Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy

Dachun Xu, Yifan Zhao, Xinyu Weng, Yuyan Lu, Weiming Li, Kai Tang, Wei Chen, Zheng Liu, Xinrui Qi, Jialing Zheng, John Fassett, Yi Zhang, Yawei Xu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.

Original languageEnglish (US)
Pages (from-to)105-116
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume128
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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GTP Phosphohydrolases
Cardiomegaly
Hypertrophy
Cardiac Myocytes
Oxidative Stress
Heart Failure
Pressure
Mitochondrial Proteins
Acetylcysteine
Dilated Cardiomyopathy
Ventricular Pressure
Electron Transport
Mitochondrial DNA
Ribosomes
Angiotensin II
Endoplasmic Reticulum
Small Interfering RNA
Fibrosis
Down-Regulation

Keywords

  • Cardiac hypertrophy
  • MAPK
  • Mitochondrial GTPases 1
  • Oxidative stress
  • TAK1

PubMed: MeSH publication types

  • Journal Article

Cite this

Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy. / Xu, Dachun; Zhao, Yifan; Weng, Xinyu; Lu, Yuyan; Li, Weiming; Tang, Kai; Chen, Wei; Liu, Zheng; Qi, Xinrui; Zheng, Jialing; Fassett, John; Zhang, Yi; Xu, Yawei.

In: Journal of Molecular and Cellular Cardiology, Vol. 128, 01.03.2019, p. 105-116.

Research output: Contribution to journalArticle

Xu, D, Zhao, Y, Weng, X, Lu, Y, Li, W, Tang, K, Chen, W, Liu, Z, Qi, X, Zheng, J, Fassett, J, Zhang, Y & Xu, Y 2019, 'Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy', Journal of Molecular and Cellular Cardiology, vol. 128, pp. 105-116. https://doi.org/10.1016/j.yjmcc.2019.01.025
Xu, Dachun ; Zhao, Yifan ; Weng, Xinyu ; Lu, Yuyan ; Li, Weiming ; Tang, Kai ; Chen, Wei ; Liu, Zheng ; Qi, Xinrui ; Zheng, Jialing ; Fassett, John ; Zhang, Yi ; Xu, Yawei. / Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy. In: Journal of Molecular and Cellular Cardiology. 2019 ; Vol. 128. pp. 105-116.
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AU - Chen, Wei

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AB - While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.

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