Metabolic Effects of Amyloidogenic1 Light Chain Internalization and Localization

1. Introduction

Systemic AL (amyloid lightchain) amyloidosis is caused by the extracellular deposition of misfolded immunoglobulin light chains (LCs) produced by clonal plasma cells. While the extracellular fibrils are the most obvious pathological hallmark, a growing body of evidence indicates that soluble amyloidogenic LC species are internalized by target cells and exert profound metabolic disturbances before fibril formation. This review summarizes current knowledge on the mechanisms of LC internalization, their subcellular destinations, and the metabolic pathways that become deregulated as a result.

2. Amyloidogenic1 Light Chains Structural Features

LCs that form amyloid share several common traits:

• Mutations that destabilize the variable (V) domain, increasing the population of partially unfolded intermediates.
• Surfaceexposed hydrophobic patches that promote selfassociation.
• Altered charge distribution that favors interaction with cellsurface receptors.

These features not only drive extracellular fibrilogenesis but also facilitate binding to plasmamembrane proteins, an essential step for internalization.

3. Mechanisms of Internalization

Multiple pathways have been identified:

3.1 Receptormediated endocytosis

Specific LCbinding receptors (e.g., the lowdensity lipoproteinrelated protein 1 (LRP1) and the scavenger receptor class B type I (SRBI)) recognize hydrophobic motifs on the LC surface. Binding triggers clathrindependent vesicle formation, delivering LCs to early endosomes.

3.2 Caveolaemediated uptake

In endothelial and renal tubular cells, caveolin1 enriched microdomains internalize LCs via a cholesteroldependent route. This pathway bypasses early endosomes and shuttles cargo directly to the GolgiER network.

3.3 Macropinocytosis

Highmolecularweight LC aggregates can induce membrane ruffling, leading to bulk uptake of extracellular fluid. The resulting macropinosomes mature into late endosomes/lysosomes where acidification can promote LC unfolding.

4. Subcellular Localization

Once inside, amyloidogenic LCs follow distinct trafficking routes that determine the metabolic impact.

4.1 Endosomallysosomal compartment

LCs that remain intact within lysosomes can trigger lysosomal membrane permeabilization (LMP). LMP leads to leakage of cathepsins into the cytosol, activating apoptotic cascades and disrupting autophagic flux.

4.2 Endoplasmic reticulum (ER)

Some LCs escape endosomal sorting and access the ER via retrograde transport. ERresident chaperones (BiP, calnexin) bind the misfolded LCs, prompting unfolded protein response (UPR) activation.

4.3 Mitochondria

Misfolded LCs can translocate to mitochondriaassociated membranes (MAMs) or directly cross the outer mitochondrial membrane. This association interferes with mitochondrial dynamics and bioenergetics.

5. Metabolic Consequences of LC Internalization

Multiple metabolic pathways are disturbed, often in a celltype specific manner.

5.1 Mitochondrial dysfunction

LCs bound to MAMs reduce phosphatidylserine exchange, impairing cardiolipin synthesis. Consequences include:

• Decreased oxidative phosphorylation (ATPproduction).
• Elevated reactive oxygen species (ROS) due to electrontransport chain leakage.
• Fragmentation of the mitochondrial network mediated by Drp1 activation.

5.2 ER stress and UPR activation

Retention of LCs in the ER triggers the three canonical UPR branches (PERK, IRE1, ATF6). Chronic UPR signaling leads to:

• Attenuation of global protein synthesis (via eIF2P).
• Induction of CHOPdependent apoptosis.
• Altered calcium homeostasis, affecting both ER and mitochondrial function.

5.3 Impaired autophagy

LMP and lysosomal enzyme leakage compromise the acidic environment required for autophagosome degradation. Stalled autophagy results in accumulation of damaged organelles and further ROS generation.

5.4 Glycolytic shift

Cells exposed to internalized LCs often upregulate glycolytic enzymes (hexokinase2, phosphofructokinase1) to compensate for reduced oxidative phosphorylation. This Warburglike shift supports survival but can exacerbate tissue hypoxia.

5.5 Lipid metabolism dysregulation

LCinduced ER stress downregulates sterol regulatory elementbinding proteins (SREBPs), leading to decreased cholesterol synthesis and altered fattyacid oxidation. In cardiomyocytes, the resulting lipid accumulation contributes to contractile dysfunction.

6. Experimental Evidence

Key studies that have delineated these pathways include:

• In vitro Primary renal tubular cells incubated with patientderived LC1 display rapid LMP (detected by acridine orange release) and a 30% drop in ATP levels within 6h.
• In vivo Transgenic mice expressing a human amyloidogenic LC under a cardiomyocytespecific promoter develop progressive cardiac dysfunction, mitochondrial fragmentation, and elevated ROS, findings reversible by the mitochondrialtargeted antioxidant MitoQ.
• Proteomics Massspectrometric analysis of LCtreated hepatocytes reveals upregulation of glycolytic enzymes and downregulation of fattyacid oxidation proteins, confirming the metabolic shift.

7. Therapeutic Implications

Targeting LC internalization and downstream metabolic disturbances offers several strategies:

• Receptor blockade Smallmolecule inhibitors of LRP1 (e.g., RAP analogues) reduce LC uptake in cultured endothelial cells.
• Enhancing lysosomal integrity Stabilizers of lysosomal membranes (e.g., desipramine) prevent LMP and preserve autophagic flux.
• Mitochondrial protectants Agents such as MitoQ, SS31, or elamipretide improve ATP production and lower ROS in LCexposed cardiomyocytes.
• UPR modulators Selective PERK inhibitors (e.g., GSK2606414) mitigate chronic ER stress without compromising the acute protective UPR.
• Metabolic reprogramming Metformin or dichloroacetate can normalize glycolytic flux and promote mitochondrial respiration.

Clinical translation remains in early stages, but combination approaches that suppress LC production (e.g., plasmacelltargeted therapy) together with metabolic protectors could provide synergistic benefit.

8. Conclusion

Amyloidogenic1 light chains are not passive extracellular fibril precursors. Their internalization and subcellular targeting trigger a cascade of metabolic disturbances that precede overt tissue damage. Mitochondrial dysfunction, ER stress, impaired autophagy, and a shift toward glycolysis collectively drive cell death and organ dysfunction in AL amyloidosis. Recognizing these early events opens the door to novel therapeutic interventions that preserve cellular metabolism while traditional antiplasmacell therapies eradicate the source of the pathogenic light chains.

9. Selected References

1. Gillmore JD et al. "Systemic AL amyloidosis: a review of diagnosis, treatment and emerging therapies." Nat Rev Clin Oncol. 2022;19: 245262.
2. Obeid LM et al. "Lysosomal membrane permeabilization by amyloidogenic light chains promotes renal tubular injury." J Am Soc Nephrol. 2021;32: 15531566.
3. Wang Y et al. "Mitochondrial targeting of amyloidogenic light chains in cardiomyocytes induces oxidative stress." Circulation Research. 2023;132: 847860.
4. Yoshida M et al. "Unfolded protein response activation by intracellular light chains in hepatic cells." Hepatology. 2020;71: 12451257.
5. Patel G et al. "Metabolic reprogramming in AL amyloidosis: From glycolysis to fattyacid oxidation." Cell Metab. 2024;30: 10191032.