Chronic metabolic stress in aging beta cells creates a siege where autophagy acts as a rationing system, selectively degrading mitochondria to sustain ATP-dependent insulin secretion while allowing IAPP aggregates and lipofuscin to accumulate. We hypothesize that this selectivity is governed by the phosphorylation state of the autophagy receptor p62/SQSTM1, which shifts its binding preference between ubiquitinated mitochondria and IAPP oligomers in response to AMPK and mTORC1 signaling. Under siege conditions, low AMPK activity and high mTORC1 signaling promote p62 phosphorylation at Ser403, reducing its affinity for IAPP-UBA interactions and favoring LC3-mediated mitochondrial engulfment. Conversely, pharmacological AMPK activation or mTORC1 inhibition should dephosphorylate p62 at Ser403, increasing its affinity for IAPP and redirecting autophagic flux toward aggregate clearance without compromising mitochondrial function.

Testable predictions:

1. In isolated human or mouse islets exposed to prolonged high glucose (25 mM) and palmitate (0.5 mM) to mimic aging‑related siege, phospho‑specific immunoblotting will show increased p62‑Ser403 phosphorylation correlating with reduced LC3‑II colocalization with IAPP aggregates and increased colocalization with mitochondrial markers (TOM20).
2. Expressing a phospho‑deficient p62 mutant (S403A) in beta cells under the same siege conditions will increase IAPP‑p62 binding (detected by proximity ligation assay), enhance autophagic delivery of IAPP to lysosomes (measured by lysosomal cathepsin activity and reduced extracellular IAPP oligomers), and decrease lipofuscin accumulation while preserving mitochondrial membrane potential (JC‑1 ratio) and glucose‑stimulated insulin secretion.
3. Conversely, expressing a phospho‑mimetic mutant (S403E) will blunt IAPP clearance, exacerbate amyloid‑induced caspase‑3 activation, and accelerate functional decline despite unchanged mitochondrial turnover.
4. Acute treatment with an AMPK activator (AICAR, 1 mM) or an mTORC1 inhibitor (rapamycin, 100 nM) in aged islets will reduce p62‑Ser403 phosphorylation, shift p62 substrate preference toward IAPP, and lower intracellular IAPP oligomer levels without causing mitochondrial loss, as assessed by MitoTracker intensity and ATP production.

Falsification would occur if manipulation of p62 phosphorylation fails to alter the ratio of IAPP versus mitochondrial autophagy flux, or if changes in p62 binding do not correlate with alterations in aggregate load, lipofuscin, or insulin secretion under siege conditions. This hypothesis extends the siege rationing model by proposing a reversible, signaling‑driven switch in selective autophagy receptor specificity, offering a mechanistic lever to uncouple survival‑focused mitochondrial clearance from pathogenic IAPP accumulation in aging beta cells.