Tead1 is essential for mitochondrial function in cardiomyocytes

Liu, Ruya; Jagannathan, Rajaganapathi; Sun, Lingfei; Li, Feng; Yang, Ping; Lee, Jeongkyung; Negi, Vinny; Perez-Garcia, Eliana Melissa; Shiva, Sruti; Yechoor, Vijay; Moulik, Mousumi

doi:10.1152/ajpheart.00732.2019

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…We have recently shown that global knockout (KO) of Tead1 in mice leads to early embryonic lethality between E9.5 and E10.5 [18,19]. Although the importance of TEAD1 in CMs has been established [20][21][22], the specific role of Tead1 in adult tissue homeostasis especially in the adult heart remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes

et al. 2021

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The Hippo signaling effector, TEAD1 plays an essential role in cardiovascular development. However, a role for TEAD1 in postmitotic cardiomyocytes (CMs) remains incompletely understood. Herein we reported that TEAD1 is required for postmitotic CM survival. We found that adult mice with ubiquitous or CM-specific loss of Tead1 present with a rapid lethality due to an acute-onset dilated cardiomyopathy. Surprisingly, deletion of Tead1 activated the necroptotic pathway and induced massive cardiomyocyte necroptosis, but not apoptosis. In contrast to apoptosis, necroptosis is a proinflammatory form of cell death and consistent with this, dramatically higher levels of markers of activated macrophages and pro-inflammatory cytokines were observed in the hearts of Tead1 knockout mice. Blocking necroptosis by administration of necrostatin-1 rescued Tead1 deletion-induced heart failure. Mechanistically, genome-wide transcriptome and ChIP-seq analysis revealed that in adult hearts, Tead1 directly activates a large set of nuclear DNA-encoded mitochondrial genes required for assembly of the electron transfer complex and the production of ATP. Loss of Tead1 expression in adult CMs increased mitochondrial reactive oxygen species, disrupted the structure of mitochondria, reduced complex I-IV driven oxygen consumption and ATP levels, resulting in the activation of necroptosis. This study identifies an unexpected paradigm in which TEAD1 is essential for postmitotic CM survival by maintaining the expression of nuclear DNA-encoded mitochondrial genes required for ATP synthesis.

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Section: Introductionmentioning

confidence: 99%

TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes

et al. 2021

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“… 49 Recent studies have also demonstrated that Tead1 is also required for maintenance of adult cardiomyocyte mitochondrial and overall heart function, with its loss associated with lethal dilated cardiomyopathy. 24 , 25 While these data support Tead1 as a potentially potent cardio‐differentiation factor, the use of Tead1 for this purpose has not to our knowledge been previously reported.…”

Section: Discussionmentioning

confidence: 78%

“…These findings of the epigenetic effects of Tead1 is consistent with the observations of the mechanism of action of other potent reprogramming formulations. 25 , 27 , 30 , 33 , 43 …”

Section: Discussionmentioning

confidence: 99%

“… 17 , 23 A recent report also suggests that Tead1 is an integral component of the cardiac transcriptional regulatory network and that it regulates core cardiomyocyte‐specific functions including contraction and metabolism, and shares binding domains with key cardio‐differentiation factors such as p300, Gata4, Nkx2.5, and Mef2a. 24 , 25 , 26 , 27 These observations led us to hypothesize that Tead1 may provide an important transcriptional regulatory role in cardiac fibroblast transdifferentiation essential for iCMs generation. We consequently sought to test Tead1 (Td) as a potential factor that could increase the efficiency of cardiac reprogramming by enhancing cardio‐differentiating gene activation.…”

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confidence: 99%

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Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming

Singh

Pinnamaneni

Pugazenthi

et al. 2021

JAHA

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Background The conversion of fibroblasts into induced cardiomyocytes may regenerate myocardial tissue from cardiac scar through in situ cell transdifferentiation. The efficiency transdifferentiation is low, especially for human cells. We explored the leveraging of Hippo pathway intermediates to enhance induced cardiomyocyte generation. Methods and Results We screened Hippo effectors Yap (yes‐associated protein), Taz (transcriptional activator binding domain), and Tead1 (TEA domain transcription factor 1; Td) for their reprogramming efficacy with cardio‐differentiating factors Gata4, Mef2C, and Tbx5 (GMT). Td induced nearly 3‐fold increased expression of cardiomyocyte marker cTnT (cardiac troponin T) by mouse embryonic and adult rat fibroblasts versus GMT administration alone ( P <0.0001), while Yap and Taz failed to enhance cTnT expression. Serial substitution demonstrated that Td replacement of TBX5 induced the greatest cTnT expression enhancement and sarcomere organization in rat fibroblasts treated with all GMT substitutions (GMTd versus GMT: 17±1.2% versus 5.4±0.3%, P <0.0001). Cell contractility (beating) was seen in 6% of GMTd‐treated cells by 4 weeks after treatment, whereas no beating GMT‐treated cells were observed. Human cardiac fibroblasts likewise demonstrated increased cTnT expression with GMTd versus GMT treatment (7.5±0.3% versus 3.0±0.3%, P <0.01). Mechanistically, GMTd administration increased expression of the trimethylated lysine 4 of histone 3 (H3K4me3) mark at the promoter regions of cardio‐differentiation genes and mitochondrial biogenesis regulator genes in rat and human fibroblast, compared with GMT. Conclusions These data suggest that the Hippo pathway intermediate Tead1 is an important regulator of cardiac reprogramming that increases the efficiency of maturate induced cardiomyocytes generation and may be a vital component of human cardiodifferentiation strategies.

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“…YAP, and TEAD) (56) suggesting a functional analogy in salmon with mammals. Intriguingly, the same pathways also control mitochondrial biogenesis and function (57)(58)(59), further supporting that vgll3 genetic variation might affect mitochondrial functional variation.…”

Section: Discussionmentioning

confidence: 84%

Adipose tissue mitochondrial respiration in Atlantic salmon: implications for sex-dependent life-history variation

Prokkola

Wagner

Koskinen

et al. 2022

Preprint

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Adipose tissue is essential for energy homeostasis, with mitochondria having a central role in its function. Mitochondria-mediated adipose tissue dysfunction has been linked to several metabolic disorders in humans but surprisingly little is known about whether variation in adipose tissue processes, such as mitochondrial function, is maintained in wild animal populations, how it is related to reproductive success, and its evolutionary significance. Early sexual maturation (age-at-maturity) in Atlantic salmon (Salmo salar) is promoted by higher adiposity and has a strong genetic association with the vestigial like 3 (vgll3) locus. Vgll3 is also linked to the control of adipose tissue growth and pubertal timing in mammals. This makes Atlantic salmon ideal for studying whether functional variation in adipose tissue processes is linked to reproductive timing. Here, using 16 Atlantic salmon individuals of different sexes reared in common-garden conditions, we conducted a proof-of-principle study and tested whether mitochondrial respiration in adipose tissue, mitochondrial DNA (mtDNA) amount, and adipocyte size are associated with sex and vgll3 genotype. Mitochondrial respiration was quantified from freshly collected white adipose tissue using high-resolution respirometry, and mtDNA amounts were quantified relative to nuclear DNA amounts. We found differences in mtDNA amount between sexes, plausibly caused by a confounding effect of maturation status, but without corresponding differences in mitochondrial respiration. Mitochondrial respiration, leak respiration, and coupling capacity (P/E ratio) were marginally lower in immature females carrying the vgll3 early maturation genotype compared to those with the late maturation genotype, although larger sample sizes are required to validate this difference. Our results generate new hypotheses on how coupling capacity of oxidative phosphorylation could be linked with the timing of maturation via adiposity as well as pave the way to study the mechanistic relationships between life-history variation and mitochondrial bioenergetics in wild populations.

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Tead1 is essential for mitochondrial function in cardiomyocytes

Cited by 22 publications

References 37 publications

TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes

TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes

Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming

Adipose tissue mitochondrial respiration in Atlantic salmon: implications for sex-dependent life-history variation

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