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

Lam, Chi Keung; Zhao, Wen; Liu, Guansheng; Cai, Wenfeng; Gardner, George; Adly, George; Kranias, Evangelia G.

doi:10.1073/pnas.1508760112

Cited by 67 publications

(78 citation statements)

References 35 publications

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“…We have shown here an evidence that Hax1 inhibits ER stress-induced downregulation of MFN1 and MFN2 mRNA. Moreover, this study is in agreement with previous findings which demonstrated that Hax1 protects from mitochondrial membrane depolarization [57]. This is important because loss of MFN1 or MFN2 could render the mitochondria more susceptible to lose their membrane potential [65].…”

Section: Discussionsupporting

confidence: 92%

“…Hax1 has been recently shown to suppress apoptosis in various models including cardiac cells, both in vitro and in vivo [24, 25, 27, 31, 57, 58]. Moreover, Hax1 may regulate many unrelated molecules, indicating its contribution to diverse signaling mechanisms within the cell [23, 57–60]. Given the crucial pro-death role of ER stress in the diseased heart, it is essential to dissect different preferential apoptotic pathways triggered by this mechanism in different cardiac cell models.…”

Section: Discussionmentioning

confidence: 99%

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Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Abdelwahid

et al. 2016

Apoptosis

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Cardiomyocyte apoptosis is a major process in pathogenesis of a number of heart diseases, including ischemic heart diseases and cardiac failure. Ensuring survival of cardiac cells by blocking apoptotic events is an important strategy to improve cardiac function. Although the role of ER disruption in inducing apoptosis has been demonstrated, we do not yet fully understand how it influences the mitochondrial apoptotic machinery in cardiac cell models. Recent investigations have provided evidences that the prosurvival protein HCLS1-associated protein X-1 (Hax1) protein is intimately associated with the pathogenesis of heart disease, mitochondrial biology, and protection from apoptotic cell death. To study the role of Hax1 upon ER stress induction, Hax1 was overexpressed in cardiac cells subjected to ER stress, and cell death parameters as well as mitochondrial alterations were examined. Our results demonstrated that the Hax1 is significantly downregulated in cardiac cells upon ER stress induction. Moreover, overexpression of Hax1 protected from apoptotic events triggered by Tunicamycin-induced ER stress. Upon treatment with Tunicamycin, Hax1 protected from mitochondrial fission, downregulation of mitofusins 1 and 2 (MFN1 and MFN2), loss of mitochondrial membrane potential (ΔΨm), production of reactive oxygen species (ROS) and apoptotic cell death. Taken together, our results suggest that Hax1 inhibits ER stress-induced apoptosis at both the pre- and post-mitochondrial levels. These findings may offer an opportunity to develop new agents that inhibit cell death in the diseased heart.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Abdelwahid

et al. 2016

Apoptosis

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“…CypD and TSPO are potent components that act as regulators of MPTP opening . Down‐regulation of CypD prevents MPTP opening and protects against the loss of ΔΨm . Conversely, the loss function of TSPO causes MPTP opening and leads to a reduced ΔΨm .…”

Section: Discussionmentioning

confidence: 99%

“…21,34 Down-regulation of CypD prevents MPTP opening and protects against the loss of ΔΨm. 35 Conversely, the loss function of TSPO causes MPTP opening and leads to a reduced ΔΨm. 21,36 Our results showed that both CypD and TSPO could be poly-ADP-ribosylated, but the effects of this modification on the functions of CypD and TSPO were not studied.…”

Section: Mitophagy Inhibition Due To Knockdown Ofmentioning

confidence: 99%

Poly (ADP‐ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy

Cao

Sun

Wang

et al. 2019

J Cellular Molecular Medi

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Myocardial ischaemia/reperfusion (I/R) injury attenuates the beneficial effects of reperfusion therapy. Poly(ADP‐ribose) polymerase (PARP) is overactivated during myocardial I/R injury. Mitophagy plays a critical role in the development of myocardial I/R injury. However, the effect of PARP activation on mitophagy in cardiomyocytes is unknown. In this study, we found that I/R induced PARP activation and mitophagy in mouse hearts. Poly(ADP‐ribose) polymerase inhibition reduced the infarct size and suppressed mitophagy after myocardial I/R injury. In vitro, hypoxia/reoxygenation (H/R) activated PARP, promoted mitophagy and induced cell apoptosis in cardiomyocytes. Poly(ADP‐ribose) polymerase inhibition suppressed H/R‐induced mitophagy and cell apoptosis. Parkin knockdown with lentivirus vectors inhibited mitophagy and prevented cell apoptosis in H/R‐treated cells. Poly(ADP‐ribose) polymerase inhibition prevented the loss of the mitochondrial membrane potential (ΔΨm). Cyclosporin A maintained ΔΨm and suppressed mitophagy but FCCP reduced the effect of PARP inhibition on ΔΨm and promoted mitophagy, indicating the critical role of ΔΨm in H/R‐induced mitophagy. Furthermore, reactive oxygen species (ROS) and poly(ADP‐ribosylation) of CypD and TSPO might contribute to the regulation of ΔΨm by PARP. Our findings thus suggest that PARP inhibition protects against I/R‐induced cell apoptosis by suppressing excessive mitophagy via the ΔΨm/Parkin pathway.

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“…demonstrates that a newly identified partner of Hsp90, the hematopoietic-substrate-1 associated protein x-1 (HAX-1) is involved in the regulation of CypD in the heart. HAX-1 binds to CypD and interfere its binding to Hsp-90, rendering CypD ubiquitination and degradation, resulting in protection against MPTP opening and cell death[49]. …”

Section: Mitochondria Bcl2 Family and Cell Deathmentioning

confidence: 99%

Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?

Yuan

Padanilam

2016

Cell. Mol. Life Sci.

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In contrast to apoptosis and autophagy, necrotic cell death was considered to be a random, passive cell death without definable mediators. However, this dogma has been challenged by recent developments suggesting that necrotic cell death can also be a regulated process. Regulated necrosis includes multiple cell death modalities such as necroptosis, parthanatos, ferroptosis, pyroptosis, and mitochondrial permeability transition pore (MPTP)-mediated necrosis. Several distinctive executive molecules, particularly residing on the mitochondrial inner and outer membrane, amalgamating to form the MPTP have been defined. The c-subunit of the F1F0ATP synthase on the inner membrane and Bax/Bak on the outer membrane are considered to be the long sought components that form the MPTP. Opening of the MPTP results in loss of mitochondrial inner membrane potential, disruption of ATP production, increased ROS production, organelle swelling, mitochondrial dysfunction and consequent necrosis. Cyclophilin D, along with adenine nucleotide translocator (ANT) and the phosphate carrier (PiC) are considered to be important regulators involved in the opening of MPTP. Increased production of ROS can further trigger other necrotic pathways mediated through molecules such as PARP1, leading to irreversible cell damage. This review examines the roles of PARP1 and cyclophilin D in necrotic cell death. The hierarchical role of p53 in regulation and integration of key components of signaling pathway to elicit MPTP-mediated necrosis and ferroptosis is explored. In the context of recent insights, the indistinct role of necroptosis signaling in tubular necrosis after ischemic kidney injury is scrutinized. We conclude by discussing the participation of p53, PARP1 and cyclophilin D and their overlapping pathways to elicit MPTP-mediated necrosis and ferroptosis in acute kidney injury.

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

Cited by 67 publications

References 35 publications

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Poly (ADP‐ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy

Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?

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