Lysosomes in Atherosclerosis

Comprehensive vocabulary flashcards covering lysosomal biology, mTORC1 nutrient sensing, macrophage metabolic polarization, foam cell formation, and therapeutic interventions in atherosclerosis.

mTORC1

Mechanistic target of rapamycin complex 1; a major metabolic checkpoint located on lysosomal membranes that promotes cell growth, protein synthesis, and anabolism while suppressing autophagy when nutrients are abundant.

what does mTORC1 have to do to prevent lysosome biogenesis

mTORC1 inhibits:

1. ULK1 (phosphorylates) - preventing autophagosome (self eating cells when under stress)

2. PhosphorylatesTFEB

Lysosome-mTORC1 Axis

An integrated signaling platform on the lysosome that coordinates cellular responses to amino acids, cholesterol, and growth factors (via the PI3K-AKT pathway) to regulate cell fate, immune function, and metabolism.

Lysosomal Nutrient Sensing Pathway

The signaling system that integrates amino acid detection (via sensors such as SESN2, CASTOR1, SAMTOR, LARS1, and TARS1) and growth factor signals through Rag GTPases and Rheb to activate mTORC1, thereby phosphorylating TFEB, ULK1, S6K, and 4EBP1.

PI3K / AKT / TSC Upstream Signaling - Growth Factor Pathway

GFR —> P13K —> AKT —> Inhibit TSC1/TSC2 complex, promoting mTORC1 activation and influencing cellular growth and metabolism.

M1 Macrophage Phenotype

A pro-inflammatory macrophage state characterized by glycolytic metabolism, fragmented mitochondria,

• decreased …

  • LIPA activity

  • free fatty acids

• 
  

• increased…

  • elevated triglycerides

  • more lipids accumulated (given the decrease in LIPA)

M2 Macrophage Phenotype

An anti-inflammatory and pro-resolving macrophage state characterized by oxidative phosphorylation (OXPHOS), fused mitochondria,

• increased …

  • LIPA activity

  • free fatty acids

• deccreased…

  • elevated triglycerides

Macrophage Metabolic Polarization

The plastic reprogramming of macrophage functional states between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, orchestrated by lysosomal signaling, mitochondrial dynamics, and lipid metabolism.

LIPA (Lysosomal Acid Lipase) - lipid gatekeeper

The lipid gatekeeper enzyme in lysosomes

hydrolyzes:

• cholesteryl esters

• triglycerides

  • into free cholesterol and free fatty acids, providing fuel for mitochondrial oxidation and determining whether macrophages store lipids or use them efficiently.

Christian de Duve (1974)

The scientist who identified a fundamental pathological connection between atherosclerosis and lysosomal storage disease in 1974.

Foam Cells

Atherosclerotic macrophages with defective lysosomal degradative function

• decreased LIPA activity that internalize excess oxidized low-density lipoprotein (oxLDL) via scavenger receptors, driving intracellular lipid and cholesterol crystal accumulation.

Whats happpens when there’s impaired LDL (bad cholesterol) degradation

1. LDL uptake : becomes elevated, leading to increased deposition of cholesterol in arterial walls, which contributes to plaque formation and progression of atherosclerosis.

2. Lysosomal Dysfunction: reduced lysosomal deposition = impaired lipid processing

3. Foam cell formation : cholesterol accumulation = foam cell formation

Cholesterol Crystals

Insoluble crystalline deposits of excess cholesterol that form inside lysosomes

crystals cause:

• lysosomal membrane permeabilization (LMP)

• leaking cathepsins into the cytosol ( proteins that degrade other proteins) and triggering inflammatory responses, contributing to atherosclerosis progression.

NLRP3 Inflammasome - triggered by crystal formation

A cytosolic multiprotein complex activated following lysosomal membrane rupture and cathepsin leakage

• triggers the secretion of pro-inflammatory cytokines ($\text{IL-1}\beta$, $\text{IL-6}$, and $\text{IL-18}$) that drive vascular inflammation.

2 things macrophage can become: promote or resolve inflammation

1. pro - inflammation: Foam cells (decreased LIPA )

2. anti - inflammatory: efferocytosis ( removal of cells)

Efferocytosis

The clearance of apoptotic (dying) cells by specialized phagocytes;

• efficient in early atherosclerotic lesions to promote resolution

  • helps produce anti-inflammatory cytokines

• but impaired in advanced lesions due to elevated lysosomal pH and defective degradative enzymes.

LAP (LC3-Associated Phagocytosis) - alternative clearance

A non-canonical autophagic pathway where LC3 is recruited directly to the single-membrane phagosome

• Alternative pathways for clearing apoptotic cells

• requires NOX2-dependent reactive oxygen species (ROS) production to mediate the clearance of apoptotic cells

• suppress inflammation

Canonical Autophagy

The classical degradation pathway characterized by:

• formation of a double-membrane autophagosome that fuses with a lysosome to degrade sequestered cytoplasmic constituents.

Lysosomal Fusion-Fission Cycle

The continuous dynamic remodeling process in which lysosomes fuse with other vesicles and divide into smaller organelles, maturing into fully functional acidic digestive units

Lysophagy

The selective autophagic degradation and removal of severely damaged lysosomes that cannot be rescued by endogenous membrane repair machinery.

Lysosome Life Cycle and Damage Repair

The coordinated maintenance pathway comprising V-ATPase-mediated acidification ($\text{pH } 4.5\text{--}5.5$), microtubule translocation, membrane repair via HSP70 and ESCRT complexes, and clearance of irreparable lysosomes by lysophagy.

Senescent Macrophages - “Exhausted Lysosomes”

Chronologically aged (senescent) macrophages develop:

• increased organelle volume

• larger lysosomes & less efficient

• reduced degradative efficiency

• enhanced inflammatory signaling, and sustained mTORC1 activation.

TFEB (Transcription Factor EB)

A master transcriptional regulator of lysosomal biogenesis and autophagy that translocates into the nucleus upon dephosphorylation to activate gene programs that rescue lipid-induced lysosomal dysfunction.

Trehalose Therapy

A therapeutic approach using a naturally occurring disaccharide to activate TFEB and stimulate lysosomal biogenesis, limited by potential pro-oncogenic risks and requirement of intraperitoneal delivery.

Acidic Nanoparticles

Engineered particles taken up via phagocytosis by atherosclerotic macrophages to release acid, rescue acidic lysosomal pH, restore enzyme degradative capacity, and limit plaque development.

LIPA Supplementation

A therapeutic strategy employing recombinant LIPA engineered with $\alpha$-mannosyl-terminal motifs to facilitate targeting to lysosomes and enhance cholesteryl ester and triglyceride breakdown.

Galectin-3 (we love)

A component of the lysosomal repair system that detects membrane damage and recruits ESCRT complexes to repair ruptured lysosomal membranes.

Galectin-8

Promotes autophagy to remove defective organelles.

Galectin-9

Promotes lysosome biogenesis to replace damaged organelles.

TRPML1

A lysosomal calcium channel essential for regulating digestive function, membrane dynamics, and intracellular trafficking.

Cell-Specific mTORC1 Targeting

A selective pharmacological strategy aimed at inhibiting pro-atherogenic macrophage mTORC1 and enhancing T cell Treg differentiation and memory formation, while navigating complex dual effects in B lymphocytes.

LAM Transitions

Lipid-associated macrophage phenotype transitions; a research frontier examining the mechanisms that govern phenotypic switching in specialized lipid-laden macrophages during atherosclerosis.

mTORC1 promotes what and mTORC2 promotes what???

mTORC1 activity - inflammation!

mTORC2 activity - cell survival and metabolism.