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      Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics

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          Abstract

          At present, the etiology of idiopathic pulmonary fibrosis (IPF) remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in metabolic dysregulation, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of IPF lungs. Metabolic changes and mitochondrial dysfunction in IPF include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in IPF have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-β and predispose to the development of pulmonary fibrosis. IPF is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of IPF. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in IPF, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of IPF.

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          Most cited references52

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          Telomere dysfunction induces metabolic and mitochondrial compromise.

          Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
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            Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

            Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.
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              Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.

              Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                05 February 2018
                2018
                : 5
                : 10
                Affiliations
                [1] 1Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [2] 2Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [3] 3McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [4] 4Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                Author notes

                Edited by: Argyrios Tzouvelekis, Alexander Fleming Biomedical Sciences Research Center, Greece

                Reviewed by: Bruno Crestani, Paris Diderot University, France; Eleni Papakonstantinou, Aristotle University of Thessaloniki, Greece

                *Correspondence: Ana L. Mora, anamora@ 123456pitt.edu ; Mauricio Rojas, rojasm@ 123456upmc.edu

                Specialty section: This article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2018.00010
                5807592
                29459894
                1c70f61e-72ac-420d-b503-7d025b69def9
                Copyright © 2018 Zank, Bueno, Mora and Rojas.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 September 2017
                : 15 January 2018
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 75, Pages: 9, Words: 7364
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: RO1 HL131789, R01 HL123766
                Categories
                Medicine
                Review

                aging,mitochondrial dysfunction,lung fibrosis,bioenergetics,mitophagy,senescence

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