Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats

Hasan, Prottoy; Saotome, Masao; Ikoma, Takenori; Iguchi, Keisuke; Kawasaki, Hideya; Iwashita, Toshihide; Hayashi, Hideharu; Maekawa, Yuichiro

doi:10.1016/j.yjmcc.2018.07.004

Cited by 55 publications

(37 citation statements)

References 12 publications

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“…The balancing of mitochondrial dynamics is not only essential for maintaining normal cellular metabolism but also required for the proper functioning of organs with high-energy demand such as the heart. The imbalance of mitochondrial dynamics leads to mitochondrial dysfunction and contributes to the development of cardiac hypertrophy and heart dysfunction 11, 12, 37, 38.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study found that leptin acts as a pro-hypertrophic factor by promoting mitochondrial fission process and mitochondrial dysfunction through calcineurin-pathway mediated dephosphorylation of Drp1 and its translocation to mitochondria 11. The dysregulation of fission or fusion processes due to the enhanced activity of fission proteins such as Drp1 38 or suppressed expression/activity of fusion proteins such as Mfn1 37 triggers aberrant mitochondrial fission and promotes hypertrophic response. Consistent with the reports mentioned above, our results also demonstrated that a hypertrophic stimulant, ISO, induced mitochondrial fission by suppressing Mfn1 protein expression, which led to hypertrophy in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

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NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression

Wang¹,

Zhai²,

Xu³

et al. 2020

Theranostics

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Mitochondrial dysfunction is involved in the pathogenesis of various cardiovascular disorders. Although mitochondrial dynamics, including changes in mitochondrial fission and fusion, have been implicated in the development of cardiac hypertrophy, the underlying molecular mechanisms remain mostly unknown. Here, we show that NFATc3, miR-153-3p, and mitofusion-1 (Mfn1) constitute a signaling axis that mediates mitochondrial fragmentation and cardiomyocyte hypertrophy.Methods: Isoprenaline (ISO) was used to stimulate the hypertrophic response and mitochondrial fragmentation in cultured cardiomyocytes and in vivo. We performed immunoblotting, immunofluorescence, and quantitative real-time PCR to validate the function of Mfn1 in cardiomyocyte hypertrophy. Bioinformatic analyses, a luciferase reporter assay, and gain- and loss-of-function studies were used to demonstrate the biological function of miR-153-3p, which regulates mitochondrial fragmentation and hypertrophy by targeting Mfn1. Moreover, ChIP-qPCR and a luciferase reporter assay were performed to identify transcription factor NFATc3 as an upstream regulator to control the expression of miR-153-3p.Results: Our results show that ISO promoted mitochondrial fission and enhanced the expression of miR-153-3p in cardiomyocytes. Knockdown of miR-153-3p attenuated ISO-induced mitochondrial fission and hypertrophy in cultured primary cardiomyocytes. miR-153-3p suppression inhibited mitochondrial fragmentation in ISO-induced cardiac hypertrophy in a mouse model. We identified direct targeting of Mfn1, a key protein of the mitochondrial fusion process, by miR-153-3p. Also, miR-153-3p promoted ISO-induced mitochondrial fission by suppressing the translation of Mfn1. We further found that NFATc3 activated miR-153-3p expression. Knockdown of NFATc3 inhibited miR-153-3p expression and blocked mitochondrial fission and hypertrophic response in cardiomyocytes.Conclusions: Our data revealed a novel signaling pathway, involving NFATc3, miR-153-3p, and Mfn1, which could be a therapeutic target for the prevention and treatment of cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression

Wang¹,

Zhai²,

Xu³

et al. 2020

Theranostics

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“…These studies suggest that PRKAR1A deficiency diminished cardiomyocyte hypertrophy in vitro, likely through inactivation of Drp1. It has been shown that loss of Drp1 activity suppresses cardiac hypertrophy and reduces skeletal muscle mass in vivo (Favaro et al, 2019; Hasan et al, 2018). Although phospho‐Drp1 (S637) was undetectable in the heart at 3 months of age (data not shown), it cannot be excluded that ablation of PRKAR1A might enhance Drp1 S637 phosphorylation during early cardiac development.…”

Section: Discussionmentioning

confidence: 99%

PRKAR1A deficiency impedes hypertrophy and reduces heart size

et al. 2020

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Protein kinase A (PKA) activity is pivotal for proper functioning of the human heart, and its dysregulation has been implicated in a variety of cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity by sequestering PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) in early adulthood, and may die later in life from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart development. Here, we showed that left ventricular mass was reduced in young CNC patients with PRKAR1A mutations or deletions. Cardiac‐specific heterozygous ablation of PRKAR1A in mice increased cardiac PKA activity, and reduced heart weight and cardiomyocyte size without altering contractile function at 3 months of age. Silencing of PRKAR1A, or stimulation with the PKA activator forskolin completely abolished α1‐adrenergic receptor‐mediated cardiomyocyte hypertrophy. Mechanistically, depletion of PRKAR1A provoked PKA‐dependent inactivating phosphorylation of Drp1 at S637, leading to impaired mitochondrial fission. Pharmacologic inhibition of Drp1 with Mdivi 1 diminished hypertrophic growth of cardiomyocytes. In conclusion, PRKAR1A deficiency suppresses cardiomyocyte hypertrophy and impedes heart growth, likely through inhibiting Drp1‐mediated mitochondrial fission. These findings provide a potential novel mechanism for the cardiac manifestations associated with CNC.

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“…We reported that mutated desmin expression in D7-Des Tg mouse caused a reduction in mitochondrial respiration in both isolated mitochondria and intact cardiomyocytes (Alam et al, 2018) (Figure 6). Excessive mitochondrial fission is also attributable to hypertensive cardiac hypertrophy (Hasan et al, 2018) and sepsisinduced cardiomyopathy (Haileselassie et al, 2019). Aberrant mitochondrial fission may involve several possible mechanisms such as excessive production of reactive oxygen species and activation of fission regulatory proteins (Hasan et al, 2018).…”

Section: Mitochondrial Dynamics In Cardiac Proteostasismentioning

confidence: 99%

Molecular Perspectives of Mitochondrial Adaptations and Their Role in Cardiac Proteostasis

et al. 2020

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; TIM, translocase of inner membrane; TIM44, translocase of inner membrane 44; TOM, translocase of outer membrane; Tom40, translocase of outer membrane 40; UPR, unfolded protein response; UPR am , unfolded protein response activated by the mistargeting of proteins; UPR ER , endoplasmic reticulum (ER)-unfolded protein response; UPR mt , mitochondrial unfolded protein response; UPS mt , mitochondrial unfolded protein response; VDAC, voltage-dependent anionic channel.

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Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats

Cited by 55 publications

References 12 publications

NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression

NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression

PRKAR1A deficiency impedes hypertrophy and reduces heart size

Molecular Perspectives of Mitochondrial Adaptations and Their Role in Cardiac Proteostasis

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