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      Novel targets for mitochondrial medicine

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      Author(s): 1 , 2 , 1
      Publication date PMC-release:
      Journal: Science translational medicine

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          Abstract

          Mitochondria—classically viewed as the powerhouses of the cell—have taken center stage in disease pathogenesis and resolution. Mitochondrial dysfunction, which originates from primary defects within the organelle or is induced by environmental stresses, plays a critical role in human disease. Despite their central role in human health and disease, there are no approved drugs that directly target mitochondria. We present possible new druggable targets in mitochondrial biology, including protein modification, calcium ion (Ca 2+) transport, and dynamics, as we move into a new era of mitochondrial medicine.

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          Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.

          Ann Cassidy-Stone, Jerry E Chipuk, Elena Ingerman … (2008)
          Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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            Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury.

            Elizabeth Murphy, Charles Steenbergen (2008)
            Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca(2+)), which further accelerates ATP depletion. The rise in Ca(2+) during ischemia and reperfusion leads to mitochondrial Ca(2+) accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however, damage to the electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca(2+) overload and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca(2+) overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca(2+) overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca(2+) overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals are discussed in detail.
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              Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface.

              György Csordás, Péter Várnai, Tünde Golenár … (2010)
              The ER-mitochondrial junction provides a local calcium signaling domain that is critical for both matching energy production with demand and the control of apoptosis. Here, we visualize ER-mitochondrial contact sites and monitor the localized [Ca(2+)] changes ([Ca(2+)](ER-mt)) using drug-inducible fluorescent interorganelle linkers. We show that all mitochondria have contacts with the ER, but plasma membrane (PM)-mitochondrial contacts are less frequent because of interleaving ER stacks in both RBL-2H3 and H9c2 cells. Single mitochondria display discrete patches of ER contacts and show heterogeneity in the ER-mitochondrial Ca(2+) transfer. Pericam-tagged linkers revealed IP(3)-induced [Ca(2+)](ER-mt) signals that exceeded 9 microM and endured buffering bulk cytoplasmic [Ca(2+)] increases. Altering linker length to modify the space available for the Ca(2+) transfer machinery had a biphasic effect on [Ca(2+)](ER-mt) signals. These studies provide direct evidence for the existence of high-Ca(2+) microdomains between the ER and mitochondria and suggest an optimal gap width for efficient Ca(2+) transfer. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101505086
                Journal ID (pubmed-jr-id): 36963
                Journal ID (nlm-ta): Sci Transl Med
                Journal ID (iso-abbrev): Sci Transl Med
                Title: Science translational medicine
                ISSN (Print): 1946-6234
                ISSN (Electronic): 1946-6242
                Publication date Nihms-submitted: 25 March 2016
                Publication date (Print): 17 February 2016
                Publication date PMC-release: 17 February 2017
                Volume: 8
                Issue: 326
                Page: 326rv3
                Affiliations
                [1 ]Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA 98109, USA
                [2 ]Pfizer Global Research and Development CVMED (Cardiovascular and Metabolic Diseases), Cambridge, MA 02139, USA
                Author notes
                [* ]Corresponding author. wangwang@ 123456uw.edu (W.W.); rongtian@ 123456uw.edu (R.T.)
                Article
                Accession ID: PMC4819426 Pmcid ID: PMC4819426 Pmc-uid ID: 4819426 Manuscript ID: nihpa769346
                DOI: 10.1126/scitranslmed.aac7410
                PMC ID: 4819426
                PubMed ID: 26888432
                SO-VID: 423873ea-a705-455e-80b0-31f8e710137e
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