Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy

Martin G. Yussman, Tsuyoshi Toyokawa, Amy Odley, Roy A. Lynch, Guangyu Wu, Melissa C. Colbert, Bruce J. Aronow, John N. Lorenz, Gerald W. Dorn

Research output: Contribution to journalArticle

226 Citations (Scopus)

Abstract

Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in Gαq-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation.

Original languageEnglish (US)
Pages (from-to)725-730
Number of pages6
JournalNature Medicine
Volume8
Issue number7
DOIs
StatePublished - Jul 2002

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Mitochondrial Proteins
Cardiomegaly
Cardiomyopathies
Mitochondria
Cell death
Apoptosis
Cardiac Myocytes
Hypertrophy
Cell Death
Peripartum Period
Proteins
Fibroblasts
Microarray Analysis
Microarrays
Cytochromes c
Caspase 3
Protein Isoforms
Heart Failure
Chemical activation
Pressure

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yussman, M. G., Toyokawa, T., Odley, A., Lynch, R. A., Wu, G., Colbert, M. C., ... Dorn, G. W. (2002). Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nature Medicine, 8(7), 725-730. https://doi.org/10.1038/nm719

Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. / Yussman, Martin G.; Toyokawa, Tsuyoshi; Odley, Amy; Lynch, Roy A.; Wu, Guangyu; Colbert, Melissa C.; Aronow, Bruce J.; Lorenz, John N.; Dorn, Gerald W.

In: Nature Medicine, Vol. 8, No. 7, 07.2002, p. 725-730.

Research output: Contribution to journalArticle

Yussman, MG, Toyokawa, T, Odley, A, Lynch, RA, Wu, G, Colbert, MC, Aronow, BJ, Lorenz, JN & Dorn, GW 2002, 'Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy', Nature Medicine, vol. 8, no. 7, pp. 725-730. https://doi.org/10.1038/nm719
Yussman, Martin G. ; Toyokawa, Tsuyoshi ; Odley, Amy ; Lynch, Roy A. ; Wu, Guangyu ; Colbert, Melissa C. ; Aronow, Bruce J. ; Lorenz, John N. ; Dorn, Gerald W. / Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. In: Nature Medicine. 2002 ; Vol. 8, No. 7. pp. 725-730.
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