ER–Mitochondrial Calcium Routing as a GLA Amplifier Module

Scope & interpretation note
The material presented here synthesizes mechanistic research on endoplasmic reticulum (ER)–mitochondrial calcium handling and maps it into the GLA framework as a downstream amplifier of instability.

Source studies are drawn primarily from acute injury and cellular stress models and are used to inform system-level control and recovery dynamics, rather than to propose direct causality, diagnosis, or treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Within the GLA framework, ER–mitochondrial calcium routing is interpreted as a mechanism that modulates recovery bandwidth and delayed vulnerability following stress exposure, rather than as a disease-initiating lesion.

Conceptual framing — ER–mitochondrial calcium routing as a downstream amplifier

Shear stress does not directly damage mitochondria. Instead, it exposes a pre-existing control fragility at the endothelial and membrane level. When endothelial shear sensing and nitric-oxide timing fail, downstream tissues experience heterogeneous perfusion, oxidative signaling, and intracellular stress.

Under these conditions, ER–mitochondrial calcium routing functions as a secondary amplifier, not a trigger. Persistent stress signaling and impaired termination increase cytosolic Ca²⁺ load, which—via mitochondria-associated membranes (MAMs)—is transferred into mitochondria with excessive gain and duration.

This promotes mitochondrial Ca²⁺ overload, oxidative stress, and a shift toward fission-dominant dynamics, reducing recovery bandwidth.

Importantly, this module does not initiate post-exertional malaise (PEM). Instead, it explains how a shear-activated failure state is converted into delayed and prolonged post-exertional vulnerability, even after the original shear exposure has ended.

Shear stress exposure
        ↓
Endothelial sensing failure / NO mistiming
        ↓
Heterogeneous perfusion & cellular stress
        ↓
ER–MAM Ca²⁺ routing amplification
        ↓
Mitochondrial fragmentation → delayed PEM
  

1) Snapshot

1.1 What the source literature shows

• Persistent endoplasmic reticulum (ER) stress and Ca²⁺ dysregulation are tightly coupled through mitochondria-associated membranes (MAMs), enabling abnormal ER→mitochondrial Ca²⁺ transfer under sustained stress conditions (Baral et al., 2025).
• Excess mitochondrial Ca²⁺ promotes oxidative stress, impaired respiration, and a shift toward fission-dominant mitochondrial dynamics, reducing functional resilience and recovery capacity (Baral et al., 2025).
• This coupling forms a self-reinforcing loop in which ER stress and mitochondrial dysfunction prolong each other, leading to cellular damage and impaired recovery rather than isolated energetic failure (Baral et al., 2025).
• Human ME/CFS studies report evidence of chronic ER stress and altered unfolded protein response signaling, establishing ER stress as a baseline feature of the illness, even though calcium routing and MAM integrity are not directly assessed (Glass et al., 2025).
• Independent ischemia–reperfusion cell studies show that pharmacological activation of SERCA restores ER Ca²⁺ reuptake, reduces intracellular Ca²⁺ overload, and suppresses ER stress–linked injury (Rahi & Kaundal, 2025).

1.2 GLA placement

Within the GLA framework, ER–mitochondrial calcium routing is best understood as a downstream amplifier module, not a disease-initiating mechanism. Instability arising upstream—whether immune, metabolic, autonomic, or membrane-level—can be converted at the ER–MAM interface into prolonged ER stress and mitochondrial execution failure, ultimately shrinking recovery bandwidth. The primary pathological effect is not reduced baseline energy production, but loss of recovery reliability following stress (Baral et al., 2025).

1.3 Non-overreach guardrails

• This module does not represent a root cause of ME/CFS or related post-infectious illness.
• The cited literature does not directly test post-exertional malaise (PEM), shear-activated failure states, or MAM dysfunction in ME/CFS.
• Experimental interventions discussed here are mechanistic demonstrations, not treatment recommendations.

2) Detailed GLA interpretation

2.1 Conceptual placement in the GLA stack

Within the GLA framework, ER–mitochondrial calcium routing is positioned as a control–execution interface, not an initiating lesion.

Primary placement — Layer 2 (execution surfaces / membrane interfaces):
Mitochondria-associated membranes (MAMs) are specialized membrane contact sites that regulate ER–mitochondrial communication. Their integrity and regulation directly determine execution-surface stability, signal containment, and stress tolerance (Baral et al., 2025).

Secondary placement — Layer 3 (routing / throughput):
Calcium transfer from ER to mitochondria represents a high-impact routing decision. When gain, timing, or termination precision is impaired, stress signals are routed downstream with excessive intensity and duration (Baral et al., 2025).

Downstream expression — Layer 5 (recovery bandwidth):
Persistent ER stress, combined with mitochondrial fragmentation, reduces recovery depth and durability, increasing delayed vulnerability following stress exposure rather than uniformly altering baseline function (Baral et al., 2025).

2.2 Mechanistic chain

The literature supports the following convergent chain, abstracted for GLA interpretation:

• Stress or injury produces an initial rise in cytosolic Ca²⁺ (Baral et al., 2025).
• ER stress and unfolded protein response (UPR) activation impair timely signal resolution and recovery (Baral et al., 2025).
• MAM coupling enables abnormal ER→mitochondrial Ca²⁺ transfer under sustained or poorly terminated stress (Baral et al., 2025).
• Mitochondrial Ca²⁺ overload promotes oxidative stress, respiratory impairment, and energetic instability (Baral et al., 2025).
• Mitochondrial dynamics shift via Ca²⁺-sensitive pathways (DRP1 activation, calpain-mediated OPA1 cleavage, calcineurin signaling), biasing the network toward fission and fragmentation (Baral et al., 2025).
• Outcome: fragmented mitochondrial networks and prolonged ER stress collapse recovery bandwidth, producing delayed and amplified vulnerability to subsequent stressors (Baral et al., 2025).

2.3 The “control vs capacity” interpretation

This module highlights a core distinction within the GLA framework:

Control framing:
SERCA activity, MAM integrity, and calcium routing govern signal noise, gain, timing, and termination precision. Proper function limits downstream stress propagation and preserves recovery reliability (Baral et al., 2025; Rahi & Kaundal, 2025).

Capacity framing (explicitly rejected):
Simply increasing mitochondrial output or “boosting energy” does not address upstream routing and control failure and may exacerbate instability when stress signals remain poorly regulated.

GLA rule:
Precision and stability must be restored before any increase in throughput or drive. Control-layer correction precedes capacity-layer intervention.

2.4 Node map (functional “hardware list”)

Key components of the ER–MAM–mitochondrial calcium control module include:

• ER Ca²⁺ handling: SERCA (SERCA2b, SERCA1a), IP3R
• MAM tethering and bridging: MFN2, GRP75, PACS-2, Sigma-1 receptor (Sig-1R)
• Mitochondrial entry and gating: VDAC, mitochondrial calcium uniporter complex (MCU/MICU)
• Mitochondrial dynamics switch: DRP1 (fission), OPA1 (fusion)
• Ca²⁺-responsive effectors: Calpain-2, calcineurin

Together, these nodes determine whether calcium signaling remains adaptive and contained or becomes amplifying and recovery-limiting under sustained stress (Baral et al., 2025).

2.5 “Damage reduction lever” — SERCA evidence box

Model: Oxygen–glucose deprivation / reperfusion (OGD/R) in mouse neuroblastoma (N2a) cells

Observed signal:

• Reduced SERCA expression (SERCA1a and SERCA2b)
• Intracellular Ca²⁺ overload
• Elevated ER stress and apoptotic signaling

Intervention: CDN1163, a small-molecule SERCA activator

Observed effect:

• Restoration of SERCA expression
• Reduction of intracellular Ca²⁺ overload
• Suppression of ER stress–associated injury

GLA interpretation:
SERCA activation functions as a control-layer stabilizer, restoring calcium reuptake capacity and reducing ER stress load without increasing metabolic drive. This supports calcium handling as a modifiable amplifier, not a fixed or initiating failure (Rahi & Kaundal, 2025).