Organization of the Cell

Question 1

Peroxisomal Disorders

Answer 1

1. Zellweger Syndrome (ZS)
2. Neonatal adrenoleukodystrophy (NALD)
3. Infatile Refsum’s disease (IRD)
4. Rhizomelic chondrodysplasia punctata (RCDP)

Question 2

Peroxisomes

Answer 2

1. Diverse morphology/enzymes
2. Function: Oxidation of organic substrates/Fatty Acids
   RH2 + O2 –> R + H2O2
   Catalase
   H2O2 +RH2 --> R + 2H2O
3. Fatty acids producing acetyl CoA

Question 3

Kearns-Sayre Syndrome (KSS)

Answer 3

Defect in the mitochondria

Question 4

Mitochondrial Disease (general deff)

Answer 4

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

Question 5

Fatty Acids enter mitochondria as…

Answer 5

Fatty acyl CoA

Question 6

Increase in cytosolic Ca+2 (mitochondria)

Answer 6

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.

Question 7

Mitochondrial Apoptogenic Factors

Answer 7

1. Cytocrome c
2. Apoptosis Inducing Factor (AIF)

Mitochondria to cytoplasm
Lead to DNA fragmentation and cell death

Question 8

Extrinsic Caspase Activation cascade

Answer 8

Death Receptors (activated by ligands) or Dependency Receptors (in the absence of ligands) –> Activate DISK on CYTOPLASMIC SIDE –> (+) Caspase-8

From Caspase-8

1. (+) Caspase-3, -6, and -7
2. (+) BID promotes mitochondrial membrane permeabiliztion (MMP) Main link btwn extrinsic and intrinsic

Question 9

Instrinsic Pathways Caspase Activation Cascade

Answer 9

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

Question 10

Mitochondrial division…

Answer 10

Binary fission similar to bacterial cell division. Unlike bacteria, mitochondria can also fuse with other mitochondria

Question 11

Mitochondirial DNA: Location of synthesis for

1. mtDNA
2. Most proteins localized in the mitochondria

Answer 11

1. All proteins encoded by mtDNA are synthesized on mitochondrial ribosomes
2. Most proteins localized in the mitochondria are syntheszed on cytosolic ribosomes and imported into the organelle

Question 12

ATP From fatty Acids (6 steps)

Answer 12

1. Fatty acids (<C20) converted to fatty acyl CoA in cytosol
2. Fatty acyl group covalently linked to CARNITINE on outer cytosolic membrane of mitochondria (the CoA is exchanged for carnitine) and transported to matrix
3. 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

Question 13

Tay Sachs disease

Answer 13

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

Question 14

Pyrimethamine drug trial

Answer 14

Treatment of patients affected with chronic GM2 gangliosidosis (Tay-sachs or Sandhoff variants)

Question 15

Lysosomes (general)

Answer 15

1. Major digestive organelle; single membrane
2. pH of lumen ~5 driven by ATP pump
3. Contains large number of hydrolases
   a. proteases
   b. phospholipases
   c. phopholipases
   d. >40 other hydrolases
4. Optimal pH of ~5

Question 16

Rough Endoplasmic Reticulum (General)

Answer 16

1. Studded with ribosomes
2. synthesis of plasma membrane proteins and membranes
3. Core glycosylation
4. Disulfide bond formation
5. Polypeptide folding
6. Protein subunit assembly

Question 17

Smooth ER (general)

Answer 17

1. Lacks ribosome; commonly tubular
2. Synthesis of fatty acids/phopholipids (STEROID SYNTHESIS)
3. SER enzymes detoxify hydrophobic compounds

Question 18

Golgi Apparatus (General)

Answer 18

1. Flattened sacs/spherical vesicles
2. 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
3. Function:
   a. Glycosylation of proteins and lipids
   b. Glycosylation/assembly of proteoglycans
   c. Tag with M6P
   d. Sorting for transport

Question 19

Golgi Apparatur: M6P

Answer 19

1. Lysosomal enzymes are tagged with a carbohydrate residue, Mannose-6-phophate (M6P) in the cis-golgi
2. In the trans-Golgi, these tagged enzymes bind with M6P receptors and are directed (sorted) into clathrin-coated vesicles
3. The clathrin rapidly de-polymerizes and the vesicles fuse with late endosomes, which in turn transfer the lysosomal enzyme into the lysosome

Question 20

I-Cell disease (inclusion) a.k.a. Mucolipidosis II

Answer 20

Lysosomal Storage Disorder

*Defect in targeting lysosomal enzyme M6P

Characteristics
abnormalities of face/skull
Growth delays
Mental retardation

Question 21

Enzyme replacement therapy (ERT) and Haematopoietic stem cell transplantation (HSCT)

Answer 21

Provide effective treatment (NOT CURE) for some forms of lysosomal storage diseases

Question 22

Hutchinson-Gilford Progeria Syndrome

Answer 22

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)

Question 23

Macrolide antibiotic rapamycin

Answer 23

Treatment of HFPS cells: abolished nuclear blebbin, delayed the onset of cellular senescene and enhanced the degradation of progerin in HGPS cells

Question 24

Nucleolus (General)

Answer 24

1. Site of rDNA transcription and rRNA processing
2. Assembly of ribosomal subunits
3. Assepbly of large ribonucleoprotein particle (ribosome precursor)
4. Growing cells synthesize 10 million ribosome/generation

Question 25

Alopecia, progressive Neurological defects, and Endocrineopathy (ANE Syndrome)

Answer 25

• 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.

Question 26

Woodhouse-Sakati Syndrome (WSS)

Answer 26

• *Nucleus disorder**
  1. rare autosomal recessive disorder that encompasses hypognadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects

2. Caused by Mutation of the C2orf37 gene, a nucleolar protein of unknown function

Question 27

Werener Syndrome

Answer 27

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