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      Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine

      review-article
      Author(s): 1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 ,
      Publication date (Electronic):
      Journal: The EPMA Journal
      Publisher: Springer International Publishing
      Keywords: Mitochondrial impairment, Injury, ROS, Energy imbalance, Vicious circle, Oxidative stress, Aetiopathology multi-organ dysfunction, Suboptimal health, Reversible damage, Vasospasm, Mitigating measures, Repair, Mechanisms, Multifactorial disease, Ageing, Neurodegeneration, Glaucoma, Alzheimer, Cancer, Cardiovascular disease, Predictive preventive personalised medicine (PPPM/3PM), Multi-modal diagnostics, Liquid biopsy, Molecular patterns, Biomarker panel, Patient stratification, Individualised patient profiling, Origin, Outcomes, Complementary medicine, Health policy, Cost efficacy, COVID-19

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          Abstract

          Mitochondrial injury plays a key role in the aetiopathology of multifactorial diseases exhibiting a “vicious circle” characteristic for pathomechanisms of the mitochondrial and multi-organ damage frequently developed in a reciprocal manner. Although the origin of the damage is common (uncontrolled ROS release, diminished energy production and extensive oxidative stress to life-important biomolecules such as mtDNA and chrDNA), individual outcomes differ significantly representing a spectrum of associated pathologies including but not restricted to neurodegeneration, cardiovascular diseases and cancers. Contextually, the role of predictive, preventive and personalised (PPPM/3P) medicine is to introduce predictive analytical approaches which allow for distinguishing between individual outcomes under circumstance of mitochondrial impairments followed by cost-effective targeted prevention and personalisation of medical services. Current article considers innovative concepts and analytical instruments to advance management of mitochondriopathies and associated pathologies.

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          Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.

          Dmitry Zorov, Magdalena Juhaszova, Steven J. Sollott (2014)
          Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca(2+), etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca(2+)). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo. Copyright © 2014 the American Physiological Society.
          Article 0 comments Cited 1146 times – based on 0 reviews     Review now
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            Tumour heterogeneity and resistance to cancer therapies

            Ibiayi Dagogo-Jack, Alice Shaw (2018)
            Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.
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              Alzheimer's disease: the amyloid cascade hypothesis

              Christopher J. Hardy, Larry G. Higgins (1992)
              Article 0 comments Cited 849 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Olga Golunitschaja: olga.golubnitschaja@ukbonn.de
                Journal
                Journal ID (nlm-ta): EPMA J
                Journal ID (iso-abbrev): EPMA J
                Title: The EPMA Journal
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1878-5077
                ISSN (Electronic): 1878-5085
                Publication date (Electronic): 4 March 2021
                Publication date PMC-release: 4 March 2021
                Pages: 1-14
                Affiliations
                [1 ]GRID grid.7634.6, ISNI 0000000109409708, Department of Obstetrics and Gynaecology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 036 01 Martin, Slovakia
                [2 ]GRID grid.418818.c, ISNI 0000 0001 0516 2170, Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, , Qatar Foundation, ; Doha, 24144 Qatar
                [3 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Department of Radiation Oncology, University Hospital Bonn, , Rheinische Friedrich-Wilhelms-Universität Bonn, ; 53127 Bonn, Germany
                [4 ]GRID grid.7634.6, ISNI 0000000109409708, Department of Medical Biology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 03601 Martin, Slovakia
                [5 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, , Rheinische Friedrich-Wilhelms-Universität Bonn, ; 53127 Bonn, Germany
                Article
                Publisher ID: 237
                DOI: 10.1007/s13167-021-00237-2
                PMC ID: 7931170
                PubMed ID: 33686350
                SO-VID: 8f2b3386-ac60-4691-a867-17df1e2bcb14
                Copyright © © The Author(s) 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 9 February 2021
                Date accepted : 11 February 2021
                Funding
                Funded by: Rheinische Friedrich-Wilhelms-Universität Bonn (1040)
                Open Access :

                Open Access funding enabled and organized by Projekt DEAL.

                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: mitochondrial impairment,injury,ros,energy imbalance,vicious circle,oxidative stress,aetiopathology multi-organ dysfunction,suboptimal health,reversible damage,vasospasm,mitigating measures,repair,mechanisms,multifactorial disease,ageing,neurodegeneration,glaucoma,alzheimer,cancer,cardiovascular disease,predictive preventive personalised medicine (pppm/3pm),multi-modal diagnostics,liquid biopsy,molecular patterns,biomarker panel,patient stratification,individualised patient profiling,origin,outcomes,complementary medicine,health policy,cost efficacy,covid-19
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: mitochondrial impairment, injury, ros, energy imbalance, vicious circle, oxidative stress, aetiopathology multi-organ dysfunction, suboptimal health, reversible damage, vasospasm, mitigating measures, repair, mechanisms, multifactorial disease, ageing, neurodegeneration, glaucoma, alzheimer, cancer, cardiovascular disease, predictive preventive personalised medicine (pppm/3pm), multi-modal diagnostics, liquid biopsy, molecular patterns, biomarker panel, patient stratification, individualised patient profiling, origin, outcomes, complementary medicine, health policy, cost efficacy, covid-19

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