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GLA × Itaconate — Diagram Series

The Itaconate Shunt within the GLA Framework — Diagram Series

Conceptual diagrams examining how immune–metabolic constraint described by the itaconate shunt may interact with system-level control and recovery processes in the GLA framework.

Figure A1 — Placement of the Itaconate Shunt within the GLA Architecture

The itaconate shunt is positioned as an immune-metabolic mechanism operating within the broader GLA control architecture, potentially amplifying energy limitation when upstream buffering and recovery systems fail to resolve post-infectious stress.

Placement of the Itaconate Shunt within the GLA Architecture Vertical layered stack: External triggers → GLA control & buffering → immune-metabolic layer (itaconate shunt) → cellular energy expression → clinical output. Downward arrows only. EXTERNAL TRIGGERS Initiating load that activates stress programs • Infection • Inflammatory stress • Repeated exertional load GLA CONTROL & BUFFERING LAYER Distributed regulation that determines safety under load • Vascular perfusion distribution • Autonomic regulation • Hepatic clearance / bile-acid signaling • Membrane regulatory stability (SMPDL3B) IMMUNE–METABOLIC LAYER Contained immune-metabolic program that can cap throughput Itaconate shunt (highlighted mechanism) IRG1 induction SDH inhibition (Complex II) TCA throughput constraint Note: shown as a boxed sub-layer to indicate containment within broader control dynamics. CELLULAR ENERGY EXPRESSION Downstream energetic consequences • ATP ceiling / limited oxidative ramp • Increased amino-acid catabolism • Ammonia / ROS accumulation CLINICAL OUTPUT PEM Brain fog Exercise intolerance
Design note: Downward arrows only to avoid implying a single causal loop; the itaconate shunt is emphasized as a contained immune-metabolic sub-layer rather than a primary system-level driver. :contentReference[oaicite:1]{index=1}
Figure A2 — Phenotype-Dependent Relevance of the Itaconate Shunt

The contribution of immune-metabolic suppression varies by GLA amplifier phenotype, aligning most strongly with metabolic-dominant (M1) presentations and acting as a secondary lock-in mechanism in vascular-dominant (M2) disease.

Phenotype-Dependent Relevance of the Itaconate Shunt Three vertical columns representing M1 metabolic, M2 vascular, and M3 autonomic amplifier phenotypes. Each column begins with the same exertional load icon, then shows a dominant failure path. The itaconate shunt node is emphasized most in M1, secondary in M2, and faint/dashed in M3. A2 — PHENOTYPE-DEPENDENT RELEVANCE Same load, different dominant failure: M1 (metabolic) vs M2 (vascular) vs M3 (autonomic) M1 — Metabolic Energy throughput limitation dominates Same exertional load DOMINANT PATH Itaconate shunt IRG1 ↑ · SDH inhibition · TCA cap Primary amplifier (metabolic ceiling) ATP ceiling / early anaerobic shift AA catabolism ↑ → ammonia/ROS PEM pattern: metabolic crash muscle burn, brain fog, delayed recovery load → ATP demand exceeds capped ramp M2 — Vascular Perfusion distribution failure dominates Same exertional load DOMINANT PATH Perfusion mismatch Regional under-delivery under load Primary amplifier (distribution instability) Intermittent ischemic metabolism ROS / Ca²⁺ stress signals Itaconate shunt (secondary) Immune-metabolic lock-in risk PEM pattern: vascular / cognitive M3 — Autonomic Low volume / HR control dominates Same exertional load DOMINANT PATH Autonomic mismatch HR/BP compensation + low volume Primary amplifier (upright intolerance) Immediate symptom escalation posture/standing sensitivity Itaconate shunt (minor) Possible downstream modifier PEM pattern: orthostatic-first Visual encoding: itaconate shunt emphasis decreases from M1 → M2 → M3 to reflect phenotype-dependent relevance.
Caption: The contribution of immune-metabolic suppression varies by GLA amplifier phenotype, aligning most strongly with metabolic-dominant (M1) presentations and acting as a secondary lock-in mechanism in vascular-dominant (M2) disease. :contentReference[oaicite:1]{index=1}
Figure A3 — Phase Dependence: When the Itaconate Shunt Matters Most

Immune-metabolic suppression may emerge as a secondary stabilizing response early in disease but becomes most impactful as a lock-in amplifier once baseline recovery capacity erodes.

Phase Dependence: When the Itaconate Shunt Matters Most Horizontal timeline from Phase 1 to Phase 4. Baseline erosion rises over time while the recovery window shrinks. Itaconate shunt relevance is shown as optional in Phase 1, conditional in Phase 2, lock-in amplifier in Phase 3, and present but non-informative in Phase 4. A3 — PHASE DEPENDENCE Baseline threshold erosion rises while recovery window shrinks; itaconate relevance changes by phase. Phase 1 Phase 2 Phase 3 Phase 4 early / oscillatory established, fragile severe control loss depolarization-locked Baseline threshold erosion (rising) Recovery window (shrinking) Itaconate shunt relevance (phase-dependent) Phase 1 Optional / dotted secondary stabilizing response Phase 2 Conditional depends on phenotype & stress load Phase 3 Lock-in amplifier prolongs PEM & delays recovery as baseline headroom erodes Phase 4 Present, but non-informative Legend Baseline threshold erosion (rising) Recovery window (shrinking) Itaconate: optional (Phase 1) Itaconate: conditional (Phase 2) Itaconate: lock-in (Phase 3)
Caption: Immune-metabolic suppression may emerge as a secondary stabilizing response early in disease but becomes most impactful as a lock-in amplifier once baseline recovery capacity erodes. :contentReference[oaicite:1]{index=1}
Figure B1 — Different Questions, Different Layers

The itaconate shunt focuses on intracellular metabolic state, whereas GLA addresses system-level regulation of load, recovery, and buffering.

Different Questions, Different Layers A split panel comparing the Itaconate Shunt Hypothesis (cell-centric metabolic state) with the GLA Framework (system-level control and buffering). Includes a central statement that these are different explanatory layers. B1 — COMPARISON Different explanatory layers, not competing claims Itaconate Shunt Hypothesis Cell-centric metabolic state constraint Cell / mitochondria TCA SDH constraint Innate immune signaling (IRG1) ATP ramp is capped throughput constraint during/after load PRIMARY EMPHASIS • intracellular throughput limitation • amino-acid reliance / delayed toxicity GLA Framework System-level control, buffering, and recovery Control under load Perfusion distribution Autonomic regulation Hepatic / BA clearance signals Membrane stability (SMPDL3B) PEM = loss of buffering phenotype- & phase-dependent collapse PRIMARY EMPHASIS • control vs capacity; buffering size • heterogeneity (phenotypes/phases) Different explanatory layers not competing claims Reading guide: the left panel models intracellular “permission” for energy throughput; the right panel models whole-system regulation of load, recovery, and buffering.
Caption: The itaconate shunt focuses on intracellular metabolic state, whereas GLA addresses system-level regulation of load, recovery, and buffering. :contentReference[oaicite:1]{index=1}
Figure B2 — Two Explanations of PEM (Side-by-Side)

Distinct mechanistic paths can converge on similar post-exertional symptom amplification.

Two Explanations of PEM (Side-by-Side) Two horizontal flowcharts. Top shows an itaconate shunt explanation from exertion to PEM via ATP demand and TCA constraint with delayed toxicity. Bottom shows a GLA explanation from exertion to PEM via buffering exceeded, perfusion mismatch, ischemia/ROS, and failed recovery. Both converge on PEM. B2 — PEM MECHANISMS Two distinct paths that converge on PEM Itaconate shunt path (metabolic constraint) PEM emerges from capped oxidative ramp and delayed metabolic toxicity Exertion energy demand ↑ ATP demand requires ramp TCA constraint SDH / Complex II limit AA catabolism ↑ nitrogen load ↑ Delayed toxicity ammonia / redox stress GLA path (control & buffering failure) PEM emerges when buffering capacity is exceeded and recovery control fails Exertion load + stress Buffering exceeded control headroom ↓ Perfusion mismatch regional under-delivery Ischemia / ROS Ca²⁺ stress signals Failed recovery baseline not restored PEM post-exertional malaise Design rule: distinct upstream chains, identical endpoint (PEM). Paths are intentionally non-overlapping to avoid model conflation. Metabolic constraint emphasis Scope cue Control & buffering emphasis
Caption: Distinct mechanistic paths can converge on similar post-exertional symptom amplification. :contentReference[oaicite:1]{index=1}
Figure B3 — Treatment Risk Visualization (Control vs Capacity)

Interventions targeting metabolic throughput may be stabilizing or destabilizing depending on underlying control state.

Treatment Risk Visualization (Control vs Capacity) Conceptual chart with system control integrity on the x-axis and treatment intensity on the y-axis. Shows two paths: an intensity-first approach (itaconate-only logic) and a control-first approach (GLA logic). B3 — TREATMENT RISK Control-first vs capacity-first sequencing Highest risk zone high intensity + low control More stable zone higher control supports intensity System control integrity low high Treatment intensity low high Itaconate-only logic increase intensity early Potential destabilization throughput ↑ while control is low GLA logic restore control → then intensity Phenotype-safe sequencing control regained before throughput ↑ start control restored then intensify Takeaway: the same “metabolic activation” can stabilize when control is high, but destabilize when control is low.
Caption: Interventions targeting metabolic throughput may be stabilizing or destabilizing depending on underlying control state. :contentReference[oaicite:1]{index=1}