Table 1.
NAD+ and the mitophagy machinery.
| Protein | Function in mitophagy | Relation to NAD + | Refs |
|---|---|---|---|
| PINK1 | Ser/Thr kinase; initiates mitophagy by phosphorylating components of mitophagy machinery including Ubiquitin and Parkin among others. | NAD+ → ↑PINK1-SARM1-TRAF1 complex→ ↑mitophagy NAD+↑ → ↑SIRT1/SIRT3→ PINK1/PARKIN |
(Das et al., 2014; Lazarou et al., 2015; Murata et al., 2013) |
| PARKIN | E3 ubiquitin ligase: initiates mitophagy by ubiquitinating proteins on the OMM. PTEN-L inhibits PINKl/Parkin dependent mitophagy via dephosphorylation of PINK1- mediated pSer65Ub. | NAD+ → ↑PINK1-SARM1-TRAF1 complex→ ↑ mitophagy | (Murata et al., 2013; Wang et al., 2018) |
| FISI | Protein of the OMM and component of the mitochondrial fission machinery at the mitochondrial surface. Mitochondrial fission and fusion cycles enable a cell to segregate damaged mitochondria from its network. | ↑NAD+→ ↑SIRT1/PGC-1a —FIS1↑ → ↑mitochondrial function and mitochondrial size↓ | (Kang and Hwang, 2009; Stojanovski et al., 2004) |
| OPA1 | Dynamin-related GTPase involved in promoting mitochondrial fusion, interacts with the IMM, structures the cristae & cristae junctions, and contributes to network fusion & mitochondrial respiration. Mitochondrial fission and fusion cycles enable a cell to segregate damaged mitochondria from its network. | ↑NAD+→ ↑SIRT3 ÔPA1 activation | (Lenaers et al., 2009; Samant et al., 2014) |
| DRP1 | DRP1 is located on the OMM and controls distribution and fission of mitochondria. Mitochondrial fission and fusion cycles enable a cell to segregate damaged mitochondria from its network. | NMN→ ↓DRP1→ ↓Fission in AD mice | (Labrousse et al., 1999; Long et al., 2015; Smirnova et al., 1998) |
| MFN1/2 | Mitofusin 1/2 are essential for mitochondrial fusion by tethering mitochondrial membranes. Mitochondrial fission and fusion cycles enable a cell to segregate damaged mitochondria from its network. | NR→ ↑NAD + → ↑SIRT activity → ↑MFN2 | (Canto et al., 2012; Ishihara et al., 2004) |
| LC3 | Essential for autophagosome biogenesis/maturation, mediates the fusion with lysosomes and in addition functions as an adaptor protein for selective autophagy | NAD+ ↑SIRT1 deacetylation of LC3 & ↑expression of LC3 deacetylation and acetylation of FOXO1 and FOXO3 | (Hariharan et al., 2010; Huang et al., 2015; Kume et al., 2010; Lee et al., 2008; Lee and Lee, 2016; Sengupta et al., 2009) |
| ATG5, ATG12 | Essential for autophagosome formation; ATG5 mediates membrane binding whereas ATG12 inhibits binding | NAD + → ↑SIRT1 deacetylation of ATG5 & ↑ expression of ATG12 | (Lee et al., 2008; Romanov et al., 2012; Sengupta et al., 2009) |
| LRPPRC | LRPPRC suppress Parkin mediated mitophagy and acts as a checkpoint protein that prevents mitochondria from autophagy degradation | NAD + → ↑SIRT3 → deacetylation of LRPPRC -→LRPPRC-POLMAT interactions with mtDNA | (Cui et al., 2019; Zou et al., 2014) |
| BNIP3 | Involved in hypoxia-induced mitophagy; regulates OPA1 disassembling, DRP1-mediated fission and recruitment of parkin to mitochondria to facilitate mitophagy; stabilizes PINK1. | NAD+ →↑SIRT1 → deacetylation FOXO3 → ↑BNIP3 | (Hariharan et al., 2010; Landes et al., 2010; Lee et al., 2011; Zhang et al., 2016c) |
| FUNDC1 | OMM protein: initiates hypoxia-induced mitophagy, where phosphorylation of FUNDC1 by CK2 and Src is inhibited and dephosphorylation by PAGM5 is stimulated, hereby allowing FUNDC1 to bind to LC3 and recruit DRP1/DNM1L. | ↑NAD+→ ↑SIRT3-PGAM5-FUNDC1→ ↑FUNDC1- dependent mitophagy | (Cheng et al., 2014; Liu et al., 2012; Yoshino et al., 2018) |
| Cardiolipin | IMM phospholipid: involved in cargo labelling, via interaction with LC3 following mitochondrial membrane rupture. | NAD + → CL binds SIRT5 ↑respiratory chain function | (Chu et al., 2013; Zhang et al., 2017) |
| AMPK | Integrator of mitochondrial homeostasis by controlling mitochondrial life cycle, biogenesis & mitophagy | AMPK→ ↑NAD + → ↑SIRT1 → ↑mitophagy | (Canto et al., 2009; Herzig and Shaw, 2018) |
| ULK1 | Ser/Thr kinase: Activation of AMPK or inhibition of mTOR induces composition of ULK1 initiation complex. | NAD+ →SIRT1 →↓mTOR →↑ULK1 → ↑mitophagy | (Dunlop and Tee, 2014; Egan et al., 2011; Lee et al., 2008) |
| p62 (SQSTM1) | Autophagy/mitophagy receptor: involved in cargo sequestration; degrades sperm-derived mitochondria in fruit flies and mammals. | NAD+ ↑SIRT1 ↑p62- transcription | (Cetrullo et al., 2016; Pankiv et al., 2007; Politi et al., 2014; Song et al., 2016) |
| Beclin 1 | Promotes formation of PI3KC3-C1 and regulates the lipid kinase. | NAD+ → ↑SIRT1 → ↑Beclin1 | (Ou et al., 2014; Wang et al., 2015) |
Abbreviations: PINK1PTEN induced kinase 1; FIS1fission, mitochondrial 1; OPA1OPA1 mitochondrial dynamin like GTPase; DRP1, dynamin-related protein; MFNmitofusin; LC3microtubule-associated protein 1 light chain 3; ATGautophagy-related; LRPPRCleucine rich pentatricopeptide repeat containing; BNIP3BCL2 interacting protein 3; FUNDC1FUN14 domain containing 1; AMPKAMP-activated protein kinase: OMM: outer mitochondrial membrane.