Molecular mechanisms of cell death by parthanatos: More questions than answers

Moura, Rafael Dias de; Mattos, Priscilla Doria de; Valente, Penélope Ferreira; Hoch, Nícolas Carlos

doi:10.1590/1678-4685-GMB-2023-0357

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Young Latin American Geneticists - Special Issue • Genet. Mol. Biol. 47 (Suppl 1) • 2024 • https://doi.org/10.1590/1678-4685-GMB-2023-0357 copy

Molecular mechanisms of cell death by parthanatos: More questions than answers

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Regulated cell death by a non-apoptotic pathway known as parthanatos is increasingly recognised as a central player in pathological processes, including ischaemic tissue damage and neurodegenerative diseases. Parthanatos is activated under conditions that induce high levels of DNA damage, leading to hyperactivation of the DNA damage sensor PARP1. While this strict dependence on PARP1 activation is a defining feature of parthanatos that distinguishes it from other forms of cell death, the molecular events downstream of PARP1 activation remain poorly understood. In this mini-review, we highlight a number of important questions that remain to be answered about this enigmatic form of cell death.

Keywords:
Cell death; parthanatos; PARP1; PARG; AIF

Model	Insult	Effect of PARG on cell death	AIF translocation	TRPM2 contribution to cell death	Reference
Mouse embryos	MNNG, menadione	Protective (knockout increased cell death)	-	-	Koh et al., 2004Koh DW, Lawler AM, Poitras MF, Sasaki M, Wattler S, Nehls MC, Stöger T, Poirier GG, Dawson VL and Dawson TM (2004) Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. Proc Natl Acad Sci U S A 101:17699-17704.
MEFs	H₂O₂	Protective (knockdown increased cell death	-	-	Blenn et al., 2006Blenn C, Althaus FR and Malanga M (2006) Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death. Biochem J 396:419-429.
Cortical neurons	NMDA	Protective (overexpression reduced cell death	-	-	Andrabi et al., 2006Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC et al. (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 103:18308-18313.
Mice	middle cerebral artery occlusion (MCAO)	Protective (heterozygous KO increased tissue damage; overexpression reduced tissue damage)	-	-	Andrabi et al., 2006Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC et al. (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 103:18308-18313.
Cortical neurons	MNNG	Protective (overexpression prevented glycolytic defect)	-	-	*Andrabi et al.,* 2014**Andrabi SA, Umanah GK, Chang C, Stevens DA, Karuppagounder SS, Gagné JP, Poirier GG, Dawson VL and Dawson TM (2014 ) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A 111:10209-10214.
MEFs	MNNG	No effect	-	-	Blenn et al., 2006Blenn C, Althaus FR and Malanga M (2006) Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death. Biochem J 396:419-429.
HK-2 cells	TGHQ	No effect	-	-	Munoz et al., 2017Munoz FM, Zhang F, Islas-Robles A, Lau SS and Monks TJ (2017) ROS-induced store-operated Ca2+ entry coupled to PARP-1 hyperactivation is independent of PARG activity in necrotic cell death. Toxicol Sci 158:444-453.
Mice and rats	splanchnic artery occlusion (SAO) shock	Detrimental (knockout and inhibition protected tissues)	-	-	Cuzzocrea et al., 2005Cuzzocrea S, Di Paola R, Mazzon E, Cortes U, Genovese T, Muià C, Li W, Xu W, Li JH, Zhang J et al. (2005) PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion. FASEB J 19:558-566.
Glioblastoma cells	MNNG	Detrimental (knockdown prevented ATP depletion and glycolytic defect)	-	-	Fouquerel et al., 2014Fouquerel E, Goellner Eva M, Yu Z, Gagné J-P, Barbi de Moura M, Feinstein T, Wheeler D, Redpath P, Li J, Romero G et al. (2014) ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ Depletion. Cell Rep 8:1819-1831.
Glioblastoma cells	MMS	Protective (knockdown increased cell death)	No	-	Tang et al., 2010Tang JB, Goellner EM, Wang XH, Trivedi RN, St Croix CM, Jelezcova E, Svilar D, Brown AR and Sobol RW (2010) Bioenergetic metabolites regulate base excision repair-dependent cell death in response to DNA damage. Mol Cancer Res 8:67-79.
Pancreatic cancer cells	ZZW-115 (NUPR1 inhibitor)	Protective (inhibition increased cell death)	No	-	Santofimia-Castaño et al., 2022Santofimia-Castaño P, Huang C, Liu X, Xia Y, Audebert S, Camoin L, Peng L, Lomberk G, Urrutia R, Soubeyran P et al. (2022) NUPR1 protects against hyperPARylation-dependent cell death. Commun Biol 5:732.
Trophoblast stem cells	UV	Protective (knockout increased cell death)	Yes	-	Zhou et al., 2011Zhou Y, Feng X and Koh DW (2011) Activation of cell death mediated by apoptosis-inducing factor due to the absence of poly(ADP-ribose) glycohydrolase. Biochemistry 50:2850-2859.
MEFs	H₂O₂	Detrimental (knockdown reduced cell death)	Yes	-	Mashimo et al., 2013Mashimo M, Kato J and Moss J (2013) ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress. Proc Natl Acad Sci U S A 110:18964-18969.
Rat fibroblasts	MNNG	-	Yes	-	Yu et al., 2002Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM and Dawson VL (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259-263.
Neurons	NMDA	-	Yes	-	Yu et al., 2006Yu S-W, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM and Dawson VL (2006) Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A 103:18314-18319.
MEFs	H₂O₂	-	Yes	-	Kolthur-Seetharam et al., 2006Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G and Sassone-Corsi P (2006) Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 5:873-877.
MEFs	MNNG	-	Yes	-	Wang et al., 2009Wang Y, Kim NS, Li X, Greer PA, Koehler RC, Dawson VL and Dawson TM (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110:687-696.
Cortical neurons	NMDA	-	Yes	-	Wang et al., 2011Wang Y, Kim NS, Haince JF, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL and Dawson TM (2011) Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos), Sci Signal 4:ra20.
Glioma cells	DPT	-	Yes	-	Ma et al., 2016Ma D, Lu B, Feng C, Wang C, Wang Y, Luo T, Feng J, Jia H, Chi G, Luo Y et al. (2016) Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS. Cancer Lett 371:194-204.
SH-SY5Y cells	MNNG	-	Yes	-	Zhong et al., 2018Zhong H, Song R, Pang Q, Liu Y, Zhuang J, Chen Y, Hu J, Hu J, Liu Y, Liu Z et al. (2018) Propofol inhibits parthanatos via ROS-ER-calcium-mitochondria signal pathway in vivo and vitro. Cell Death Dis 9:932.
HK-2 cells	TGHQ	-	No	-	Zhang et al., 2014Zhang F, Xie R, Munoz FM, Lau SS and Monks TJ (2014) PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death. Toxicol Sci 140:118-134.
Retinal cells	H₂O₂	-	No	-	Jang et al., 2017Jang KH, Do YJ, Son D, Son E, Choi JS and Kim E (2017) AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration. Cell Death Dis 8:e2526.
Mouse bone-marrow derived macrophages	H₂O₂	-	No	-	Regdon et al., 2019Regdon Z, Robaszkiewicz A, Kovács K, Rygielska Ż, Hegedűs C, Bodoor K, Szabó É and Virág L (2019) LPS protects macrophages from AIF-independent parthanatos by downregulation of PARP1 expression, induction of SOD2 expression, and a metabolic shift to aerobic glycolysis. Free Radic Biol Med 131:184-196.
HEK293 expressing recombinant TRPM2	H₂O₂	-	-	Increased	Fonfria et al., 2004Fonfria E, Marshall ICB, Benham CD, Boyfield I, Brown JD, Hill K, Hughes JP, Skaper SD and McNulty S (2004) TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol 143:186-192.
Rat striatal neurons	H₂O₂ and amyloid β-peptide(1-42)	-	-	Increased	Fonfria et al., 2005Fonfria E, Marshall IC, Boyfield I, Skaper SD, Hughes JP, Owen DE, Zhang W, Miller BA, Benham CD and McNulty S (2005) Amyloid beta-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. J Neurochem 95:715-723.
Rat cardiomyocytes	H₂O₂	-	-	Increased (apoptosis markers also present)	Yang et al., 2006Yang KT, Chang WL, Yang PC, Chien CL, Lai MS, Su MJ and Wu ML (2006) Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death Differ 13:1815-1826.
Mice	MCAO	-	-	Increased infarct volumes (also androgen signalling-dependent)	Shimizu et al., 2013Shimizu T, Macey TA, Quillinan N, Klawitter J, Perraud AL, Traystman RJ and Herson PS (2013) Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury. J Cereb Blood Flow Metab 33:1549-1555.
RIN-5F (rat pancreatic β-cells)	H₂O₂	-	-	Increased	Ishii et al., 2014Ishii M, Hagiwara T, Mori Y and Shimizu S (2014) Involvement of TRPM2 and L-type Ca²⁺ channels in Ca²⁺ entry and cell death induced by hydrogen peroxide in rat β-cell line RIN-5F. J Toxicol Sci 39:199-209.
Mouse hippocampal neurons	H₂O₂	-	-	Increased (death is also partly Zn²⁺ dependent)	Li et al., 2017Li X, Yang W and Jiang LH (2017) Alteration in intracellular Zn(2+) homeostasis as a result of TRPM2 channel activation contributes to ROS-induced hippocampal cell death. Front Mol Neurosci 10:414.
SH-SY5Y overexpressing TRPM2	H₂O₂	-	-	Increased	An et al., 2019An X, Fu Z, Mai C, Wang W, Wei L, Li D, Li C and Jiang LH (2019) Increasing the TRPM2 channel expression in human neuroblastoma SH-SY5Y cells augments the susceptibility to ROS-Induced Cell Death. Cells 8:28.

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[1] Send correspondence to
Nícolas Carlos Hoch. Universidade de São Paulo, Instituto de Química, Departamento de Bioquímica, Av. Prof. Lineu Prestes, 748, Butantã, 05508-000, São Paulo, SP, Brasil. E-mail: nicolas@iq.usp.br.