Table 1.
Key mitophagy regulators
| Gene | Protein | Molecular Function | Physiological Functions and Disease Links | Reference Nos. |
|---|---|---|---|---|
| Park6 | PINK1 | Mitochondrial serine/threonine protein kinase. Phosphorylates ubiquitin, Mfn2, and Parkin to initiate mitophagy. | Recruits Parkin to mitochondria. Loss-of-function mutations contribute to familial Parkinson's disease. | 33, 42, 118, 122, 143, 155, 181, 187, 203, 215, 223, 300, 306 |
| Park2 | Parkin | Cytosolic E3 ubiquitin ligase. Ubiquitinates proteins to label them for proteasomal or autophagic degradation. | Labels mitochondria for mitophagic degradation. Induces mitophagy during metabolic remodeling and in response to stress in myocardium. Involved in mitophagy of paternal mitochondria in mouse embryos. Loss-of-function mutations contribute to familial Parkinson's disease. | 33, 84, 90, 92, 134, 147, 181, 202, 240, 261, 276 |
| Mul1 | Mul1 (Mulan, Mapl) | Mitochondrial E3 ubiquitin ligase. | Participates in the elimination of paternal mitochondria in mouse embryos. | 240 |
| Atg32 | Atg32 | Mitophagy receptor in yeast. Interacts with Atg8 and Atg11. | Involved in selective removal of mitochondria in yeast. | 5, 123, 140, 213 |
| Bnip3 | BNIP3 | Mitophagy receptor in the OMM that interacts directly with LC3B. | Activates mitophagy during hypoxia or increased oxidative stress. Regulates mitochondrial content in tissues. Loss of Bnip3 can promote tumor metastasis. | 9, 39, 60, 87, 99, 235, 237 |
| Bnip3L | BNIP3L/Nix | Bnip3 homologue and mitophagy receptor. Interacts preferentially with GABARAP. | Programmed mitophagy and regulation of mitochondrial mass in tissues. Involved in clearance of mitochondria in erythrocyte differentiation and in reprogramming of somatic cells. Can compensate for Parkin deficiency. | 55, 60, 69, 139, 211, 244, 257 |
| Fundc1 | FUNDC1 | Mitophagy receptor that interacts with LC3. Regulated by MARCH5, PGAM5, and Ulk1. | Involved in hypoxia-mediated mitophagy. | 31, 37, 145, 169, 323 |
| Phb2 | Prohibitin2 | Mitophagy receptor in the inner mitochondrial membrane. | Involved in removal of paternal mitochondria. | 314 |
| Becn1 | Beclin1 | Scaffolding protein involved in regulating autophagy and mitophagy. | Facilitates translocation of Parkin from cytosol to mitochondria and ensures formation of autophagosomes at MAMs via its interaction with PINK1. | 38, 86 |
| Gapdh | GAPDH | Regulates microautophagy of mitochondria. Catalytically inactive GAPDH associates with damaged mitochondria and promotes their engulfment directly into lysosomes for degradation. | Involved in eliminating damaged mitochondria after exposure to I/R. Impaired GAPDH-induced micromitophagy contributes to the pathology of Huntington disease. | 111, 335 |
| Ambra1 | Ambra1 | Positive regulator of autophagy. Can function as a mitophagy inducer at the mitochondria. Localizes to mitochondria by interacting with Bcl-2. Contains a LIR and interacts with LC3. | Promote Parkin independent mitophagy but can also augment Parkin-mediated mitophagy. | 73, 283, 301 |
| Fkbp8 | FKBP8 | Mitophagy receptor localized to the OMM. Preferentially interacts with LC3A via its LIR motif. | Promotes mitophagy of damaged mitochondria in a Parkin-independent manner. Escapes from the mitochondria to the endoplasmic reticulum after recruitment of LC3A to avoid degradation. | 17 |
| Bcl2l13 | BCL2L13 | Mammalian homologue of Atg32. Contains a LIR and interacts with LC3. | Promotes mitophagy of damaged mitochondria in a Parkin-independent manner. | 195 |
| N/A | Cardiolipin | Lipid unique to mitochondria that is localized in the inner membrane. Interacts with LC3. | Redistributes to the outer membrane of damaged mitochondria where it interacts with LC3 to promote mitophagy. | 40 |
| Sqstm1 | p62/SQSTM1 | Autophagy adaptor. Binds polyubiquitinated proteins to facilitate their removal by autophagy. | Recruited to damaged ubiquitinated mitochondria. Promotes perinuclear aggregation of mitochondria which may allow for more efficient mitophagy. | 85, 156, 201, 214 |
| Optn | OPTN/Optineurin | Autophagy adaptor for Parkin-mediated mitophagy. Binds both ubiquitinated targets on the mitochondria via its UBD and to LC3 on the phagophore via its LIR. | Recruited to damaged ubiquitinated mitochondria. Facilitates their removal by anchoring them to the autophagosome. Mutations have been linked to ALS. | 102, 156, 179, 236, 317 |
| Calcoco2 | NDP52 (nuclear dot protein 52) | Autophagy adaptor for Parkin-mediated mitophagy. Binds both ubiquitinated targets on the mitochondria via its UBD and to LC3 on the phagophore via its LIR. | Recruited to damaged ubiquitinated mitochondria. Facilitates their removal by anchoring them to the autophagosome. | 102, 156 |
| Tax1bp1 | TAX1BP1 | Autophagy adaptor | Recruited to damaged ubiquitinated mitochondria. Facilitates their removal by anchoring them to the autophagosome. | 156 |
I/R, ischemia/reperfusion; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ALS, amyotrophic lateral sclerosis.