Table 1.

Major signaling pathways controlling different PCD-related events in the mammalian ovary

Pathway	Ovarian event	PCD type	Upstream regulators	Downstream effectors	Effect on ovarian cells	References
PI3K/AKT	PGC depletion	Apoptosis	KITLG	Upregulation of BCL-2, BCL-XL, MCL-1 Inactivation of BIM, BAX, BAD, and FOXO3	Pro-survival	[72, 77–80]
	Follicular atresia	Apoptosis	FSH, IGF, EGF, bFGF	Upregulation of NFκB, cFLIPL, BCL-2, MDM2, and XIAP Inactivation of caspase-8, BIM, BAX, BAD, FOXO1, and FOXO3	Pro-survival	[77, 141–144, 150, 157–170, 173–177]
		Autophagy	FSH	Downregulation of MAP1LC3-II, BECN1, ATG7, and ATG12	Pro-survival	[188, 191]
	Luteolysis	Apoptosis	PGF2α	Inhibition of AKT Upregulation of BAX	Pro-apoptotic	[247]
PLC/PKC	Follicular atresia	Apoptosis	FSH	Stabilization of cFLIPS	Pro-survival	[143]
	Luteolysis	Apoptosis	PGF2α	Activation of NFAT	Pro-apoptotic	[231, 242, 243]
Ca2+/AMPK	Luteolysis	Autophagy	PGF2α	Activation of BECN1 Upregulation of MAP1LC3-II	Pro-autophagic	[286]
MEK/ERK	PGC depletion	Apoptosis	KITLG	Activation of RPS6KA1, MYC, STAT1/3	Pro-survival	[72, 77]
	Follicular atresia	Apoptosis	FSH through β-arrestin	Activation of RPS6KA1, MYC, STAT1/3	Pro-survival	[150, 152]
	Luteolysis	Apoptosis	LH/hCG through β-arrestin	Activation of RPS6KA1, MYC	Pro-survival	[255, 261]
		Autophagy	PGF2α	Upregulation of MAP1LC3-II	Pro-autophagic	[288]
cAMP/PKA	Follicular atresia	Apoptosis	FSH	Phosphorylation of CREB, ERK1/2, AKT, GSK3B, β-catenin, FOXO1, p38 MAPK Downregulation of BIM	Pro-survival	[153–155]
	Luteolysis	Apoptosis	LH/hCG	Progesterone synthesis stimulation Activation of CREB, GSK3B, and β-catenin Upregulation of LHCGR, BCL-2, MCL-1, survivin, STAR, and PGE2α Downregulation of BAX and CD95/Fas	Pro-survival	[156, 256–258, 262, 263, 265–269, 277]
			PGE2α	Upregulation of LHCGR, BCL-2, STAR	Pro-survival	[273, 277]
		Autophagy	LH/hCG	Downregulation of MAP1LC3-II	Pro-survival	[286]
Estrogen signaling	Luteolysis	Apoptosis	Progesterone	Downregulation of CD95/Fas Upregulation of BCL-2	Pro-survival	[270–273]
HIF1α	Follicular atresia	Autophagy	Hypoxic stress, FSH	Upregulation of PINK1, Parkin, and BNIP3	Pro-survival	[197–201]
	Luteolysis	Autophagy	PGF2α	Upregulation of BNIP3	Pro-autophagic	[287]
JAK/STAT	PGC depletion	Apoptosis	LIF	Upregulation of BCL-2, BCL-XL, MCL-1	Pro-survival	[74–76]
	Follicular atresia	Apoptosis	IFNγ	Upregulation of CD95/Fas	Pro-apoptotic	[125–128]
	Luteolysis	Apoptosis	PGF2α	Activation of STAT3 Upregulation of SOCS3	Not defined/pro-apoptotic	[247]
			IFNγ	Upregulation of CD95/Fas	Pro-apoptotic	[224, 232]
CHK2/p53/p63	PGC depletion	Apoptosis	Lack of growth factors, nutrient starvation, stress	Activation of p53/TAp63 Upregulation of NOXA, BBC3, and BAX	Pro-apoptotic	[35, 63–65, 84, 85]
Death receptor/FADD/caspase-8	PGC depletion	Apoptosis	TNFα	Activation of BAK, BAX, and caspase-3	Pro-apoptotic	[87]
			TRAIL	Activation of BAK, BAX, and caspase-3	Pro-apoptotic	[88]
	Follicular atresia	Apoptosis	FasL	Activation of BAK, BAX, and caspase-3	Pro-apoptotic	[117–126]
			TNFα	Activation of BAK, BAX, and caspase-3 Downregulation of BCL-2	Pro-apoptotic	[126, 131–133]
			TRAIL/DR4/5 receptors	Activation of BAK, BAX, and caspase-3	Pro-apoptotic	[88, 134–136]
	Luteolysis	Apoptosis	FasL	Activation of BAK, BAX, and caspase-3	Pro-apoptotic	[123, 125, 228, 229]
			TNFα	Activation of BAK, BAX, and caspase-3 Upregulation of CD95/Fas	Pro-apoptotic	[224, 226, 229, 231, 232]
NFκB-RelA	Follicular atresia	Autophagy	FSH	Activation of JNK Upregulation of MAP1LC3-II	Pro-autophagic, pro-survival	[193]
	Luteolysis	Apoptosis	IFNγ	Upregulation of CD95/Fas	Pro-apoptotic	[224, 232, 235, 236]
			TNFα	Upregulation of CD95/Fas	Pro-apoptotic	[224, 232, 235, 236]
RIPK1/RIPK3	Follicular atresia	Apoptosis	SIRT1	Activation of caspase-3	Pro-apoptotic	[210]
		Necroptosis	AChE-R-derived peptide	Activation of MLKL	Pro-necroptotic	[207–209]
	Luteolysis	Apoptosis	PGF2α	Activation of RIPK3 and caspase-8	Pro-apoptotic	[292]
		Necroptosis	AChE-R-derived peptide	Activation of MLKL	Pro-necroptotic	[207]
			Ceramide	Activation of MLKL	Pro-necroptotic	[289]
Iron turnover	PGC depletion	Ferroptosis	Transferrin, PCBP2	SLC7A11	Not defined	[110, 111]
NF2/YAP	Follicular atresia	Ferroptosis	BNC1 inactivation	Downregulation of GPX4 Upregulation of NOX1, COX2, TFRC and ACSL4	Pro-ferroptotic	[212]
xc− system	Follicular atresia	Ferroptosis	circRHBG-miR-515-5p	Cystine metabolism	Pro-ferroptotic	[214]
Pathways are not determined up to date	PGC depletion	Apoptosis	Starvation at birth	Upregulation of BAX	Pro-apoptotic	[103]
		Autophagy	Starvation at birth	Upregulation of MAP1LC3-II and LAMP1	Pro-autophagic, contradictory effects	[103, 105]
	Follicular atresia	Apoptosis	Oxidative stress	Upregulation of BIM and caspase-3 Activation of caspase-3	Pro-apoptotic	[195]
		Autophagy	Oxidative stress	Activation of JNK Upregulation of BECN1, ATG5, ATG7, and MAP1LC3-II	Pro-autophagic, pro-ADCD	[194, 195]
	Luteolysis	Apoptosis	PGF2α	Upregulation of FasL, CD95/Fas, BAX, IFNγ, and TNFα Activation of caspase-3	Pro-apoptotic	[221, 244, 245, 248]
			TNFα	Stimulation of PGF2α secretion	Pro-apoptotic	[246]
		Autophagy	PGF2α	Upregulation of MAP1LC3-II	Pro-autophagic, pro-survival	[248]