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      Impact of pharmacological agents on mitochondrial function: a growing opportunity?

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          Abstract

          Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

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          Most cited references111

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          Molecular mechanisms regulating NLRP3 inflammasome activation.

          Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome.
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            Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration.

            Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier.
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              The mitochondrial genome: structure, transcription, translation and replication.

              J Taanman (1999)
              Mitochondria play a central role in cellular energy provision. The organelles contain their own genome with a modified genetic code. The mammalian mitochondrial genome is transmitted exclusively through the female germ line. The human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16569 bp and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 polypeptides. The mtDNA-encoded polypeptides are all subunits of enzyme complexes of the oxidative phosphorylation system. Mitochondria are not self-supporting entities but rely heavily for their functions on imported nuclear gene products. The basic mechanisms of mitochondrial gene expression have been solved. Cis-acting mtDNA sequences have been characterised by sequence comparisons, mapping studies and mutation analysis both in vitro and in patients harbouring mtDNA mutations. Characterisation of trans-acting factors has proven more difficult but several key enzymes involved in mtDNA replication, transcription and protein synthesis have now been biochemically identified and some have been cloned. These studies revealed that, although some factors may have an additional function elsewhere in the cell, most are unique to mitochondria. It is expected that cell cultures of patients with mitochondrial diseases will increasingly be used to address fundamental questions about mtDNA expression.
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                Author and article information

                Journal
                Biochem Soc Trans
                Biochem. Soc. Trans
                ppbiost
                BST
                Biochemical Society Transactions
                Portland Press Ltd.
                0300-5127
                1470-8752
                20 December 2019
                7 November 2019
                : 47
                : 6
                : 1757-1772
                Affiliations
                [1 ]NDWRH, The Women's Centre, University of Oxford, Oxford, U.K.
                [2 ]Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, U.K.
                [3 ]Novintum, London, U.K.
                [4 ]Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Byran, TX, U.S.A.
                Author notes
                Correspondence: Karl Morten ( karl.morten@ 123456wrh.ox.ac.uk )
                Author information
                http://orcid.org/0000-0001-6926-6550
                Article
                BST-47-1757
                10.1042/BST20190280
                6925523
                31696924
                8ec823c4-d2fb-4427-bbe8-836a1a032483
                © 2019 The Author(s)

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).

                History
                : 23 August 2019
                : 9 October 2019
                : 18 October 2019
                Categories
                Organelles & Localization
                Cancer
                Metabolism
                Immunology & Inflammation
                Bioenergetics
                Review Articles

                Biochemistry
                Biochemistry

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