Cellular Organelles

Question 1

mitochondria main points

Answer 1

• source of ATP! enzymes required for ATP production are found in mitochondrial membranes and matrix
• the process of storing energy from pyruvate and fatty acids in ATP (oxidative phosphorylation) takes place in ETC.
• ETC dysfunction increases free radical production!!!

Question 2

where do the proteins of the ETC come from?

Answer 2

the ETC consists of 90 proteins - 77 are encoded by nDNA (synthesized in the nucleus), and 13 are encoded by mtDNA (synthesized in the mitochondria)

Question 3

what are the consequences of cellular damage in mitochondria disorders?

Answer 3

cellular damage causes ETC dysfunction which increases free radical production. free radicals themselves cause more ETC dysfunction, which results in energy deficiency that ultimately leads to necrosis and apoptosis

Question 4

describe the changes that occur after cellular injury in regard to the mitochondria

Answer 4

cellular injury that leads to mitochondrial damage, specifically ETC dysfunction/free radical production, leads to depletion of intracellular ATP. this affects ion gradients by decreasing activity of pumps such as the Na/K pump. gradient changes cause morphologic changes - think hydropic swelling!! increased intracellular Na causes water to enter the cell

Question 5

what organ systems are affected by mitochondrial disorders?

Answer 5

mitochondria disorders affect virtually all organ systems, but most severely affected are the systems that require the most energy, namely the nervous tissue, skeletal muscle, and cardiac muscle. hence the term “mitochondrial encephalomyopathies.”

Question 6

which two genomes regulate mitochondria myopathies and how does this relate to genetics?

Answer 6

mitochondrial myopathies are regulated by nDNA and mtDNA. nDNA-related mitochondrial myopathies are passed on via Mendelian inheritance (autosomal dominant/recessive). mtDNA-related mitochondrial myopathies have maternal inheritance, typically displaying heteroplasmy (a mixture of normal/mutant mitochondria)

Question 7

leber congenital amaurosis (LCA)

Answer 7

• a family of congenital retinal dystrophies resulting in vision loss at an early age (it is the most severe type of retinal dystrophy)
• nDNA, so two genotypes have been identified, and it is normally autosomal recessive
• mitochondrial disorder

Question 8

leber’s hereditary optic neuropathy (LHON)

Answer 8

• progressive loss of vision due to degeneration of the optic nerve (only affects the eye)
• usually affects males (possible susceptibility locus on the Y chromosome?)
• most common inherited mitochondrial disorder
• mtDNA, so passed on maternally

Question 9

kearns-sayre syndrome

Answer 9

• characterized by eye pain, degeneration of retinal pigments, progressive weakness of extra-ocular muscles, cardiac conduction defect
• mtDNA, loss of genes important for mitochondrial protein formation and oxidative phosphorylation

Question 10

what types of mutations are primarily responsible for mitochondrial disorders?

Answer 10

most mitochondrial disorders are due to mutations in nDNA, though there are a good amount caused by mtDNA mutations

Question 11

what is a major hallmark if mitochondrial disease?

Answer 11

ragged red ribers: these are a buildup/enlargement of mitochondria in myofibers (muscle cells). they appear as red subsarcolemmal deposits, and occur in no other metabolic disease

Question 12

what are the main functions of a normal SER?

Answer 12

lipid and glycogen metabolism, Ca2+ storage, and detoxification (of drugs)

Question 13

what are the cytochrome P450 proteins?

Answer 13

monooxygenases (enzymes!) within the SER that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids

Question 14

what are the two phases of metabolism of commonly used medicines?

Answer 14

• phase 1: oxidative metabolism (hydroxylation reactions) prior to conjugation (which leaves the compound water soluble and unable to have an affect)
• phase 2: metabolism of activation or inactivation
• phase 1 is heavily affected by cytochrome P450 proteins

Question 15

what happens with induction of P450 activity?

Answer 15

• P450 can be induced by alcohol and barbiturates
• induction causes SER hyperplasia, which increases drug detoxification.
• this results in lower-than-expected therapeutic drug levels
• ultrafast metabolizers risk being undertreated because their bodies go through the drug so fast and there is not enough of it lingering in the system

Question 16

what happens with inhibition of P450 activity?

Answer 16

• P450 can be inhibited by drugs such as proton receptor blockers
• inhibition results in decreased drug detoxification
• this results in higher-than-expected therapeutic drug levels because the drugs break down slower and therefore there is more drug in the body at any given time
• poor metabolizers are at risk for toxicity because the drug hangs around in their system

Question 17

what is the overall normal function of the golgi?

Answer 17

• terminal protein processing, packing, and transport
• the golgi decides whether a given protein will leave the cell, be delivered to the cell surface, or another destination
• sorts and modifies cell products like hormones, growth factors, enzymes, etc.

Question 18

describe the phosphotransferase enzyme and the consequences of its inactivity

Answer 18

• phosphotransferase is an enzyme in the golgi itself that transfers phosphate to mannose residues on specific proteins
• this serves as a marker for these proteins to be taken to lysosomes in the cell
• without this marker, the proteins leave the cell (default pathway) instead of going to lysosomes
• lysosomes need these proteins to function, so this dysfunction leads to buildup of substances inside lysosomes that are supposed to be broken down
• these are called “I cells” or inclusion bodies,” and this describes inclusion cell disease/mucolipidosis II

Question 19

dysfunctional golgi results in what?

Answer 19

cellular inclusions!

Question 20

describe golgi pathophysiology as it relates to neurodegenerative diseases and cell death

Answer 20

• golgi apparatus is fragmented in neurodegenerative diseases and cell death
• this is an early and probably irreversible lesion caused by a variety of mechanisms
• these mechanisms include Alzheimer’s disease, ALS, and creutzfeldt-jacob disease

Question 21

what are the types of lysosomes and what do they do?

Answer 21

• 1 lysosomes: bud from the golgi, rich in lytic enzymes like acid hydrolases (active at pH 5), ready to clean up the cell
• 2 lysozomes: where actual digestion occurs (heterophagosomes: digestion of material exogenous to cell), (autophagosomes: digestion of cells and cell components)
• post-digestive 2 lysosomes: residual bodies, lipofuscin granules (wear and tear pigment, yellow/brown)

Question 22

what is the basis behind lysosomal storage diseases?

Answer 22

• inherited deficiency of one or more lysosomal enzymes, which causes accumulation of materials that would normally be degraded

Question 23

what are sphingolipids?

Answer 23

• a class of lipids found in membranes of mammalian cells, specifically in the plasma membrane and golgi network
• they serve a structural and recognition role in membranes and are synthesized in cells where they are needed
• the are normally digested by lysosomes, and deficiency of lysosomal enzymes leads to buildup of sphingolipids

Question 24

pompe’s disease

Answer 24

• lysosomal storage disease
• glycogenosis (buildup of glycogen)
• deficiency of alpha 1,4-glucosidase (lysosomal enzyme)

Question 25

hunter and hurler syndromes

Answer 25

• lysosomal storage disease
• mucopolysaccharidoses (buildup of mucopolysaccharides)
• due to deficiency of alpha L-iduronidase

Question 26

tay-sachs disease

Answer 26

• gangliosidosis (buildup of gangliosides, which are molecules made of lipids and carbs)
• from deficiency of hemosaminidase (lysosomal enzyme)

Question 27

gaucher disease

Answer 27

• lysosomal storage disease
• buildup of cerebrosides (type of sphingolipid)
• deficiency of glucocerebrosidase (lysosomal enzyme)
• enlargement of spleen and anemia, not fatal

Question 28

niemann-pick disease types A and B

Answer 28

-
- lysosomal storage disease
- buildup of sphingolipids
- deficiency of sphingomyelinase

Question 29

niemann-pick disease type C

Answer 29

• not a sphingonyelinase deficiency (so no buildup of sphingolipids), but mutations in the NPC1 or NPC2 genes, preventing transport of cholesterol and other lipids, causing cholesterol lipidosis
• causes premature death because many normal cell functions, including formation of the cell membrane, require lipids

Question 30

what is the overall function of peroxisomes?

Answer 30

• packets of oxidative enzymes
• these enzymes are involved in various metabolic pathways, ultimately breaking down toxic chemicals and organic compounds
• many of these pathways involve production of hydrogen peroxide and its breakdown into oxygen and water

Question 31

what does catalase do?

Answer 31

• catalase is a peroxisomal enzyme that breaks hydrogen peroxide down onto oxygen and water
• it oxidizes alcohol and is thus very important in the liver and kidney
• is also oxidizes uric acid, amino acids, and fatty acids

Question 32

describe fatty acid oxidation as it relates to peroxisomes

Answer 32

• peroxisomes oxidize fatty acids that are too long (VLCFA) for the mitochondria
• this yields metabolic energy!!

Question 33

how do peroxisomes participate in the biosynthesis of lipids and phospholipids?

Answer 33

• they contain enzymes that make plasmalogens, a unique class of glycerophospholipids that make up about 20% of the total phospholipid mass in humans)
• plasmalogens are very important in brain and heart development
• they also synthesize cholesterol (which can be made into bile acids in the liver) and dolichol (which aids in glycoprotein synthesis in a variety of cells)

Question 34

what are glycerophospholipids?

Answer 34

phospholipids in which the hydrocarbon chain is linked to the glycerol by an ether bond instead of an ester bond

Question 35

what diseases are caused by reduced number or absence of peroxisomes?

Answer 35

impaired functions in many enzymes and transport proteins, causing chondrodysplasia punctate (CDP) and leukodystrophies

Question 36

what is chondrodysplasia punctate (CDP)?

Answer 36

punctate calcification of cartilage

Question 37

what are leukodystrophies?

Answer 37

• a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord, and often peripheral nerves. each type is caused by a specific gene abnormality that leads to abnormal development or destruction of white matter (myelin sheath) of the brain
• these are peroxisome-related disorders (involving peroxisomal enzymes or transport of VLCFA’s to peroxisomes)

Question 38

autosomal recessive leukodystrophy

Answer 38

• primary defect is mutation of PEXR1 (peroxisome receptor 1) that is required for transport of peroxisome-targeted enzymes
• ZS (zellweger syndrome) is the most severe form and is characterized by reduction or absence of peroxisomes in liver, kidney, and brain (cerebrohepatorenal syndrome)
• clinical features of ZS include liver enlargement, high serum levels of iron and copper, and defective vision

Question 39

x-linked recessive leukodystrophy

Answer 39

this is a mutation in the ABCD1 gene, impairing transport of VLCFAs to peroxisomes. this causes them to accumulate in all tissues. specifically, this results in progressive demyelination that is associated with dysfunction of adrenal cortex. the prognosis is poor except with a successful bone marrow transplant

Question 40

what does lorenzo’s oil do?

Answer 40

lorenzo’s oil inhibits ELOVL1, which is the enzyme that elongates fatty acids. this means that they would not build up in tissues as a result of defective ABCD1 gene impairing transport of VLCFAs, so theoretically should stop progressive demyelination and adrenal dysfunction associated with x-linked recessive leukodystrophy