BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo

Scott J. Bultman, Darcy Wood Holley, Gustaaf G De Ridder, Salvatore V. Pizzo, Tatiana N. Sidorova, Katherine T. Murray, Brian C. Jensen, Zhongjing Wang, Ariana Bevilacqua, Xin Chen, Megan T. Quintana, Manasi Tannu, Gary B. Rosson, Kumar Pandya, Monte Willis

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)258-269
Number of pages12
JournalCardiovascular Pathology
Volume25
Issue number3
DOIs
StatePublished - May 1 2016
Externally publishedYes

Fingerprint

Mitochondrial Degradation
Mitochondrial Dynamics
Cardiac Myocytes
Adenosine Triphosphatases
Homeostasis
Quality Control
Chromatin Assembly and Disassembly
Heart Failure
Autophagy
Organelle Biogenesis
Mitochondria
Mitochondrial Size
Amyloidogenic Proteins
Unfolded Protein Response
Gene Fusion
Amyloid
Epigenomics
Disease Progression
Adenosine Triphosphate
Proteins

Keywords

  • Autophagy
  • BRG1
  • BRM
  • Cardiomyocyte
  • CHOP
  • GRP78
  • IRE-1
  • Mitochondrial dynamics
  • Mitophagy
  • SWI/SNF complex
  • Unfolded protein response

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo. / Bultman, Scott J.; Holley, Darcy Wood; G De Ridder, Gustaaf; Pizzo, Salvatore V.; Sidorova, Tatiana N.; Murray, Katherine T.; Jensen, Brian C.; Wang, Zhongjing; Bevilacqua, Ariana; Chen, Xin; Quintana, Megan T.; Tannu, Manasi; Rosson, Gary B.; Pandya, Kumar; Willis, Monte.

In: Cardiovascular Pathology, Vol. 25, No. 3, 01.05.2016, p. 258-269.

Research output: Contribution to journalArticle

Bultman, SJ, Holley, DW, G De Ridder, G, Pizzo, SV, Sidorova, TN, Murray, KT, Jensen, BC, Wang, Z, Bevilacqua, A, Chen, X, Quintana, MT, Tannu, M, Rosson, GB, Pandya, K & Willis, M 2016, 'BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo', Cardiovascular Pathology, vol. 25, no. 3, pp. 258-269. https://doi.org/10.1016/j.carpath.2016.02.004
Bultman, Scott J. ; Holley, Darcy Wood ; G De Ridder, Gustaaf ; Pizzo, Salvatore V. ; Sidorova, Tatiana N. ; Murray, Katherine T. ; Jensen, Brian C. ; Wang, Zhongjing ; Bevilacqua, Ariana ; Chen, Xin ; Quintana, Megan T. ; Tannu, Manasi ; Rosson, Gary B. ; Pandya, Kumar ; Willis, Monte. / BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo. In: Cardiovascular Pathology. 2016 ; Vol. 25, No. 3. pp. 258-269.
@article{f44ec00026454cb595a0a99aa21ad2c0,
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.",
keywords = "Autophagy, BRG1, BRM, Cardiomyocyte, CHOP, GRP78, IRE-1, Mitochondrial dynamics, Mitophagy, SWI/SNF complex, Unfolded protein response",
author = "Bultman, {Scott J.} and Holley, {Darcy Wood} and {G De Ridder}, Gustaaf and Pizzo, {Salvatore V.} and Sidorova, {Tatiana N.} and Murray, {Katherine T.} and Jensen, {Brian C.} and Zhongjing Wang and Ariana Bevilacqua and Xin Chen and Quintana, {Megan T.} and Manasi Tannu and Rosson, {Gary B.} and Kumar Pandya and Monte Willis",
year = "2016",
month = "5",
day = "1",
doi = "10.1016/j.carpath.2016.02.004",
language = "English (US)",
volume = "25",
pages = "258--269",
journal = "Cardiovascular Pathology",
issn = "1054-8807",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo

AU - Bultman, Scott J.

AU - Holley, Darcy Wood

AU - G De Ridder, Gustaaf

AU - Pizzo, Salvatore V.

AU - Sidorova, Tatiana N.

AU - Murray, Katherine T.

AU - Jensen, Brian C.

AU - Wang, Zhongjing

AU - Bevilacqua, Ariana

AU - Chen, Xin

AU - Quintana, Megan T.

AU - Tannu, Manasi

AU - Rosson, Gary B.

AU - Pandya, Kumar

AU - Willis, Monte

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - BRG1

KW - BRM

KW - Cardiomyocyte

KW - CHOP

KW - GRP78

KW - IRE-1

KW - Mitochondrial dynamics

KW - Mitophagy

KW - SWI/SNF complex

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=84961990835&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961990835&partnerID=8YFLogxK

U2 - 10.1016/j.carpath.2016.02.004

DO - 10.1016/j.carpath.2016.02.004

M3 - Article

C2 - 27039070

AN - SCOPUS:84961990835

VL - 25

SP - 258

EP - 269

JO - Cardiovascular Pathology

JF - Cardiovascular Pathology

SN - 1054-8807

IS - 3

ER -