Table 1 Mitophagic failure molecular signatures in AD patient brains, fluids and cells.

From: Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches

	Experimental approaches/methods	Molecular modifications	Expected phenotypic manifestations	Refs.
Hippocampus Braak stage II-III	WB & RT-qPCR	↑ TOMM20 protein ↑ Mitochondrial mRNA 16S/MT-NRN2	↑ Mitochondrial mass	[12]
Hippocampus Braak stage II-III	WB & RT-qPCR	↑ PINK1 and PINK1₅₂ proteins ↔ Parkin protein	↓ PINK1/Parkin activation
Hippocampus & frontal cortex Braak stage V-VI	WB & RT-qPCR	↑ TOMM20 protein ↑ Mitochondrial mRNA 16S/MT-NRN2	↑ Mitochondrial mass
Hippocampus & frontal cortex Braak stage V-VI	WB & RT-qPCR	↔ PINK1 and PINK1₅₂ proteins ↑ Parkin protein	↓ PINK1/Parkin activation
ND	RT-qPCR	↓ PINK1 and Parkin mRNA	↓ PINK1/Parkin activation
Hippocampus & frontal cortex Braak stage II-III & V-VI	WB	↓ Cytosolic Parkin protein	↓ PINK1/Parkin activation	[17]
ND	TEM	↑ Number of damaged mitochondria
	WB	↑ Parkin protein	Parkin activation
	WB	↔ p62, TOMM20 and HSP60 proteins	↓ lysosomal degradation
	TEM	↑ Number of mitochondria in autophagic vesicles	↓ lysosomal degradation
	WB	↑ LC3-II/I protein ratio	↑ Phagophore recruitment
Hippocampus & frontal cortex Braak stage V-VI	RT-qPCR	↓ PINK1 mRNA and protein	↓ PINK1/Parkin activation	[13]
Hippocampus & frontal cortex Braak stage V-VI	ELISA	↑ p-S65-Ub protein	↑ Mitochondria tagged for degradation	[28]
ND	TEM	↑ Number of damaged mitochondria		[16]
	WB	↑ pT172 AMPK protein ↓ pS555 ULK1 and pS172 TBK1 proteins	↓ Mitophagy initiation
	WB	↓ LC3-II protein	↓ Phagophores number
	IHC	↓ TOMM20 – LAMP2 colocalization	↓ Mitolysosomes formation
	WB	↓ DISC1 protein	↓ PINK1/Parkin-independent mitophagy	[19]
	Microarray analysis	↓ NIX, BNIP3 and FUNDC1 mRNA	↓ PINK1/Parkin-dependent mitophagy	[14]
	Microarray analysis	↓ OPTN, VDAC1 and VCP/p97 mRNA	↓ PINK1/Parkin-independent mitophagy	[14]
	WB of Mit fraction	↓ PINK1 and Parkin protein	↓ PINK1/Parkin activation	[18]
		↑ p62 protein	↓ Lysosomal degradation
		↑ LC3-II/I protein ratio	↑ Phagophore recruitment
Bearers of APOEε4 allele	WB	↓ FOXO3a protein ↑ pS253 / tot FOXO3a ratio	↓ FOXO3a activity	[15]
		↓ Bcl-1 and ATG12 proteins	↓ Phagosomes formation
		↓ PINK1 protein ↓ p-S65-Ub protein	↓ PINK1/Parkin activation
		↔ p62 protein	↓ Lysosomal degradation
Plasma	RT-qPCR	↑ PINK1 & LC3 mRNA ↓ Parkin mRNA	ND	[27]
Serum	ELISA	↓ Parkin & ATG5 proteins	ND	[26]
SAD fibroblasts	WB (Mit fraction ± CCCP	↑ TOMM20 protein ↓ Parkin protein	↑ Mitochondrial mass ↓ PINK1/Parkin activation	[12]
	IF ± CCCP	↓ Parkin & SCaMC-1 colocalization	↓ Parkin recruitment to mitochondria
	WB	↓ LAMP1 protein	Defective lysosomal function
	MitoTimer probe	↓ Mitochondria maturation	Accumulation of dysfunctional mitochondria	[20]
	WB	↓ PINK1 protein ↑ LC3-II/ I ratio	↓ PINK1/Parkin activation ↑ Phagophores number
	IF & MTG probe	↔ p62 protein & ↔ mitochondrial mass	↓ Degradation
PS1 (A246E) fibroblasts	IF & WB	↑ TOMM20 protein ↑ Parkin protein	↑ Mitochondrial mass ↑ PINK1/Parkin activation	[21]
	IF ± CCCP	↑ Parkin & TOMM20 colocalization	↑ Parkin recruitment to mitochondria
	IF ± CCCP	↑ LC3 & TOMM20 colocalization	↑ Phagophore recruitment
	LysoTracker probe ± CCCP & Baf	↓ Lysosomes acidification	↓ Lysosomal degradation
PS1 (A246E) iPSC-differentiated neurons	IF & WB	↑ TOMM20 protein ↑ PINK1 & Parkin proteins	↑ Mitochondrial mass ↑ PINK1/Parkin activation
	IF ± CCCP	↑ Parkin & TOMM20 colocalization	↑ Parkin recruitment to mitochondria
	WB	↓ Pro-cathepsin B activation	↓ Lysosomal degradation
APP (V717L) & APOEε4/ε4 iPSC-differentiated neurons	WB	↓ Bcl-1 protein & pS555 ULK1 and pS172 TBK1 proteins ↓ PINK1 protein ↓ AMBRA1, BCL2L13 & FUNDC1 proteins	↓ Mitophagy initiation ↓ PINK1/Parkin initiation ↓ PINK1/Parkin-independent mitophagy activation	[16]
KI PS1 (M146L) iPSC-differentiated neural stem cells	WB ± CCCP	↑ TOMM20 protein ↑ PINK1 & Parkin proteins	↑ Mitochondrial mass ↑ PINK1/Parkin activation	[24]
	IF ± CCCP	↑ PINK1 & Parkin proteins ↑ Parkin & TOMM20 colocalization	Parkin recruitment to mitochondria ↓ Phagophore recruitment
	RT-qPCR and WB	↓ LC3 & TOMM20 colocalization ↓ TFEB & LAMP1 mRNA & proteins	↓ Lysosomal degradation
Neuronal cybrids	WB	↓ PINK1 protein	↓ PINK1/Parkin activation	[25]

Phenotype modifications and/or levels of mRNA or proteins are depicted as ↑ (increased), ↓ (decreased), or ↔ (unchanged) as compared to control individual (brain samples, blood, serum and cells). ND Not determined, iPSC Induced pluripotent stem cells, iNSC Induced neural stem cells, FAD Familial Alzheimer’s disease, SAD Sporadic Alzheimer’s disease, PS1/2 Presenilin 1/2, KI Knock in, WB Western blot, TEM Transmission electron microscopy, IHC Immunohistochemistry, IF Immunofluorescence, Baf Bafilomycin, CCCP Carbonyl cyanide m-chlorophenylhydrazone, Mit fraction Mitochondrial fraction, MTG Mitotracker green probe.

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Table 1 Mitophagic failure molecular signatures in AD patient brains, fluids and cells.

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