Fig. 2: Physiological mitophagy processes and alterations linked to Tau, Aβ, APP-CTFs and APOE.
From: Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches
A Following mitochondrial stress (i.e., mitochondria membrane (ΔΨmit) depolarization, or a general cellular stress (i.e. hypoxia, ischemia, starvation)), mitochondria undergo a specific degradation mechanism by mitophagy. The PINK1/Parkin-dependent mitophagy is driven by a decrease of ∆Ψmit, triggering the stabilization of PTEN-induced putative kinase 1 (PINK1) at the OMM and the recruitment of the E3 Ubiquitin ligase Parkin, generating poly-phospho-ubiquitinated chains (p-S65-Ub) on OMM proteins that act as a “eat-me” signal for damaged mitochondria. Cytosolic proteins that can act as mitophagy receptors (p62, OPTN, NDP52, NBR1, or TAX1BP1) will recognize and bind to p-S65-Ub decorated proteins and will recruit the phagosome through their interaction, via their LIR motif with LC3-II (the activated form of the microtubule-associated protein 1 A/1B light chain 3) present at the surface of the phagosome. Besides, in the PINK1/Parkin-independent mitophagy, the phagosome is recruited around mitochondria directly through LIR motif-containing OMM receptors (NIX/BNIP3L, BNIP3, FUNDC1, BCL2L13, FKBP8, DISC1, AMBRA1, or MCL-1) or through the recognition of cardiolipin (CL) exposed on the OMM. Once the phagophore is recruited, it engulfs damaged mitochondria to generate the mitophagosome. Then, lysosomes can fuse with mitophagosomes to form mitolysosomes and degrade damaged mitochondria by acidic hydrolases. B–E Mitophagic process is perturbed in AD by Tau species (B), Aβ species (C). APP-CTFs (D), and APOE4 isoform and/or high cholesterol levels (E). Proteins that are impacted in the mitophagy process are depicted in grey in (B–E) instead of being colored as in (A). Inhibitory functions are indicated by red arrows, and green arrows indicate PINK1/Parkin activation and phagophore formation or recruitment.
