID: PMC8339406 DOI: 10.3389/fendo.2021.679655] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022] Open
Abstract
The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated morbidity and mortality; therefore, a comprehensive understanding of DCM development is required for more effective treatment. A disorder of epigenetic posttranscriptional modification of histones in chromatin has been reported to be associated with the pathology of DCM. Recent studies have implicated that histone deacetylases could regulate cardiovascular and metabolic diseases in cellular processes including cardiac fibrosis, hypertrophy, oxidative stress and inflammation. Therefore in this review, we summarized the roles of histone deacetylases in the pathogenesis of DCM, aiming to provide insights into exploring potential preventative and therapeutic strategies of DCM.
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Affiliation(s)
- Xiangyu Ke
- Centre of Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Zhirui Lin
- Centre of Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Zebing Ye
- Department of Cardiology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Meifang Leng
- Department of Cardiology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Bo Chen
- Department of Endocrinology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Chunjie Jiang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyun Jiang
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
- *Correspondence: Xiaoyun Jiang, ; Guowei Li,
| | - Guowei Li
- Centre of Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
- *Correspondence: Xiaoyun Jiang, ; Guowei Li,
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George EK, Reddy PH. Can Healthy Diets, Regular Exercise, and Better Lifestyle Delay the Progression of Dementia in Elderly Individuals? J Alzheimers Dis 2020; 72:S37-S58. [PMID: 31227652 DOI: 10.3233/jad-190232] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of total AD patients can be explained by genetic mutations in APP, PS1, and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state.
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Affiliation(s)
| | - P Hemachandra Reddy
- Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Pharmacology & Neuroscience Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Neurology Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Speech, Language and Hearing Sciences Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Public Health, Graduate School of Biomedical Sciences, Lubbock, TX, USA
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41
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Singh N. Antioxidant metal oxide nanozymes: role in cellular redox homeostasis and therapeutics. PURE APPL CHEM 2020. [DOI: 10.1515/pac-2020-0802] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Abstract
Nanomaterials with enzyme-like activity, generally referred to as ‘nanozymes’, find myriad potential in various biomedical fields. More importantly, the nanoparticles that can functionally mimic the activity of cellular antioxidant enzymes attract tremendous interest owing to their possible therapeutic candidature in oxidative stress-mediated disorders. Oxidative stress culminating due to excess reactive oxygen species (ROS) level and dysregulated cellular antioxidant machinery is implicated in the development and progression of various pathophysiological disorders such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Moreover, the optimum essentiality of ROS due to its pivotal role in cell signaling evokes the requirement of novel artificial antioxidant enzymes that can circumvent the detrimental effects of enhanced ROS levels without perturbing the basal redox status of cells. In recent years, the fast emanating artificial enzymes, i.e. nanozymes with antioxidant enzyme-like activity, has made tremendous progress with their broad applications in therapeutics, diagnostic medicine, bio-sensing, and immunoassay. Among various antioxidant nanoparticles reported till-date, the metal oxide nanozymes have emerged as the most efficient and successful candidates in mimicking the activity of first-line defense antioxidant enzymes, i.e. superoxide dismutase, catalase, and glutathione peroxidase. This review intends to exclusively highlight the development of representative metal oxide-based antioxidant nanozymes capable of maintaining the cellular redox homeostasis and their potential therapeutic significance.
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Affiliation(s)
- Namrata Singh
- Department of Inorganic and Physical Chemistry , Indian Institute of Science , Bangalore 560012 , India
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Medici V, Sarode GV, Napoli E, Song GY, Shibata NM, Guimarães AO, Mordaunt CE, Kieffer DA, Mazi TA, Czlonkowska A, Litwin T, LaSalle JM, Giulivi C. mtDNA depletion-like syndrome in Wilson disease. Liver Int 2020; 40:2776-2787. [PMID: 32996699 PMCID: PMC8079140 DOI: 10.1111/liv.14646] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, with its main pathology attributed to copper-mediated oxidative damage. The limited therapeutic effect of copper chelators and the early occurrence of mitochondrial deficits, however, undermine the prevalence of this mechanism. METHODS We characterized mitochondrial DNA copy number and mutations as well as bioenergetic deficits in blood from patients with WD and in livers of tx-j mice, a mouse model of hepatic copper accumulation. In vitro experiments with hepatocytes treated with CuSO4 were conducted to validate in vivo studies. RESULTS Here, for the first time, we characterized the bioenergetic deficits in WD as consistent with a mitochondrial DNA depletion-like syndrome. This is evidenced by enriched DNA synthesis/replication pathways in serum metabolomics and decreased mitochondrial DNA copy number in blood of WD patients as well as decreased mitochondrial DNA copy number, increased citrate synthase activity, and selective Complex IV deficit in livers of the tx-j mouse model of WD. Tx-j mice treated with the copper chelator penicillamine, methyl donor choline or both ameliorated mitochondrial DNA damage but further decreased mitochondrial DNA copy number. Experiments with copper-loaded HepG2 cells validated the concept of a direct copper-mitochondrial DNA interaction. CONCLUSIONS This study underlines the relevance of targeting the copper-mitochondrial DNA pool in the treatment of WD separate from the established copper-induced oxidative stress-mediated damage.
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Affiliation(s)
- Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, 4150 V Street, PSSB Suite 3500, University of California Davis, Sacramento, CA 95616
| | - Gaurav Vilas Sarode
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, 4150 V Street, PSSB Suite 3500, University of California Davis, Sacramento, CA 95616
| | - Eleonora Napoli
- Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California Davis, Davis, CA 95616
| | - Gyu-Young Song
- Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California Davis, Davis, CA 95616
| | - Noreene M. Shibata
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, 4150 V Street, PSSB Suite 3500, University of California Davis, Sacramento, CA 95616
| | - Andre Oliveira Guimarães
- Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California Davis, Davis, CA 95616
- Laboratório de Ciências Físicas, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes RJ, Brazil
| | - Charles E. Mordaunt
- Department of Medical Microbiology and Immunology, Genome Center, University of California Davis, Davis, CA 95616
- Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, 2825 50 St, University of California Davis, Davis, CA 95817
| | - Dorothy A. Kieffer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, 4150 V Street, PSSB Suite 3500, University of California Davis, Sacramento, CA 95616
| | - Tagreed A. Mazi
- Department of Nutrition, University of California Davis, Davis, CA 95616
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Anna Czlonkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Janine M. LaSalle
- Department of Medical Microbiology and Immunology, Genome Center, University of California Davis, Davis, CA 95616
- Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, 2825 50 St, University of California Davis, Davis, CA 95817
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California Davis, Davis, CA 95616
- Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, 2825 50 St, University of California Davis, Davis, CA 95817
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Green JC, Jiang Y, He L, Xu Y, Sun D, Keoprasert T, Nelson C, Oh U, Lesnefsky EJ, Kellogg GE, Chen Q, Zhang S. Characterization and Discovery of a Selective Small-Molecule Modulator of Mitochondrial Complex I Targeting a Unique Binding Site. J Med Chem 2020; 63:11819-11830. [PMID: 32945676 DOI: 10.1021/acs.jmedchem.0c01021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mitochondrial dysfunction has been recognized as an essential contributor to many human diseases including neurodegenerative disorders. However, the exact pathological role of mitochondrial dysfunction, especially in mitochondrial reactive oxygen species-associated oxidative stress, remains elusive, partially due to the lack of chemical probes with well-defined mechanisms of action. Herein, we describe the characterization and discovery of a rationally designed small molecule ZCM-I-1 as a selective modulator of the production of reactive oxygen species from mitochondrial complex I that does not alter mitochondrial membrane potential and bioenergetics. Chemical biology studies employing photoaffinity probes derived from ZCM-I-1 demonstrated its novel mechanism of action of modulating complex I via interactions with the flavin mononucleotide site, proximal in the reaction pathway within complex I.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Edward J Lesnefsky
- Medical Service, McGuire Department of Veteran Affairs Medical Center, Richmond, Virginia 23224, United States
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Cao J, Cowan DB, Wang DZ. tRNA-Derived Small RNAs and Their Potential Roles in Cardiac Hypertrophy. Front Pharmacol 2020; 11:572941. [PMID: 33041815 PMCID: PMC7527594 DOI: 10.3389/fphar.2020.572941] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/28/2020] [Indexed: 12/21/2022] Open
Abstract
Transfer RNAs (tRNAs) are abundantly expressed, small non-coding RNAs that have long been recognized as essential components of the protein translation machinery. The tRNA-derived small RNAs (tsRNAs), including tRNA halves (tiRNAs), and tRNA fragments (tRFs), were unexpectedly discovered and have been implicated in a variety of important biological functions such as cell proliferation, cell differentiation, and apoptosis. Mechanistically, tsRNAs regulate mRNA destabilization and translation, as well as retro-element reverse transcriptional and post-transcriptional processes. Emerging evidence has shown that tsRNAs are expressed in the heart, and their expression can be induced by pathological stress, such as hypertrophy. Interestingly, cardiac pathophysiological conditions, such as oxidative stress, aging, and metabolic disorders can be viewed as inducers of tsRNA biogenesis, which further highlights the potential involvement of tsRNAs in these conditions. There is increasing enthusiasm for investigating the molecular and biological functions of tsRNAs in the heart and their role in cardiovascular disease. It is anticipated that this new class of small non-coding RNAs will offer new perspectives in understanding disease mechanisms and may provide new therapeutic targets to treat cardiovascular disease.
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Affiliation(s)
- Jun Cao
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Douglas B Cowan
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
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Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1323028. [PMID: 32963690 PMCID: PMC7499269 DOI: 10.1155/2020/1323028] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 02/19/2020] [Indexed: 01/09/2023]
Abstract
Mitochondrial dysfunctions caused by oxidative stress are currently regarded as the main cause of aging. Accumulation of mutations and deletions of mtDNA is a hallmark of aging. So far, however, there is no evidence that most studied oxygen radicals are directly responsible for mutations of mtDNA. Oxidative damages to cardiolipin (CL) and phosphatidylethanolamine (PEA) are also hallmarks of oxidative stress, but the mechanisms of their damage remain obscure. CL is the only phospholipid present almost exclusively in the inner mitochondrial membrane (IMM) where it is responsible, together with PEA, for the maintenance of the superstructures of oxidative phosphorylation enzymes. CL has negative charges at the headgroups and due to specific localization at the negative curves of the IMM, it creates areas with the strong negative charge where local pH may be several units lower than in the surrounding bulk phases. At these sites with the higher acidity, the chance of protonation of the superoxide radical (O2•), generated by the respiratory chain, is much higher with the formation of the highly reactive hydrophobic perhydroxyl radical (HO2•). HO2• specifically reacts with the double bonds of polyunsaturated fatty acids (PUFA) initiating the isoprostane pathway of lipid peroxidation. Because HO2• is formed close to CL aggregates and PEA, it causes peroxidation of the linoleic acid in CL and also damages PEA. This causes disruption of the structural and functional integrity of the respirosomes and ATP synthase. We provide evidence that in elderly individuals with metabolic syndrome (MetS), fatty acids become the major substrates for production of ATP and this may increase several-fold generation of O2• and thus HO2•. We conclude that MetS accelerates aging and the mitochondrial dysfunctions are caused by the HO2•-induced direct oxidation of CL and the isoprostane pathway of lipid peroxidation (IPLP). The toxic products of IPLP damage not only PEA, but also mtDNA and OXPHOS proteins. This results in gradual disruption of the structural and functional integrity of mitochondria and cells.
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Swerdlow RH, Hui D, Chalise P, Sharma P, Wang X, Andrews SJ, Pa J, Mahnken JD, Morris J, Wilkins HM, Burns JM, Michaelis ML, Michaelis EK. Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts. Alzheimers Dement 2020; 16:1164-1172. [PMID: 32543785 PMCID: PMC9847473 DOI: 10.1002/alz.12119] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/06/2020] [Accepted: 04/29/2020] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. METHODS We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. RESULTS Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. CONCLUSION This exploratory analysis suggests inherited mtDNA variants influence AD risk.
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Affiliation(s)
- Russell H. Swerdlow
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Dongwei Hui
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Prabhakar Chalise
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Palash Sharma
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xinkun Wang
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Shea J. Andrews
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judy Pa
- Alzheimer’s Disease Research Center, Mark and Mary Stevens Neuroimaging and Informatics InstituteUniversity of Southern California, Los Angeles, California, USA
| | - Jonathan D. Mahnken
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jill Morris
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Heather M. Wilkins
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jeffrey M. Burns
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Mary L. Michaelis
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Elias K. Michaelis
- Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA
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Bostwick AM, Moya GE, Senti ML, Basu U, Shen J, Patel SS, Dittenhafer-Reed KE. Phosphorylation of mitochondrial transcription factor B2 controls mitochondrial DNA binding and transcription. Biochem Biophys Res Commun 2020; 528:580-585. [PMID: 32505352 PMCID: PMC9161741 DOI: 10.1016/j.bbrc.2020.05.141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 05/20/2020] [Indexed: 11/24/2022]
Abstract
Mammalian cells contain genetic information in two compartments, the nucleus and the mitochondria. Mitochondrial gene expression must be coordinated with nuclear gene expression to respond to cellular energetic needs. To gain insight into the coordination between the nucleus and mitochondria, there is a need to understand the regulation of transcription of mitochondrial DNA (mtDNA). Reversible protein post-translational modifications of the mtDNA transcriptional machinery may be one way to control mtDNA transcription. Here we focus on a member of the mtDNA transcription initiation complex, mitochondrial transcription factor B2 (TFB2M). TFB2M melts mtDNA at the promoter to allow the RNA polymerase (POLRMT) to access the DNA template and initiate transcription. Three phosphorylation sites have been previously identified on TFB2M by mass spectrometry: threonine 184, serine 197, and threonine 313. Phosphomimetics were established at these positions. Proteins were purified and analyzed for their ability to bind mtDNA and initiate transcription in vitro. Our results indicate phosphorylation at threonine 184 and threonine 313 impairs promoter binding and prevents transcription. These findings provide a potential regulatory mechanism of mtDNA transcription and help clarify the importance of protein post-translational modifications in mitochondrial function.
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Affiliation(s)
- Alicia M Bostwick
- Hope College, Department of Chemistry, 35 E. 12th Street, Holland, MI, 49423, United States
| | - Gonzalo E Moya
- Hope College, Department of Chemistry, 35 E. 12th Street, Holland, MI, 49423, United States
| | - Mackenna L Senti
- Hope College, Department of Chemistry, 35 E. 12th Street, Holland, MI, 49423, United States
| | - Urmimala Basu
- Rutgers University, Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, NJ, 08854, United States
| | - Jiayu Shen
- Rutgers University, Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, NJ, 08854, United States
| | - Smita S Patel
- Rutgers University, Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, NJ, 08854, United States
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Swerdlow RH. The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 154:207-233. [PMID: 32739005 PMCID: PMC8493961 DOI: 10.1016/bs.irn.2020.01.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Alzheimer's disease (AD) features mitochondrial dysfunction and altered metabolism. Other pathologies could drive these changes, or alternatively these changes could drive other pathologies. In considering this question, it is worth noting that perturbed AD patient mitochondrial and metabolism dysfunction extend beyond the brain and to some extent define a systemic phenotype. It is difficult to attribute this systemic phenotype to brain beta-amyloid or tau proteins. Conversely, mitochondria increasingly appear to play a critical role in cell proteostasis, which suggests that mitochondrial dysfunction may promote protein aggregation. Mitochondrial and metabolism-related characteristics also define AD endophenotypes in cognitively normal middle-aged individuals, which suggests that mitochondrial and metabolism-related AD characteristics precede clinical decline. Genetic analyses increasingly implicate mitochondria and metabolism-relevant genes in AD risk. Collectively these factors suggest that mitochondria are more relevant to the causes of AD than its consequences, and support the view that a mitochondrial cascade features prominently in AD. This chapter reviews the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease.
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Affiliation(s)
- Russell H Swerdlow
- University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, United States.
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Peng Y, Gao P, Shi L, Chen L, Liu J, Long J. Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention. Antioxid Redox Signal 2020; 32:1188-1236. [PMID: 32050773 PMCID: PMC7196371 DOI: 10.1089/ars.2019.7763] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 02/09/2020] [Accepted: 02/10/2020] [Indexed: 12/20/2022]
Abstract
Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.
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Affiliation(s)
- Yunhua Peng
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Peipei Gao
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Le Shi
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Lei Chen
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiankang Liu
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiangang Long
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
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Kaur P, Longley MJ, Pan H, Wang W, Countryman P, Wang H, Copeland WC. Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase. J Biol Chem 2020; 295:5564-5576. [PMID: 32213598 PMCID: PMC7186178 DOI: 10.1074/jbc.ra120.012795] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/24/2020] [Indexed: 11/06/2022] Open
Abstract
Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA-binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.
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Affiliation(s)
- Parminder Kaur
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695; Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695.
| | - Matthew J Longley
- Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Hai Pan
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Wendy Wang
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Preston Countryman
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Hong Wang
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695; Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695; Toxicology Program, North Carolina State University, Raleigh, North Carolina 27695
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
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