Biology subjects

Subbaiah, K. C. V.

Publications and source records attributed to Subbaiah, K. C. V..

4 recordsLinked to original sources

bioRxiv2023

FAM210A Regulates Mitochondrial Translation and Maintains Cardiac Mitochondrial Homeostasis

AimsMitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo. Methods and ResultsTamoxifen-induced MHCMCM-driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure. ConclusionThese results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease. Translational PerspectiveMitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis in vivo. Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.

pathology↗

bioRxiv2021

FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

Cardiac fibrosis, a primary contributor to heart failure (HF) and sudden death, is considered as an important target for HF therapy. However, the signaling pathways that govern cardiac fibroblast (CF) function during cardiac fibrosis have not been fully elucidated. Here, we found that a functionally unannotated human myocardial infarction (MI) associated gene, family with sequence similarity 114 member A1 (FAM114A1), is induced in failing human and mouse hearts compared to non-failing hearts. Homozygous knockout of Fam114a1 (Fam114a1-/-) in the mouse genome reduces cardiac hypertrophy and fibrosis while significantly restores cardiac function in angiotensin (Ang) II- and MI-induced HF mouse models. Fam114a1 deletion antagonizes Ang II induced inflammation and oxidative stress. Using isolated mouse primary CFs in wild type and Fam114a1-/- mice, we found that FAM114A1 is a critical autonomous factor for CF proliferation, activation, and migration. We discovered that FAM114A1 interacts with angiotensin receptor associated protein (AGTRAP) and regulates the expression of angiotensin type 1 receptor (AT1R) and downstream Ang II signaling transduction, and subsequently influences pro-fibrotic response. Using RNA-Seq in mouse primary CFs, we identified differentially expressed genes including extracellular matrix proteins such as Adamts15. RNAi-mediated inactivation of Adamts15 attenuates CF activation and collagen deposition. Our results indicate that FAM114A1 regulates Ang II signaling and downstream pro-fibrotic and pro-inflammatory gene expression, thereby activating cardiac fibroblasts and augmenting pathological cardiac remodeling. These findings provide novel insights into regulation of cardiac fibrosis and identify FAM114A1 as a new therapeutic target for treatment of cardiac disease. SignificanceCardiac fibrosis is a hallmark of heart failure and angiotensin II signaling promotes pro-fibrotic response in the heart. This study is a pioneering investigation of the role of a functionally unknown protein FAM114A1. We show that FAM114A1 expression is induced in human and mouse failing hearts. Genetic ablation of FAM114A1 can effectively reduce cardiac fibrosis and pathological remodeling. Isolated cardiac fibroblasts from Fam114a1 knockout mice show reduced response to Ang II stimulation and compromised myofibroblast activation. Mechanistically, FAM114A1 binds to AGTRAP and influences AT1R protein expression, thereby enhancing angiotensin II signaling and pro-fibrotic response. Thus, FAM114A1 is a novel factor that modulates cardiac fibrosis and pharmacological inhibition of FAM114A1 may be a therapeutic strategy for the treatment of heart disease.

pathology↗

bioRxiv2020

MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling

Aberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of regulation of mitochondria encoded protein expression during cardiac disease remains underexplored. Here, we have shown that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in both humans and mice. miR-574 knockout mice exhibit severe cardiac disorder under heart disease-triggering stresses. miR-574-5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptome analysis of miR-574-null hearts uncovers FAM210A as a common target mRNA for both strands of miR-574. The interactome capture and translational state analyses suggest that FAM210A interacts with mitochondrial translation factors and regulates the protein expression of mitochondrial encoded electron transport chain genes. Using a human cardiomyocyte cell culture system, we discover that miR-574 regulates FAM210A expression and modulates mitochondrial encoded protein expression, which influences cardiac remodeling in heart failure.

pathology↗

bioRxiv2019

EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

RationaleIncreased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure. Despite this important observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.\n\nObjectiveThis study aimed to test the hypothesis that cardiac stress-induced expression of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS), is preferentially required for the translation of proline codon-rich (PRR) pro-fibrotic mRNAs in cardiac fibroblasts during cardiac fibrosis.\n\nMethods and ResultsBy analyses of multiple available unbiased large-scale screening datasets of human and mouse heart failure, we have discovered that EPRS acts as an integrated node among all the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at both mRNA and protein level ([~]1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs+/-) using CRISPR-Cas9 technology or in a myofibroblast-specific manner (Eprsflox/+; PostnMCM/+) strongly reduces cardiac fibrosis ([~]50% reduction) in isoproterenol- and transverse aortic constriction-induced heart failure mouse models. Inhibition of EPRS by a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreased the translation efficiency of proline-rich collagens in cardiac fibroblasts. Furthermore, using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. As a major EPRS downstream effector, SULF1 is highly enriched in human and mouse myofibroblast. siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition.\n\nConclusionsOur results indicate that EPRS preferentially controls the translational activation of proline codon-rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.\n\nNovelty and SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LITGF-{beta} and IL-11 increase synthesis of pro-fibrotic proteins during cardiac fibrosis.\nC_LIO_LIMany pro-fibrotic genes contain Pro genetic codon rich motifs such as collagens.\nC_LIO_LIEPRS is an essential house-keeping enzyme required for ligating Pro to tRNAPro for the synthesis of Pro-containing proteins.\nC_LI\n\nWhat New Information Does This Article Contribute?O_LIThis study is a pioneering investigation of translational control mechanisms of pro-fibrotic gene expression in cardiac fibrosis.\nC_LIO_LIEPRS mRNA and protein expression are induced in failing human hearts and mouse hearts undergoing pathological cardiac remodeling.\nC_LIO_LIThe first demonstration of the in vivo function of EPRS in cardiac remodeling. Heterozygous Eprs global knockout and myofibroblast-specific tamoxifen-inducible Eprs conditional knockout mice show reduced pathological cardiac fibrosis under stress, suggesting that the reduction of EPRS is cardioprotective.\nC_LIO_LIIdentification of novel preferential translational target genes of EPRS. We found that EPRS regulates translation of Pro-rich (PRR) transcripts, which comprise most of the ECM and secretory signaling molecules. Among those targets, we identified multiple novel PRR genes such as LTBP2 and SULF1.\nC_LIO_LISULF1 is validated as a myofibroblast marker protein in human and mouse heart failure and a potential anti-fibrosis target gene.\nC_LI\n\nIn cardiac fibroblasts, the synthesis of pro-fibrotic proteins is upregulated by cardiac stressors to activate extracellular matrix deposition and impair cardiac function. In this study, we have discovered an EPRS-PRR gene axis that influences translational homeostasis of pro-fibrotic proteins and promotes pathological cardiac remodeling and fibrosis. EPRS is identified as a common node downstream of multiple cardiac stressors and a novel regulatory factor that facilitates pro-fibrotic mRNA translation in cardiac fibrosis. Global and myofibroblast-specific genetic ablation of EPRS can effectively reduce cardiac fibrosis. This study reveals a novel translational control mechanism that modulates cardiac fibrosis and heart function. Mild inhibition of PRR mRNA translation could be a general therapeutic strategy for the treatment of heart disease. These findings provide novel insights into the translational control mechanisms of cardiac fibrosis and will promote the development of novel therapeutics by inhibiting pro-fibrotic translation factors or their downstream effectors.

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