Organization of the Cell Flashcards
Peroxisomal Disorders
- Zellweger Syndrome (ZS)
- Neonatal adrenoleukodystrophy (NALD)
- Infatile Refsum’s disease (IRD)
- Rhizomelic chondrodysplasia punctata (RCDP)
Peroxisomes
- Diverse morphology/enzymes
- Function: Oxidation of organic substrates/Fatty Acids
RH2 + O2 –> R + H2O2
Catalase
H2O2 +RH2 --> R+ 2H2O - Fatty acids producing acetyl CoA
Kearns-Sayre Syndrome (KSS)
Defect in the mitochondria
Mitochondrial Disease (general deff)
Any disease resulting from deficiency of any mitochondrial-located protein which is involved in energy metabolism.
Most damage to cells of skeletal muscle, heart, brain, kidney, liver, endocrine and respiratory system
Fatty Acids enter mitochondria as…
Fatty acyl CoA
Increase in cytosolic Ca+2 (mitochondria)
Motochondrion has LOW-Affinity Calcium channel that allow large boluses of calcium to enter
Increase Ca+2: Induce permeability transition (PT) of the mitochondrial membrane.
PT = apoptogenic factors leak into the cytoplasm from the mitochondrial intermembrane space
Factors: Cytochome c and Apoptosis inducing factor (AIF) begin a cascade of proteolytic activity that ultimately leads to DNA fragmentation and cell death.
Mitochondrial Apoptogenic Factors
- Cytocrome c
- Apoptosis Inducing Factor (AIF)
Mitochondria to cytoplasm
Lead to DNA fragmentation and cell death
Extrinsic Caspase Activation cascade
Death Receptors (activated by ligands) or Dependency Receptors (in the absence of ligands) –> Activate DISK on CYTOPLASMIC SIDE –> (+) Caspase-8
From Caspase-8
- (+) Caspase-3, -6, and -7
- (+) BID promotes mitochondrial membrane permeabiliztion (MMP) Main link btwn extrinsic and intrinsic
Instrinsic Pathways Caspase Activation Cascade
DNA Damage –> (+) Caspase-2. or ER Stress
Both Result in (+) MMP –> (+) Cyto c and/or (+) APAF-1; ATP/dATP’ Procaspase-9
Result in Apoptosome –> Caspase-9 –> Caspase-3, -6, -7 –> Apoptosis
Mitochondrial division…
Binary fission similar to bacterial cell division. Unlike bacteria, mitochondria can also fuse with other mitochondria
Mitochondirial DNA: Location of synthesis for
- mtDNA
- Most proteins localized in the mitochondria
- All proteins encoded by mtDNA are synthesized on mitochondrial ribosomes
- Most proteins localized in the mitochondria are syntheszed on cytosolic ribosomes and imported into the organelle
ATP From fatty Acids (6 steps)
- Fatty acids (<C20) converted to fatty acyl CoA in cytosol
- Fatty acyl group covalently linked to CARNITINE on outer cytosolic membrane of mitochondria (the CoA is exchanged for carnitine) and transported to matrix
- Fatty acyl is released from the carnitine and another molecule of COA added (to the fatty acyl group)
4: The fatty acyl CoA is oxidized to acetyl CoA, FADH2, and NADH
5: Acetyl CoA is substrate for CAC producing CO2, NADH, FADH2
6: NADH, FADH2, and O2 used to establish a proton motive force that drive ATP via oxidative phosphorylation
Tay Sachs disease
Lysomal storage disorder
Mutation in the beta-hexosaminidase A (Hex A) gene that prevents the breakdown of the ganglioside GM2 in the lysosome
Results in progressive destruction of nerve cells in the brain and spinal cord
Patients with the infantile form of TS suffer from dementia and blindness by are 2, death by age 3
Pyrimethamine drug trial
Treatment of patients affected with chronic GM2 gangliosidosis (Tay-sachs or Sandhoff variants)
Lysosomes (general)
- Major digestive organelle; single membrane
- pH of lumen ~5 driven by ATP pump
- Contains large number of hydrolases
a. proteases
b. phospholipases
c. phopholipases
d. >40 other hydrolases - Optimal pH of ~5
Rough Endoplasmic Reticulum (General)
- Studded with ribosomes
- synthesis of plasma membrane proteins and membranes
- Core glycosylation
- Disulfide bond formation
- Polypeptide folding
- Protein subunit assembly
Smooth ER (general)
- Lacks ribosome; commonly tubular
- Synthesis of fatty acids/phopholipids (STEROID SYNTHESIS)
- SER enzymes detoxify hydrophobic compounds
Golgi Apparatus (General)
- Flattened sacs/spherical vesicles
- Coated ER transfer vesicles fuse with Cis Golgi; Coats = Clathrin/COPI/COPII
a. Cis region: closest to ER
b. Middle region: middle of stacks
c. Trans region: most distal from ER - Function:
a. Glycosylation of proteins and lipids
b. Glycosylation/assembly of proteoglycans
c. Tag with M6P
d. Sorting for transport
Golgi Apparatur: M6P
- Lysosomal enzymes are tagged with a carbohydrate residue, Mannose-6-phophate (M6P) in the cis-golgi
- In the trans-Golgi, these tagged enzymes bind with M6P receptors and are directed (sorted) into clathrin-coated vesicles
- The clathrin rapidly de-polymerizes and the vesicles fuse with late endosomes, which in turn transfer the lysosomal enzyme into the lysosome
I-Cell disease (inclusion) a.k.a. Mucolipidosis II
Lysosomal Storage Disorder
*Defect in targeting lysosomal enzyme M6P
Characteristics
abnormalities of face/skull
Growth delays
Mental retardation
Enzyme replacement therapy (ERT) and Haematopoietic stem cell transplantation (HSCT)
Provide effective treatment (NOT CURE) for some forms of lysosomal storage diseases
Hutchinson-Gilford Progeria Syndrome
Nucleus Disease
Mutation of lamin A in results in a destablization of anuclear structure causing blebs.
Symptoms
- Failure to grow
- Delayed dentition
- Hair Loss
- Sclerodermatous skin
Death caused by hardening of the arteries/heart attack/stroke
Parallels the aging process (progeria is greek fro premature aging)
Macrolide antibiotic rapamycin
Treatment of HFPS cells: abolished nuclear blebbin, delayed the onset of cellular senescene and enhanced the degradation of progerin in HGPS cells
Nucleolus (General)
- Site of rDNA transcription and rRNA processing
- Assembly of ribosomal subunits
- Assepbly of large ribonucleoprotein particle (ribosome precursor)
- Growing cells synthesize 10 million ribosome/generation
Alopecia, progressive Neurological defects, and Endocrineopathy (ANE Syndrome)
- Nucleus Disorder**
1. Rare autosomal-recessive phenotype
2. Loss-of-function mutation in RBM28, encoding a nucleaolar protein involved in ribosome biogenesis
3. Cerebral MRI shows normal hypothalamus but hypoplastic this anterior pituitary gland at the bottom of the sella turcica.
Woodhouse-Sakati Syndrome (WSS)
- *Nucleus disorder**
1. rare autosomal recessive disorder that encompasses hypognadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects
- Caused by Mutation of the C2orf37 gene, a nucleolar protein of unknown function
Werener Syndrome
Protein is a helicase i.e. it unwinds DNA and is involved in DNA replication and repair, transcription, and telomere maintenance
WRN protein localizes to the nucleolus
Absence of or defects in the WRN protein causes accelerated aging in human cells
People with WRN syndrome suffer cataracts, osteoporosis, diabetes and cancer at an early age
