HAX-1: A multifaceted antiapoptotic protein localizing in the mitochondria and the sarcoplasmic reticulum of striated muscle cells

Yap, Solomon; Vafiadaki, Elizabeth; Strong, John; Kontrogianni‐Konstantopoulos, Aikaterini

doi:10.1016/j.yjmcc.2009.10.028

Cited by 25 publications

(27 citation statements)

References 43 publications

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“…HAX-1 was present in the inner mitochondrial membrane (Fig. S2), consistent with previous reports (10,21). Thus, we sought to investigate whether HAX-1 may regulate mitochondria membrane potential and control activation of cell death.…”

Section: Hax-1 Preserves Mitochondria Membrane Integrity and Inhibitssupporting

confidence: 83%

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

Lam

Zhao

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The major underpinning of massive cell death associated with myocardial infarction involves opening of the mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane integrity and programmed necrosis. Studies in human lymphocytes suggested that the hematopoietic-substrate-1 associated protein X-1 (HAX-1) is linked to regulation of mitochondrial membrane function, but its role in controlling mPTP activity remains obscure. Herein we used models with altered HAX-1 expression levels in the heart and uncovered an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival. Cardiac-specific HAX-1 overexpression was associated with resistance against loss of mitochondrial membrane potential, induced by oxidative stress, whereas HAX-1 heterozygous deficiency exacerbated vulnerability. The protective effects of HAX-1 were attributed to specific down-regulation of cyclophilin-D levels leading to reduction in mPTP activation. Accordingly, cyclophilin-D and mPTP were increased in heterozygous hearts, but genetic ablation of cyclophilin-D in these hearts significantly alleviated their susceptibility to ischemia/reperfusion injury. Mechanistically, alterations in cyclophilin-D levels by HAX-1 were contributed by the ubiquitin-proteosomal degradation pathway. HAX-1 overexpression enhanced cyclophilin-D ubiquitination, whereas proteosomal inhibition restored cyclophilin-D levels. The regulatory effects of HAX-1 were mediated through interference of cyclophilin-D binding to heat shock protein-90 (Hsp90) in mitochondria, rendering it susceptible to degradation. Accordingly, enhanced Hsp90 expression in HAX-1 overexpressing cardiomyocytes increased cyclophilin-D levels, as well as mPTP activation upon oxidative stress. Taken together, our findings reveal the role of HAX-1 in regulating cyclophilin-D levels via an Hsp90-dependent mechanism, resulting in protection against activation of mPTP and subsequent cell death responses.HAX-1 | necrosis | mitochondrial permeability transition | cyclophilin-D | heat shock protein-90

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Section: Hax-1 Preserves Mitochondria Membrane Integrity and Inhibitssupporting

confidence: 83%

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

Lam

Zhao

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, as the cellular distribution of HAX-1 differs in various cell-types 34 , it is important to note that survival mechanisms mediated by HAX-1 may be different in the heart, where it shows significant ER/SR localization 18 . This notion is supported by the findings that re-distributing HAX-1 to ER through PLN co-expression enhances survival in HEK293 cells 35, 36 . In this regard, the present study provides the first evidence that the ER/SR localized HAX-1 can modulate apoptotic signaling through the ER stress response pathways.…”

Section: Discussionmentioning

confidence: 68%

Novel Role of HAX-1 in Ischemic Injury Protection Involvement of Heat Shock Protein 90

Lam

Zhao

Cai

et al. 2013

Circulation Research

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Rationale Ischemic heart disease is characterized by contractile dysfunction and increased cardiomyocyte death, induced by necrosis and apoptosis. Increased cell survival after an ischemic insult is critical and depends on several cellular pathways, which have not been fully elucidated. Objective To test the hypothesis that the anti-apoptotic haematopoietic-lineage-substrate-1-associated protein-X-1 (HAX-1), recently identified as regulator of cardiac Ca-cycling, may also ameliorate cellular injury in the face of an ischemic insult. Methods and Results We report that cardiac ischemia/reperfusion injury is associated with significant decreases in HAX-1 levels ex vivo and in vivo. Accordingly, over-expression of HAX-1 improved contractile recovery, coupled with reduced infarct size, plasma troponin I level and apoptosis. The beneficial effects were associated with decreased ER stress response through specific inhibition of the inositol-requiring-enzyme (IRE-1) signaling pathway, including its downstream effectors caspase-12 and the transcription factor C/EBP homologous protein. Conversely, HAX-1 heterozygous deficient hearts exhibited increases in infarct size and IRE-1 activity. The inhibitory effects of HAX-1 were mediated by its binding to the N-terminal fragment of the heat shock protein 90 (Hsp90). Moreover, HAX-1 sequestered Hsp90 from IRE-1 to the phospholamban/SERCA calcium transport complex. The HAX-1 regulation was further supported by loss of IRE-1 inhibition in presence of the Hsp90 inhibitor, 17-N-Allylamino-17-Demethoxygeldanamycin. Conclusions Cardiac ischemia/reperfusion injury is associated with decreases in HAX-1 levels. Consequently, over-expression of HAX-1 promotes cardiomyocyte survival, mediated by its interaction with Hsp90 and specific inhibition of IRE-1 signaling at the ER/SR.

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“…Indeed, when the transmembrane domain of HAX-1 is deleted, truncated HAX-1 (HAX-1 aa 1–181) only distributes to the mitochondria. Additionally, when compared to full length HAX-1 cotransfected with PLN, truncated HAX-1 cotransfected with PLN did not show distribution to the ER membrane (Kaufmann et al 2003; Yap et al 2010). …”

Section: Subcellular Localization and Redistribution Of The Bcl-2 Familymentioning

confidence: 91%

Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival

Lewis

Hayashi

et al. 2013

J Bioenerg Biomembr

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Bcl-2 family proteins, known for their apoptosis functioning at the mitochondria, have been shown to localize to other cellular compartments to mediate calcium (Ca2+) signals. Since the proper supply of Ca2+ in cells serves as an important mechanism for cellular survival and bioenergetics, we propose an integrating role for Bcl-2 family proteins in modulating Ca2+ signaling. The endoplasmic reticulum (ER) is the main Ca2+ storage for the cell and Bcl-2 family proteins competitively regulate its Ca2+ concentration. Bcl-2 family proteins also regulate the flux of Ca2+ from the ER by physically interacting with inositol 1,4,5-trisphosphate receptors (IP3Rs) to mediate their opening. Type 1 IP3Rs reside at the bulk ER to coordinate cytosolic Ca2+ signals, while type 3 IP3Rs reside at mitochondria-associated ER membrane (MAM) to facilitate mitochondrial Ca2+ uptake. In healthy cells, mitochondrial Ca2+ drives pyruvate into the citric acid (TCA) cycle to facilitate ATP production, while a continuous accumulation of Ca2+ can trigger the release of cytochrome c, thus initiating apoptosis. Since multiple organelles and Bcl-2 family proteins are involved in Ca2+ signaling, we aim to clarify the role that Bcl-2 family proteins play in facilitating Ca2+ signaling and how mitochondrial Ca2+ is relevant in both bioenergetics and apoptosis. We also explore how these insights could be useful in controlling bioenergetics in apoptosis-resistant cell lines.

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HAX-1: A multifaceted antiapoptotic protein localizing in the mitochondria and the sarcoplasmic reticulum of striated muscle cells

Cited by 25 publications

References 43 publications

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

Novel Role of HAX-1 in Ischemic Injury Protection Involvement of Heat Shock Protein 90

Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival

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