The hierarchy of selective autophagy is not a fixed ranking but a dynamic outcome of receptor availability and cargo ubiquitination. During low‑dose OSKM‑induced partial reprogramming, ATG5‑dependent mitophagy removes aged mitochondria, yet excessive autophagy risks degrading identity‑maintaining proteins such as p63 and CK14. Conversely, autophagy inhibition stabilizes these markers by causing p62/NBR1 complexes to accumulate and sequester the ubiquitin ligase ITCH, which reduces ubiquitination of substrates earmarked for autophagic turnover. We hypothesize that the relative abundance of p62 and NBR1 functions as a tunable rheostat: a high NBR1:p62 ratio favors degradation of damaged organelles while sparing identity complexes, whereas a low ratio shifts cargo selection toward identity‑preserving proteins and impairs mitophagy. This shift occurs because NBR1 enhances oligomerization of p62 complexes under limiting autophagy, increasing affinity for ubiquitinated mitochondrial cargo, while excess p62 (when NBR1 is scarce) promotes ITCH sequestration, lowering global ubiquitination and thereby protecting p63/CK14 from degradation.

Mechanistic rationale: p62 and NBR1 form heterotypic oligomers that serve as scaffolds for ubiquitinated cargo. Structural studies show NBR1 contains a PB1 domain that binds p62’s PB1 with higher affinity than p62‑p62 homotypic interactions, promoting mixed oligomers that expose multiple ubiquitin‑associated (UBA) domains. When NBR1 is abundant, these mixed oligomers preferentially recruit ubiquitin chains on depolarized mitochondria (marked by PINK1/Parkin), accelerating mitophagy. When NBR1 is scarce, p62 homooligomers dominate, avidly binding ITCH through its PB1 domain and sequestering it away from cytosolic substrates. Reduced ITCH activity diminishes K48‑linked ubiquitination of p63 and CK14, making them less recognizable to the autophagy machinery and thus stabilizing them.

Testable predictions: 1) In human fibroblasts subjected to cyclic 4‑day OSKM pulses, inducible overexpression of NBR1 (with constant p62 levels) will increase mitochondrial clearance (measured by Mitotracker Red intensity and COXIV protein) without decreasing p63 or CK14 expression after three cycles. 2) Conversely, CRISPRi‑mediated knockdown of NBR1 will reduce mitophagy efficacy and lead to accumulation of damaged mitochondria, while p63/CK14 levels remain stable or increase due to ITCH sequestration. 3) Rescue experiments expressing an NBR1 mutant deficient in p62 PB1 binding will abolish the preferential mitochondrial degradation phenotype, confirming that heterotypic oligomerization is required.

Falsifiability: If altering the NBR1:p62 ratio fails to produce the predicted inverse relationship between mitochondrial load and identity‑marker levels across multiple OSKM cycles, or if ITCH sequestration does not correlate with changes in p63/CK14 ubiquitination, the hypothesis would be refuted. This approach directly links receptor stoichiometry to functional selectivity in autophagy, offering a mechanistic lever to enhance rejuvenation while preserving cell identity.