Signal Transduction and Targeted Therapy

Table 1 An overview of PINK1-Parkin-independent mitophagy regulators and their physiological functions

From: The mitophagy pathway and its implications in human diseases

Properties	Protein or Lipid	Mitochondrial localization	Mitophagy inducers	Regulators	Autophagic interactors	Physiological Functions	References
E3 Ubiquitin Ligases	ARIH1	Cytoplasm Nuclear	CCCP	PINK1 ↑	−	Regulate mitophagy by ubiquitinating of OMM proteins in damaged mitochondria	^83,84
E3 Ubiquitin Ligases	SIAH1	Cytoplasm Nuclear	−	PINK1 ↑ Synphilin-1 ↑ Sorafenib ↓ Glucose restriction ↓	LC3	Regulate mitophagy by ubiquitinating of OMM proteins in damaged mitochondria	^85,86
E3 Ubiquitin Ligases	MUL1	OMM	Selenite	ULK1 ↑	GABARAP	Rescue the PINK1 and Parkin mutant phenotypes in dopaminergic neurons and muscle Participate in the elimination of paternal mitochondria in mouse embryos	^368,369
E3 Ubiquitin Ligases	HUWE1	Cytoplasm	−	−	−	Regulate mitophagy by ubiquitinating proteins	^92,93
E3 Ubiquitin Ligases	GP78	Endoplasmic reticulum membrane	CCCP	MGRN1 ↓	LC3	Ubiquitinate Mfn1, thereby promoting mitochondrial fission to induce mitophagy	^94,95
Autophagy Receptors	BNIP3	OMM	Hypoxia	FOXO3 ↑ HIF1A ↑ MA-5 ↑ ULK1 ↑ JNK1/2 ↑ PP1/2 A ↓	LC3B GABARAPL2	Activate mitophagy during hypoxia or increased oxidative stress	^{96,98,100,101,102}
Autophagy Receptors	NIX	OMM	Hypoxia High OXPHOS activity	HIF1A ↑	GABARAPL1 LC3A LC3B LC3-independent	Participate in retinal ganglion cell differentiation and somatic cell reprogramming to induced pluripotent stem cells Participate in generation of mature erythrocytes	^{13,106,110,111}
Autophagy Receptors	FUNDC1	OMM	Hypoxia FCCP	ULK1 ↑ SRC ↓ CK2 ↓ PGAM5 ↑ USP19 ↑ MIR137 ↓	LC3B	Involved in hypoxia-mediated mitophagy	^{14,119,120,123,125,127}
Autophagy Receptors	BCL2L13	OMM	CCCP	ULK1 ↑	LC3B LC3C GABARAP GABARAP-L	Promote mitophagy of damaged mitochondria in a Parkin-independent manner	^130,131
Autophagy Receptors	FKBP8	OMM	Starvation Iron depletion Hypoxia	RHEB↓	LC3A	Escape from the mitochondria to the endoplasmic reticulum after recruitment of LC3A to avoid degradation	^96,132,133
Autophagy Receptors	AMBRA1	OMM	FCCP Mitochondrial depolarization	IKKα kinase ↑ HUWE1 ↑ MCL1 ↓ GSK3B ↑	LC3 GABARAP	Promote Parkin-mediated mitophagy and Parkin independent mitophagy	^137,140
Autophagy Receptors	MCL-1	OMM	Oxygen-glucose deprivation FCCP Early stage of hypoxia	GSK3B ↓	LC3A	Participate in the regulation of mitophagy through various pathways Ameliorate cognitive decline and amyloid pathology in the APP/PS1 mouse model of Alzheimer’s disease	^{16,139,140,141}
Autophagy Receptors	SAMM50	OMM	Under normal circumstances	−	ATG8 protein	SAMM50-mediated piecemeal mitophagy maintain mitochondrial homeostasis Promote cell metabolism from glycolysis to OXPHOS	^142,143,144
Autophagy Receptors	FTMT	OMM	Iron loss	HIF1α ↑	LC3	Participate in iron loss-mediated mitophagy	^145,146
Autophagy Receptors	PHB2	IMM	CCCP Oligomycin Antimycin	AURKA ↑	LC3B	Involved in removal of paternal mitochondria	^15,148,149
Autophagy Receptors	Cardiolipin	OMM IMM	Rotenone CCCP	CRLS1 ↑ PLSCR3 ↑	LC3A LC3B	Redistribute to the outer membrane of damaged mitochondria where it promotes mitophagy	^151,153,155

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