title: BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo.
abstract: There has been an increasing recognition that mitochondrial perturbations play a central role in human heart failure. Mitochondrial networks, whose function is to maintain the regulation of mitochondrial biogenesis, autophagy ('mitophagy') and mitochondrial fusion/fission, are new potential therapeutic targets. Yet our understanding of the molecular underpinning of these processes is just emerging. We recently identified a role of the SWI/SNF ATP-dependent chromatin remodeling complexes in the metabolic homeostasis of the adult cardiomyocyte using cardiomyocyte-specific and inducible deletion of the SWI/SNF ATPases BRG1 and BRM in adult mice (Brg1/Brm double mutant mice). To build upon these observations in early altered metabolism, the present study looks at the subsequent alterations in mitochondrial quality control mechanisms in the impaired adult cardiomyocyte. We identified that Brg1/Brm double-mutant mice exhibited increased mitochondrial biogenesis, increases in 'mitophagy', and alterations in mitochondrial fission and fusion that led to small, fragmented mitochondria. Mechanistically, increases in the autophagy and mitophagy-regulated proteins Beclin1 and Bnip3 were identified, paralleling changes seen in human heart failure. Evidence for perturbed cardiac mitochondrial dynamics included decreased mitochondria size, reduced numbers of mitochondria, and an altered expression of genes regulating fusion (Mfn1, Opa1) and fission (Drp1). We also identified cardiac protein amyloid accumulation (aggregated fibrils) during disease progression along with an increase in pre-amyloid oligomers and an upregulated unfolded protein response including increased GRP78, CHOP, and IRE-1 signaling. Together, these findings described a role for BRG1 and BRM in mitochondrial quality control, by regulating mitochondrial number, mitophagy, and mitochondrial dynamics not previously recognized in the adult cardiomyocyte. As critical to the pathogenesis of heart failure, epigenetic mechanisms like SWI/SNF chromatin remodeling seem more intimately linked to cardiac function and mitochondrial quality control mechanisms than previously realized.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Darcy Wood
authors.initials: DW
authors.lastname: Holley
authors.affiliation: Department of Pathology, Duke University, Durham, NC 27710, USA.
authors.forename: Gustaaf
authors.initials: G
authors.lastname: G de Ridder
authors.affiliation: Department of Pathology, Duke University, Durham, NC 27710, USA.
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
authors.affiliation: Departments of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Sidorova
authors.affiliation: Departments of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Murray
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Jensen
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Zhongjing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Ariana
authors.initials: A
authors.lastname: Bevilacqua
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital affiliated to Shandong University, 250021, Jinan, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Quintana
authors.affiliation: School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Manasi
authors.initials: M
authors.lastname: Tannu
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Rosson
authors.affiliation: Transviragen, Chapel Hill, NC 27599, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Pandya
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: monte_willis@med.unc.edu.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000378:metabolism*; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000502:physiology*; D063306:Mitophagy / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D009687:Nuclear Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Autophagy; BRG1; BRM; CHOP; Cardiomyocyte; GRP78; IRE-1; Mitochondrial dynamics; Mitophagy; SWI/SNF complex; Unfolded protein response