8/22/17 Flashcards
(42 cards)
Shuttle for NADH
Get NADH reductive potential from cytoplasm into the mitochondria
Malate-Aspartate shuttle
Glycerol 3-Phosphate shuttle
Arsenic poisoning
Arsenate looks like phosphate and ruins enzyme linked glyceraldehyde 3-P dehydrogenase
Arsenite allosterically inhibits pyruvate dehydrogenase
Lactic acidosis
Pyruvate to lactate by lactate dehydrogenase to recycle NADH
Due to lack of oxygen, cyanide poisoning, Von Gierke disease of impaired pyruvate oxidation, leukemia and metastatic carcinoma that has anaerobic respiration by neoplastic cells
Pyruvate kinase deficiency
Many mutations, commonly but not always autosomal recessive
Expressed in erythrocytes so rely on reticulocytes
Cause chronic hemolytic anemia:
Lack ATP for Na/K ATPase so lead to swelling and rigidity of RBCs, gallstones, splenic hemolysis
Second most common enzyme deficient hemolytic anemia behind Glu 6P dehydrogenase, no malaria resistance, increased 2,3 BPG levels to decrease glycolysis and help the anemia
Treatment: blood transfusions, splenectomy, iron chelation, bone marrow transplant
Pyruvate dehydrogenase deficiency
Pyruvate and lactate accumulate, less ATP
X-linked mutations on the E1 alpha gene
Thiamine cofactor
Clinical heterogeneity, esp. for females
Metabolic form causes severe lactic acidosis, cells with good copy of gene though can buffer against
Chronic neurological form has mild lactic acidosis but brain dysfunction and structural abnormalities
Treatment: high fat/low carb (ketogenic diet), thiamine supplement, sodium bicarbonate and citrate to treat acidosis, dichloroacetate to inhibit E1 regulatory kinase that inhibits the PDH
What the brain does not use for energy
No fatty acid breakdown, use glucose and ketone bodies
Pyruvate Carboxylase Deficiency
Add CO2 to pyruvate to make oxaloacetate, use biotin
Rare autosomal recessive, three types
Build up of pyruvate (lactic acidosis)
Hypoglycemia (decreased gluconeogenesis)
Decrease in myelin sheath and neurotransmitters (anaplerotic effects)
Lactic acidosis, failure to thrive, seizures
Biotin, triheptanion, citrate for acidosis, aspartate for urea cycle, high carb and protein diet to avoid gluconeogenesis (avoid ketogenic diet)
Acute cyanide poisoning
CN- blocks electron transport by binding ferric (Fe3+) in cytochrome oxidase (Complex IV)
Hyperventilation from lactic acidosis from switch to glycolysis
Nitrite used to oxidize Hemoglobin to methemoglobin (Fe3+), binds cyanide tightly to remove from Complex IV
Rhodanase in 5he liver normally reacts cyanide with thiosulfate to make thiocyanate
Kearns-Sayre Syndrome
Deletions of tRNA and oxidative phosphorylation genes
Late onset ptosis, opthalmoplegia
Myopathic facies and a hearing aid in example,
looks like stoner
MERRF
Myoclonic Epilepsy and Ragged-Red Fiber disease
Mutation in mtDNA gene MT-TK for tRNA Lys
Late onset
Myoclonic epilepsy (muscle twitching), short, hearing loss, lactic acidosis, exercise intolerance, progressive dementia
Clumps of diseased mitochondria appear in muscle fibers (stain red)
No good treatment but CoQ-10 and L-carnitine may be attempted
Leber’s Hereditary Optic Neuropathy (LHON)
Sudden blindness in young adults caused by degeneration of Erin all ganglion cells of optic nerve
Three different types of mutations to NADH dehydrogenase (Complex I)
Mainly males, Northern European
Idebenone: boosts ETC, bypasses Complex I, experimental treatment
MCAD deficiency
Medium chain acyl-CoA dehydrogenase
First enzyme of beta oxidation, inability to break down C6-C12
Elevated dicarboxylic acids in urine
Acute energy deficiency, sudden hypoketotic hypoglycemia triggered by illness or fasting, can include seizure, coma, and death
Caused by a mutation, clinical heterogeneity
Avoid fasting, do glucose supplementation, low fat diet, prognosis ok if get early but may cause SIDS
VOMIT AAs: Val, Met, Ile, Thr
CPT II Deficiency
Carnitine palmitoyltransferase II
Catalyze last step of LCFAs into the mitochondrial matrix
Acute myglobinuria (brown urine) from exercise, fasting, or illness
Adult type: rhabdomyolysis (breakdown of muscle fibers, release of myoglobin), mild, myopathic
Infantile type: severe hypoketonic hypoglycemia, liver failure, cardiomyopathy
Neonatal: lethal within days, respiratory failure, hypoglycemia, seizures
Treatment: avoid fasting/extreme exercise/lipid intake, do high carb and low fat diet, carnitine supplementation, Triheptanoin for energy source
Propionyl-CoA associated disorders
Build up of toxic intermediates (organic acids) of oxidation of odd number FAs
Propionic acidemeia and methylmalonic aciduria (enzyme or B12 deficiency)
Poor feeding, lethargy, acidosis, seizures, can be life threatening
Low protein diet, specialized AA formulas, antibiotics for gut bacteria that make propionic acid
Peroxisome Roles
Oxidation of VLCFA and branched FAs
Synthesis of plasmologens and bile acids
Catabolism of D- amino acids and polyamines
Two enzymes for the PPP
Neutralize toxic substances
X-linked Adrenoleukodystrophy
Defect in ABCD1 gene that encodes a protein to transport VLCFAs into peroxisomes, they accumulate in tissues and damage myelin sheath/adrenal cortex
Progressive motor dysfunction and adrenal insufficiency
Cerebral demyelinating form: childhood, inflammatory demyelination with rapid progress to a vegetative state
Adrenomyeloneuropathy: young adults, non-inflammatory distal axonopathy with gradual progression to a spastic paraplegia
Lorenzo’s oil: special mix of unsaturated lipids that tried to clog up chain elongation machinery, doesn’t slow down disease progression
Zellweger Spectrum Disorder
Continuous spectrum of three disorders:
Zellweger syndrome- most severe
Neonatal Adrenoleukodystrophy
Infantile Refsum disease- least severe
Defect in peroxisomes biogenesis, mutation in peroxin gene
Accumulate VLCFA and branched FAs, decreased levels of plasmalogens and other lipids (DHA)
Patients with ZS (most severe form) are newborns with hypotonia, distinct facial dysmorphism, seizures, and liver dysfunction, no sight or hearing
No psychomotor development, die in a year
Less severe form have loss of hearing, vision, smell, and motor function
Adult Refsum Disease
Defect in peroxisomes alpha oxidation enzyme phytanoyl-CoA 2-hydroxylase (PHAX) leads to build up of phytanic acid
Excess phytanic acid levels are toxic to neuronal, cardiac, and bone tissues
Presents in kids
Presents as retinitis pigmentosa, anosmia, progress to blindness, deafness, cerebral ataxia, cardiomyopathy
Avoid sources of phytanic acid in diet like cod
Brown fat
Thermogenesis
Highly vascular, rich sympathetic innervation
Amount decrease with age and remains around kidneys, adrenal glands, large vessels like the aorta; regions of neck, back, and mediastinum
Metabolic syndrome
Listening of cardiovascular risk factors in visceral obesity
Adipocytes and capillaries
Lipoprotein lipase (LPL): hydrolyzed triglycerides in blood borne triglyceride rich lipoproteins to allow adipose tissue to uptake FAs (Activated by insulin)
Hormone Sensitive Lipase: hydrolyzed stored triglycerides in adipocytes, mobilizing it to meet energy needs
(Inhibited by insulin)
Type 2 diabetics with high insulin levels get fat easier and harder to lose weight
Leptin
Stimulated by insulin, FFAs, and other hormone; not directly by food uptake
Satiety hormone that informs hypothalamus about long term nutritional and fat status
Increase lipid oxidation in liver and lipolysis in muscle/adipose tissue
Low levels in anorexics and may cause amenorrhea in girls
Adiponectin
Plasma adiponectin levels decrease as adipose tissue volume increases, against trend for adipokines
Only made by adipocytes
Synthesis reduced for obesity, insulin resistance, metabolic syndrome, and type II
Lower for guys
Anti-atherosclerotic effects, enhance insulin sensitivity and glucose uptake, increase energy expenditure
Is good to have
IL-6
Pro-inflammatory cytokine that is produced by visceral adipocytes
Increased levels associated with insulin resistance and diabetes regardless of body weight
Induce energy expenditure via thermogenesis and inhibit feeding behavior of CNS
