Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
12
10
2021
received:
13
05
2021
accepted:
18
11
2021
pubmed:
23
11
2021
medline:
29
4
2022
entrez:
22
11
2021
Statut:
ppublish
Résumé
Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ). TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
Substances chimiques
DNA, Mitochondrial
0
DNA-Binding Proteins
0
Mitochondrial Proteins
0
Transcription Factors
0
Transforming Growth Factor beta
0
mitochondrial transcription factor A
0
Bleomycin
11056-06-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
871-881Informations de copyright
© 2021 American College of Rheumatology.
Références
Abraham DJ, Krieg T, Distler J, Distler O. Overview of pathogenesis of systemic sclerosis. Rheumatology (Oxford) 2009;48 suppl:iii3-7.
Distler JH, Feghali-Bostwick C, Soare A, Asano Y, Distler O, Abraham DJ. Frontiers of antifibrotic therapy in systemic sclerosis [review]. Arthritis Rheumatol 2017;69:257-67.
Leroy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro. J Clin Invest 1974;54:880-9.
Distler JH, Gyorfi AH, Ramanujam M, Whitfield ML, Konigshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019;15:705-30.
Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 2014;5:123.
Gillespie J, Ross RL, Corinaldesi C, Esteves F, Derrett-Smith E, McDermott MF, et al. Transforming growth factor β activation primes canonical Wnt signaling through down-regulation of axin-2. Arthritis Rheumatol 2018;70:932-42.
Shin JY, Beckett JD, Bagirzadeh R, Creamer TJ, Shah AA, McMahan Z, et al. Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis. Sci Transl Med 2019;11: eaaw0790.
Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut 2015;64:830-41.
Matucci-Cerinic M, Kahaleh B, Wigley FM. Evidence that systemic sclerosis is a vascular disease [review]. Arthritis Rheum 2013;65:1953-62.
Barth AS, Tomaselli GF. Gene scanning and heart attack risk. Trends Cardiovasc Med 2016;26:260-5.
Roger AJ, Munoz-Gomez SA, Kamikawa R. The origin and diversification of mitochondria. Curr Biol 2017;27:R1177-92.
Yuan Y, Ju YS, Kim Y, Li J, Wang Y, Yoon CJ, et al. Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nat Genet 2020;52:342-52.
Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 2018;20:745-54.
Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell 2016;61:199-209.
Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015;163:560-9.
Samanta D, Park Y, Andrabi SA, Shelton LM, Gilkes DM, Semenza GL. PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Res 2016;76:4430-42.
Oxenoid K, Dong Y, Cao C, Cui T, Sancak Y, Markhard AL, et al. Architecture of the mitochondrial calcium uniporter. Nature 2016;533:269-73.
Sustarsic EG, Ma T, Lynes MD, Larsen M, Karavaeva I, Havelund JF, et al. Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis. Cell Metab 2018;28:159-74.
Lill R, Freibert SA. Mechanisms of mitochondrial iron-sulfur protein biogenesis. Annu Rev Biochem 2020;89:471-99.
Tsai VW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab 2018;28:353-68.
Duan J. Metabolic remodeling induced by mitokines in heart failure. Aging 2019;11:7307-27.
Hillen HS, Temiakov D, Cramer P. Structural basis of mitochondrial transcription. Nat Struct Mol Biol 2018;25:754-65.
Bernard K, Logsdon NJ, Miguel V, Benavides GA, Zhang J, Carter AB, et al. NADPH oxidase 4 (Nox4) suppresses mitochondrial biogenesis and bioenergetics in lung fibroblasts via a nuclear factor erythroid-derived 2-like 2 (Nrf2)-dependent pathway. J Biol Chem 2017;292:3029-38.
Uchiumi T, Kang D. The role of TFAM-associated proteins in mitochondrial RNA metabolism. Biochim Biophys Acta 2012;1820:565-70.
Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998;18:231-6.
Fu Z, Ye J, Dean JW, Bostick JW, Weinberg SE, Xiong L, et al. Requirement of mitochondrial transcription factor A in tissue-resident regulatory T cell maintenance and function. Cell Rep 2019;28:159-71.
Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012;148:1145-59.
Henderson J, Duffy L, Stratton R, Ford D, O'Reilly S. Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis. J Cell Mol Med 2020;24:14026-38.
Yang C, Jiang L, Zhang H, Shimoda LA, DeBerardinis RJ, Semenza GL. Analysis of hypoxia-induced metabolic reprogramming. Methods Enzymol 2014;542:425-55.
Caporarello N, Meridew JA, Jones DL, Tan Q, Haak AJ, Choi KM, et al. PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state. Thorax 2019;74:749-60.
Li X, Zhang W, Cao Q, Wang Z, Zhao M, Xu L, et al. Mitochondrial dysfunction in fibrotic diseases. Cell Death Discov 2020;6:80.
Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 2016;17:213-26.
Jaeger VK, Lebrecht D, Nicholson AG, Wells A, Bhayani H, Gazdhar A, et al. Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis. Sci Rep 2019;9:5500.
Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 2015;125:521-38.
Mills EL, Kelly B, O'Neill LA. Mitochondria are the powerhouses of immunity. Nat Immunol 2017;18:488-98.
Angelo A, Manfredi PR. The mitochondrion-a Trojan horse that kicks off inflammation? N Engl J Med 2010;362:2132-4.
Blanco LP, Pedersen HL, Wang X, Lightfoot YL, Seto N, Carmona-Rivera C, et al. Improved mitochondrial metabolism and reduced inflammation following attenuation of murine lupus with coenzyme Q10 analog idebenone. Arthritis Rheumatol 2020;72:454-64.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016;22:146-53.
Lepelley A, Mina ED, Van Nieuwenhove E, Waumans L, Fraitag S, Rice GI, et al. Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A. J Exp Med 2021;218:e20201560.
Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, et al. Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neurosci 2014;34:14304-17.
Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2002;2:55-67.
Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab 2019;29:707-18.
Mahoney JM, Taroni J, Martyanov V, Wood TA, Greene CS, Pioli PA, et al. Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput Biol 2015;11:e1004005.
Gyorfi AH, Matei AE, Distler JH. Targeting TGF-β signaling for the treatment of fibrosis. Matrix Biol 2018;68-69:8-27.
Chung KW, Dhillon P, Huang S, Sheng X, Shrestha R, Qiu C, et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab 2019;30:784-99.
Zhao X, Psarianos P, Ghoraie LS, Yip K, Goldstein D, Gilbert R, et al. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nat Metab 2019;1:147-57.
Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini G, et al. Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 2001;44:2653-64.
Murphy-Marshman H, Quensel K, Shi-Wen X, Barnfield R, Kelly J, Peidl A, et al. Antioxidants and NOX1/NOX4 inhibition blocks TGFβ1-induced CCN2 and α-SMA expression in dermal and gingival fibroblasts. PLoS One 2017;12:e0186740.