The Sulfur-Redox Repair Capacity Hypothesis: A Mitochondrial PRDX3-TRX2-GRX2-SRX Network for Recovery Timing Across Oxidative Load, Aging, Ferroptosis, and Disease Convergence

This manuscript presents the Sulfur-Redox Repair Capacity Hypothesis, a systems-level synthesis proposing that mitochondrial recovery from oxidative load depends on the timing and completeness of an integrated repair network centered on peroxiredoxin 3 (PRDX3).

The model integrates:

Parallel fast reduction of oxidized PRDX3 by thioredoxin 2 (TRX2) and glutaredoxin 2 (GRX2)

Slower ATP-dependent repair of hyperoxidized PRDX3-SO₂H by sulfiredoxin (SRX)

Upstream modulation by cysteine allocation, glutathione, persulfides, and reactive sulfur species (RSS) involving CARS2, SQOR, and related enzymes

It distinguishes direct biochemical evidence (e.g., PRDX3 reduction by TRX2/GRX2, SRX repair, and GSH-dependent SRX recycling) from strong systems support and explicit predictions. The framework introduces the concept of temporal oxidative debt — the cumulative cost of delayed or incomplete redox recovery — as a potential contributor to aging and disease vulnerability.

The paper includes detailed evidence matrices, model evolution tracking, a reviewer attack-and-defense appendix, conceptual kinetic equations, and a comprehensive experimental roadmap focused on PRDX3-SO₂H clearance kinetics under sulfur/RSS perturbation.

Important disclaimers: This is a hypothesis/synthesis manuscript. It does not claim that sulfur cures disease, that PRDX3 persulfidation is proven as the central mechanism, or that the model is clinically validated. All clinical interpretations are presented as future testable directions.

This work builds upon earlier frameworks including the Dynamic Instability Index and Redox Synchrony Hypothesis. Code, simulations, and related materials are available at: https://github.com/psithheory/dynamic-instability-index