SOVEREIGN · INQ·12 · M9

The Defection Decision

The cell never reads one "percentage overloaded." It integrates a vector. Matrix Ca²⁺ is both a fate input and a positional one — detaching peridroplet mitochondria from fat before overload becomes defection. Move the inputs and watch L push the cell across the landscape, including the last basin where it goes it alone.
The load vector
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A brief spike signals; a sustained plateau damages. Amplitude × duration is what counts.
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Three roles at once: (1) transcriptional branches — calcineurin → NF-κB/CREB/NFAT and PKC/JNK/MAPK; (2) mPTP arming; (3) positional — a matrix Ca²⁺ surge detaches peridroplet mitochondria from lipid droplets (crescent → round), freeing lipases; NCLX clearance re-attaches. EMBO J 2026.
0.80
Enters L with a minus sign — healthy mtDNA lowers the load. Tumour-initiating cells run low.
The cell & its history
Generic Cardiomyocyte Stem cell
Thresholds are set-points, not constants — a cardiomyocyte tolerates far less than a stem cell.
Apoptosis competent Apoptosis evaded
If the self-destruct path is disabled (e.g. p53 loss), unbearable load can no longer end the cell — so it reprograms instead.
Force OXPHOS back on (UCP2)
Reversibility check: pushing a defector back onto oxidative phosphorylation makes it poorly tumorigenic.
▸ index weights & thresholds
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L = w₁(ROS·τ) + w₂·redox + w₃·energy + w₄·Ca²⁺ − w₅·mtDNA · a modeling abstraction over what is really a vector