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Bioenergetics Flashcards

1
Q

What are the products of TCA cycle?

A

2 GTP, 2 FADH2, 6 NADH

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2
Q

Where does TCA cycle occur in the cell?

A

mitochondria

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3
Q

What are the 3 energy nutrients that acetyl CoA is obtained from?

A
  1. carbohydrates: glucose is oxidized to pyruvate within gylcolysis, pyruvate is decarboxylated by pyruvate dehydrogenase to generate acetyl CoA
  2. lipids: triacyglycerols are degraded to fatty acids, which are broken down into acetyl CoA via β-oxidation
  3. proteins: broken down into AA’s, 7 of which undergo variety of rxn to form acetyl CoA
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4
Q

What are the 2 purely ketogenic amino acids?

A

leucine and lysine

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5
Q

What are the 5 amino acids that are both glucogenic and ketogenic?

A

phenylalanine, isoleucine, threonine, tryptophan, tyrosine

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6
Q

During a fasting/starvation situation, why can’t acetyl CoA be oxidized through the TCA cycle?

A

The other substrate needed for TCA cycle, oxaloacetate, is committed to gluconeogenesis during times of fasting/starvation. Acetyl CoA is therefore converted to ketone bodies by the liver

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7
Q
  • within the mitochondria, catalyzes the oxidative decarboxylation of pyrvuate into CO2 and acetyl CoA with production of NADH
  • composed of 3 enzymes: E1 (pyruvate decarboxylase), E2 (dihydrolipoyl transacetylase), and E3 (dihydrolipoyl dehydrogenase)
  • has 5 coenzymes: TPP, CoA, lipoic acid, FAD, and NAD+
  • dephospho active, phospho inactive
  • phospho occyrs in coenzyme TPP of E1 complex
A

pyruvate dehydrogenase complex (PDC)

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8
Q

What is the regulation of PDC?

A
  • activated: substrates and low energy signals (e.g. elevated NAD+, ADP, CoA, pyruvate, insulin)
  • inactivated: end products and high energy signals (e.g. elevated NADH, ATP, acetyl CoA, arsenite)
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9
Q

What are the 5 coenzymes associated with PDC and what vitamins are they derived from?

A
  1. thiamine pyrophosphate (TPP), B1 (thiamine)
  2. coenzyme A (CoA), B5 (pantothenic acid)
  3. lipoic acid
  4. flavin adenine dinucleotide (FAD), B2 (riboflavin)
  5. nicotinamide adenine dinucleotide (NAD+), B3 (niacin)
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10
Q

What is the role of PDC in tissues?

A
  • skeletal muscle: Ca2+ released during muscle contraction stimulates PDC by binding to PDP
  • cardiac muscle: Ca2+ inhibits PDK, activating PDC; stimulation of PDC by catecholamines (e.g. epinephrine) is mediated by Ca2+
  • adipose tissue: insulin may activate PDC by lowering Km for Mg2+
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11
Q
  • nutritional deficiency of vitamin B1
  • leads to increased levels of pyruvate and α-ketoglutarate due to impaired PDC and α-ketoglutarate dehydrogenase (require thiamine pyrophosphate)
  • dry form: damages nerves and can lead to decreased muscle strength, muscle paralysis
  • wet form: affects cardiac and circ system, can cause heart failure
  • diagnosed by measuring blood levels of thiamine
  • rare in Western world, commonly seen in alcoholics because ethanol inhibits thiamine absorption
  • sx: weight loss, SOB, difficulty ambulating, confusion, speech difficulties, pain, involuntary eye movements, peripheral neuropathy
  • tx: thiamine supplementation with other vitamins
A

Beriberi and Wernicke-Korsakoff syndrome

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12
Q
  • condition in male infants due to defects in PDC, especially E1
  • gene for E1 located on X chromosome
  • infants show high levels of pyruvate and lactate
  • tx: lactate levels normalized by vitamin B1, lipoic acid, and biotin; lipoic acid stimulates overal PDC; biotin metabolizes pyruvate via pyruvate carboxylase; dichloroacetate inhibits PDK and activates PDC; ketogenic diet and avoidance of alanine minimizes pyruvate formation and generates acetyl CoA by bypassing PDC
A

pyruvate dehydrogenase deficiency (neonatal lactic acidosis) LO1B

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13
Q

How is arsenite a suicide inhibitor of lipoic acid (E2 subunit of PDC)? LO1C

A
  • arsenite links to lipoic acid’s 2 sulfhydryl (SH) groups irreversibly
  • limits the avalability of lipoic acid
  • affects PDC and all enzymes that use lipoic acid coenzyme (α-ketoglutarate dehydrogenase, α-keto acid dehydrogenase)
  • arsenic is slow poison, takes time to affect enough enzymes, can be detected in hair
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14
Q

What are the products of 1 turn of TCA cycle?

A
  • 1 oxaloacetate
  • 2 CO2
  • 3 NADH (generates 3 ATP each)
  • 1 FADH2 (generates 2 ATP each)
  • 1 GTP (generates 1 ATP each)
  • 12 ATP equivalents generated by 1 molecule of acetyl CoA within 1 turn of TCA cycle
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15
Q

What are the 3 regulation steps in TCA cycle (irreversible reactions)?

A
  1. condensation of acetyl-CoA and oxaloacetate to form citrate (citrate synthase)
  2. isocitrate to α-ketoglutarate (isocitrate dehydrogenase), yields 1 NADH
  3. α-ketoglutarate to succinyl-CoA (α-ketoglutarate dehydrogenase), yields 1 NADH
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16
Q

What are the regulations on citrate synthase?

A
  • activators: acetyl CoA, insulin, oxaloacetate
  • inhibitors: ATP, citrate, NADH, succinyl CoA
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17
Q

What is the rate limiting step of TCA cycle?

A

oxidation and decarboxylation of isocitrate to α-ketoglutarate by isocitrate dehydrogenase

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18
Q

What are the regulations on isocitrate dehydrogenase?

A
  • activators: ADP (allosteric), Ca2+
  • inhibitors: ATP, NADH
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19
Q

What are the regulations on α-ketoglutarate dehydrogenase?

A
  • activators: Ca2+
  • inhibitors: ATP, arsenite, GTP, NADH, succinyl CoA
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20
Q

What are the different effects of citrate on rate limiting enzymes? LO2A

A
  • high conc of citrate in a cell are indicative of ATP-rich state
  • citrate allosterically inhibits PFK-1, to limit further catabolism of glucose
  • citrate allosterically activates acetyl CoA carboxylase to encourage fatty acid synthesis
  • citrate promotes storage of excess energy as fat
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21
Q

What are the 5 steps within TCA cycle that generate high-energy equivalent substances?

A
  1. isocitrate to α-ketoglutarate (isocitrate dehydrogenase), generates NADH
  2. α-ketoglutarate to succinyl-CoA (α-ketoglutarate dehydrogenase), generates NADH
  3. succinyl-CoA to succinate (succinate thiokinase), generates GTP
  4. succinate to fumarate (succinate dehydrogenase), generates FADH2
  5. malate to oxaloacetate (malate dehydrogenase), generates NADH
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22
Q
  • only TCA cycle enzyme that is bound to inner mitochondrial membrane
  • only TCA cycle enzyme that generates FADH2
  • also called complex II because it is a component of ETC, where if transfers electrons from FADH2 to coenzyme Q
  • inhibited by malonate (competitive inhibitor)
A

succinate dehydrogenase

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23
Q

Explain the ATP:ADP and NADH:NAD+ ratios of a cell: (LO2B)

A
  • the ATP:ADP ratio is high in energy rich cells and vice versa
  • reducing power of a cell, NADH:NAD+, represents potential energy and varies inversely with ATP:ADP ratio
  • when cellular ATP levels are low, TCA cycle activity is increased to provide more NADH as substrate for ox phos to generate more ATP
  • when ATP levels are high, TCA cycle and ox phos are inhibited

- energy charge of cell is strictly regulated in narrow range of 0.8 to 0.95

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24
Q

What is the role of succinyl CoA in heme synthesis? LO2D

A
  • condensation and decarboxylation of succinyl CoA and amino acid glycine, generates δ-aminolevulinic acid (δ-ALA), which is the first step in heme biosynthesis
  • catalyzed by ALA synthase, rate limiting enzyme of heme biosynthesis, requires pyridoxal phosphate (vitamin B6) as cofactor
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25
Q

How does rat poison inhibit TCA cycle? LO2C

A
  • fluoroacetate reacts w/ acetyl CoA to form fluoroacetyl CoA, which condenses w/ oxaloacetate to form fluorocitrate
  • fluorocitrate is analogue of citrate, and competitive inhibitor of aconitase (catalyzes citrate to isocitrate)
  • inhibition of aconitase causes citrate to accumulate, inhibiting citrate synthase (therefore inhibiting TCA cycle)
  • fluorocitrate is an allosteric inhibitor of PFK-1 (inhibits glycolysis)
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26
Q

What are the 2 major types of anaplerotic reactions in terms of TCA cycle?

A
  1. degradation of amino acids: replenishes oxaloacetate, α-ketoglutarate, succinyl CoA, and fumarate; occurs via transaminations, deaminations, and oxidation of aromatics
  2. carboxylation of pyruvate: replenishes oxaloacetate; catalyzed by pyruvate carboxylase with biotin cofactor, consumes ATP; occurs under fasting conditions where acetyl CoA supply is high, resulting oxaloacetate will be used within gluconeogenesis; lipids are degraded exclusively to acetyl CoA, therefore are not anaplerotic; pyruvate carboxylase in liver is suppressed by insulin
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27
Q
  • deficiency that causes more pyruvate to be converted to lactic acid than oxaloacetate
  • lactic acid accumulates in the blood
  • sx: (occur shortly after birth) seizures, muscle weakness, ataxia
  • more prevalent among Algonkian Indian tribes in eastern Canada
  • autosomal recessive inheritance pattern
A

pyruvate carboxylase deficiency (LO3A)

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28
Q

What are the intermediates oxaloacetate will go on to make under fasting conditions?

A
  • OAA reduced to malate in mito
  • malate transported to cyto, oxidized back to OAA, where it becomes committed to gluconeogenesis through phospho and decarboxy into PEP by PEP carboxykinase
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29
Q

What are the intermediates citrate will go on to make in a fed state?

A
  • citrate used to generate acetyl CoA (precursor for FAS)
  • citrate transported into cyto, cleaved into acetyl CoA and OAA
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30
Q

What AA’s do oxaloacetate and α-ketoglutarate produce?

A
  • OAA: aspartate > asparagine
  • α-ketoglutarate: glutamate > glutamine > proline > arginine
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31
Q
  • rare disorder of TCA cycle enzyme with global developmental delay and severe neurologic problems in infants
  • patients have variable severity of neurological involvement, metabolic acidosis, develop severe microcephaly, and mental retardation
  • dx: urine organic analysis, this condition will show variable urinary excretion of 2-oxoglutarate; genetic testing to look for SUCLA2 and SUCLG1 defects
  • patients generally do not live past 10 years
A

2-oxoglutaric aciduria (LO4a)

32
Q
  • rare disorder of TCA cycle enzyme with global developmental delay and severe neurologic problems in infants
  • sx: hypotonia, spasticity, developmental delay, metabolic acidosis, hypoketotic hypoglycemia
  • patients have fatal outcome within first 2 years of life, or subacute encephalopathy and profound speech delay without metabolic crisis
  • dx: urine organic analysis, increased excretion of fumarate associated w/ succinate and lactate excretion w/ eventual 2-oxoglutaric aciduria; genetic testing to look for SUCLA2 and SUCLG1 defects
  • patients generally do not live past 10 years, oldest patient was in second decade of life
A

fumarase deficiency (LO4b)

33
Q
  • rare disorder of TCA cycle enzyme with global developmental delay and severe neurologic problems in infants
  • sx: encephalomyopathy, hearing loss, myopathy, dystonia, lactic acidosis
  • dx: genetic testing for SUCLA2 mutation
A

succinyl-CoA synthetase deficiency (LO4c)

34
Q
  • this enzyme plays a crucial role in promoting cancer cell growth and proliferation, especially in colorectal cancer cells
  • it increases glucose and glutamine uptake in cancer cells and favours anabolic metabolism
  • this metabolic shift is important for highly proliferating cells which require a supply of precursors for the synthesis of lipids, proteins, and nucleic acids
A

phosphoenolpyruvate carboxykinase

35
Q

How does the accumulation of citrate, pyruvate, and acetyl CoA/malonyl CoA in cancer environments promote development and progression of cancer? (LO4d)

A
  • excess citrate reduces mito pyruvate dehydrogenase, cell shifts towards glycolysis
  • excess pyruvate leads to conversion of lactate and NAD+ which favors glycolysis
  • excess citrate favors the non-oxidative breakdown of glucose in cells and promotes cancer growth
  • excess citrate also activates acetyl CoA carboxylase, increasing production of acetyl CoA and malonyl CoA
  • these are directed toward lipid synthesis, which shifts the fate of lipid synthesis of the cell membrane and redox potential of cells
  • all together, these promote cellular processes like cell growth, proliferation, cell survival signaling, and differentiation
36
Q

How does 2-hydroxyglutarate act as an “oncometabolite”? (LO4b)

A
  • mutations of IDH1 and IDH2 (cys and mito forms of IDH) lead to accumulation of 2HG and act as a pathogenic metabolite (oncometabolite) in many cancers
  • this mutation is involved in converion of α-ketoglutarates to 2HG’s
  • excessive accumulation of 2HG’s acts as oncometabolite and leads to malignant progression of gliomas
37
Q
  • part of mito
  • pH is higher than that of the intermembrane space
  • serves as site for β-oxidation of fatty acids, pyruvate dehydrogenase activity, the tricarboxylic acid (TCA) cycle, ketone body synthesis, some reactions of the urea cycle, heme biosyn, and Ca2+ reservoir
A

mitochondrial matrix

38
Q
  • part of mito
  • has a large surface area due to cristae
  • only permeable to ammonia (NH3), O2, and CO2
  • harbors all proteins and electron carriers for ox phos, and all integral proteins that move other molecule across membrane’s bilayer
A

inner mitochondrial membrane

39
Q
  • part of mito
  • has a high conc of protons, lower pH than the matrix, essential for ox phos
A

mitochondrial intermembrane space

40
Q
  • part of mito
  • permeable to small molecules due to presence of protein channels (porins)
A

outer mitochondrial membrane

41
Q

How does cytochrome-c induce apoptosis in a cell? (LO5b1)

A
  • apoptotic stimuli (e.g. ROS, stress, DNA damage) open mito permeability transition pore complex, releasing cytochrome-c
  • cyto-c induces cascade of biochemical rxns that result in activation of caspases
  • caspases are executors of cell death
  • release of cyto-c into cytosol is a marker for cells undergoing apoptosis
  • to assay: mitos are fractionated into postmito supernatant fractions, detection of cyto-c occurs in each fraction by Western blotting using anticyto-c antibodies
42
Q
  • component of respiratory chain
  • structural details: transmembrane protein, electron transfers are facilitated by tightly bound FMN and Fe-S clusters
  • function/action: accepts 2 electrons from NADH and donates them to coenzyme Q; pumps 4 protons from the matrix into the intermembrane space
A

complex I (NADH dehydrogenase)

43
Q
  • component of respiratory chain
  • structural details: protein bound to the matrix side of the inner mito membrane; electron transfers are facilitated by tightly bound FAD and Fe-S clusters
  • function/action: transfers 2 electrons from FADH2 to coenzyme Q
A

complex II (succinate dehydrogenase)

44
Q
  • component of respiratory chain
  • structural details: lipophilic molecule composed of an aromatic six membered ring and a long hydrophobic side chain; mobile (it moves freely within the lipid bilayer of the inner mito membrane); converted to ubiquinol upon acceptance of 2 electrons
  • function/action: acceps 2 electrons from either complex I or complex II and transfers them to complex III
A

coenzyme Q (ubiquinone)

45
Q
  • component of respiratory chain
  • structural details: transmembrane protein; electron transfers are facilitated by Fe-S clusters and cytochromes-b and -c1, which harbor iron containing heme-b and -c molecules
  • function/action: accepts 2 electrons from ubiquinol and donates them to cytochrome-c; pumps 2 hydrogen from the matrix into the intermembrane space
A

complex III (cytochrome-c reductase)

46
Q
  • component of respiratory chain
  • structural details: small protein bound to the intermembrane space side of the inner mitochondrial membrane; mobile (held to the membrane via electrostatic forces); electron transfers are facilitated by iron-containing heme c group
  • function/action: accepts electrons from complex III and donates them to complex IV
A

cytochrome-c

47
Q
  • component of respiratory chain
  • structural details: transmembrane protein; electron transfers are facilitated by Cu centers and cytochromes-a and -a3, which harbor iron containing heme-a molecules
  • function/action: accepts electrons from cytochrome-c and transfers them to O2, which forms water; pumps 4 protons from the matrix into the intermembrane space
A

complex IV (cytochrome-c oxidase)

48
Q
  • component of respiratory chain
  • structural details: multisubunit transmembrane protein; proton movement is facilitated by its membrane spanning Fo domain, and ATP synthesis is facilitated by its F1 domain, which protrudes into the matrix
  • function/action: moves protons from the intermembrane space into the matrix to obtain the energy needed to synthesize ATP from ADP and Pi
A

complex V (ATP synthase)

49
Q

How are electrons transferred within ox phos and how does this create a proton gradient to generate ATP?

A
  • components in electron transport chain are arranged so that electrons from from molecules with the lowest ΔE to the highest
  • electrons are transferred in various forms: e-, H-, and H
  • electron transfers are facilitated by redox pairs, such as NAD+/NADH, FAD/FADH2, ubiquinone/ubiquinol, FMH/FMNH2
  • electron transfers also facilitated by redox couples, such as Fe3+/Fe2+ and Cu2+/Cu+
  • ΔG and ΔE of a rxn are directly related, but opposite in magnitude

- ΔE a/w electron transfer results in a negative ΔG that is used to pump protons from mito matrix into intermembrane space, leading to a pH and electrical gradient across inner membrane

- proton motive force (potential energy) is utilized by complex V to synthesize ATP

50
Q

How is the electron transport chain inhibited at each complex?

A
  • complex I: amytal (amobarbital), rotenone, myxothiazol, piericidin A
  • complex II: malonate
  • complex III: antimycin A
  • complex IV: carbon monoxide, cyanide, hydrogen sulfide
  • complex V: oligomycin
51
Q

What is the purpose of creating a proton gradient across the inner mito membrane?

A
  • more positively charged outer surface of inner mito membrane gives rise to a membrane potential, Δφ (voltage diff between two surfaces of inner membrane)
  • amnt of energy stored within H+ gradient is proton motive force (pmf)
  • proton gradient couples transfer of electrons to the phos of ADP to ATP
52
Q

the process by which the formation of the proton gradient couples the transfer of electrons to phosphorylation of ADP to ATP

A

chemiosmosis

53
Q
  • chemicals and proteins that allow protons to reenter the mito matrix from the intermembrane space independent of the proton-channeling function of ATP synthase
  • membrane-damaging agents, mobile proton carriers, proton channels
A

uncouplers

54
Q

What are the 3 types of uncouplers?

A
  1. membrane-damaging agents: damage to membrane renders it permeable to protons; ex: AraC, AZT (drugs used in tx of cancer and HIV respectively)
  2. mobile proton carriers: lipid soluble substances that bind to/transport protons through inner membrane; ex: DNP (form of aspirin)
  3. proton channels: ion channels that transport protons across inner mito membrane in controlled manner; ex: thermogenin (uncoupler in humans and hibernating animals, found in brown fat tissue of newborns to generate heat)
55
Q

What happens when uncouplers allow for the reduction in proton gradient?

A
  • acceleration of TCA cycle and electron transfer to O2
  • inhibition of ATP synthase
  • generation of heat due to the flow of protons in the matrix
56
Q

How is ATP synthesized within the mito?

A
  • ATP synthase (comp V) harnesses energy contained within pmf by passing protons through its channel, down their conc gradient, into the matrix, which obtains necessary power to form ATP from ADP
  • synthesis of 1 ATP molecule requires a total of 4 protons: 3 are pumped into matrix, while 1 is used to exchange ATP and ADP across inner membrane
57
Q

How is ox phos regulated?

A
  • mainly by respiratory control
  • O2: ox phos will not occur if O2 is absent
  • ATP:ADP ratio: rate of ox phos is dependent on energy requirement of cell
  • when energy is needed, ATP:ADP ratio is low, which stimulates ATP synthase which stimulates all upstream processes
  • when energy is sufficient, ATP:ADP ratio is high, which inhibits ATP synthase
58
Q

What are the respiratory chain components that are encoded by mtDNA and what are the implications in mutations of these genes?

A
  • encodes for 7 out of 43 proteins of Complex I
  • 1 out of 11 proteins of complex III
  • 3 out of 13 proteins of complex IV
  • 2 out of 8 proteins of complex V
  • no subunits of complex II are encoded by mtDNA
  • severity is variable due to heteroplasmy
  • defects in proteins are a/w high incidence of certain types of cancers (e.g. midgut carcinoid tumors) due to increased prod of ROS by defective mito; prod of ROS can damage nuclear protooncogenes and cause unregulated cell division
59
Q
  • naturally occurring pesticide and has been used as fish poison for centuries
  • moderately toxic in humans, rapid photodecomposition in sunlight prevents it from becoming groundwater contaminant
  • potent inhibitor of complex I (NADH dehydrogenase), prevents electron transfer from Fe-S to ubiquinone
  • inhibition can be overcome by menadione (vitamin K3), which allows electrons to bypass the site of blockade
  • acute poisoning: tx includes washing of contaminated skin/eyes, gastric lavage, IV glucose and menadione, and hydration
  • chronic poisoning: linked to Parkinson’s dz
A

rotenone

60
Q

How does cyanide inhibit ox phos?

A
  • it binds to Fe3+ form of iron in heme of cytochrome-a3 of complex IV
  • mito respiration and ATP prod cease, leading to rapid cell death, death occurs from asphyxia
  • cyanide competitors: nitrites can convert Fe2+ to Fe3+, forming methemoglobin, which competes for binding to complex IV; thiosulfate converts CN to thiocynate (nontoxic); azide binds to Fe3+ in complex IV
61
Q
  • carbon monoxide (CO) competes w/ O2 for binding of ______ heme-a3 (Fe2+) in complex IV
  • cyanide (CN) binds to _____ form of heme-a3 (Fe3+)
  • CO is a ________ inhbitor (raises the Km)
  • CN is a ________ inhibitor (decreases Vmax)
A
  • reduced
  • oxidized
  • competitive
  • noncompetitive
62
Q

What is the importance of brown adipose tissue in humans?

A
  • source of heat production for newborn infants
  • rich in mito and high expression of UCP-1 (thermogenin) in inner mito membrane
  • allows protons to leak across inner mem back into matrix
  • energy stored in proton gradient is dissipated as heat rather than used for ATP prod
  • stimulation of brown adipose: norepi released by sympathetic nerves to activate β-adrenergic receptors on the surface of brown adipose cells, cyto lipase stimulated to break down trigs into FA’s which activate UCP-1
63
Q
  • electron transport system localized in ER and some in mito
  • active in metabolism of hydrophobic compounds and xenobiotics
  • hemoproteins that act as monooxidases
  • electron transfer from NADPH to heme in mito involves a flavoprotein (adrenodoxin reductase) and an Fe-S protein (adrenodoxin), cytochrome-b5 serves as intermediate in electron transfer
A

cytochrome P-450 (CYP)

64
Q

How does aspirin overdose cause hyperthermia?

A
  • salicylate (aspirin) uncouples ox phos by disrupting proton gradient across inner mito mem leading to dissipation of energy as heat
  • also stimulates respiratory center in brain and causes hyperventilation
  • tx for overdose: gastric lavage, hemodialysis
65
Q

How do nucleoside analogue tx lead to fatigue?

A
  • ex: AZT, AraC, ddC used in antiretroviral therapy
  • inhibit mitochondrial DNA polymerase γ and deplete mitochondrial DNA
  • complex I is inhibited, leading to net loss of ATP
  • complex I inhibition leads to complex II overutilization, resulting in elevated levels of ROS and damage
  • sx of antiretroviral toxicity: fatigue, lactic acidosis, skeletal myopathy, cardiac dysfunction, hepatic failure
66
Q

How are ATP levels perserved in hypoxic conditions?

A
  • hypoxic conditions cause decrease in resp chain and pmf
  • lack of ox causes cell to depend on glycolysis, leading to lactic acidosis

- lowered pH in mito matrix causes dimerization/activation of small inhibitory protein (IF1) that binds to ATP synthase and prevents it from acting in reverse and hydrolyzing ATP

67
Q

How are free radicals reduced in terms of mito and ubiquinone?

A
  • partially reduced ubiquinone radical (Q-) can pass an electron to O2 to generate free radical superoxide (O2-) anion
  • superoxide, H2O2, and OH are ROS capable of damaging proteins, membrane lipids, and nucleic acids

- superoxide dismutase can catalyze conversion of superoxide to H2O2, which is detoxified to H2O by glutathione peroxidase

68
Q

How are the reducing equivalents of NADH transferred from the cyto to mito matrix? (2)

A
  1. malate-aspartate shuttle: heart, liver, kidneys; generates NADH (in matrix), which enters the ETC at complex I
  2. glycerophosphate shuttle: skeletal muscle, brain; generates FADH2 (inner mito membrane), which donates electrons to ETC at co-enzyme Q

mechanism: shuttles carry out redox rxns that transfer electrons from cyto NADH (generated from conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate); NADH enters ETC at lower redox potential than FADH2, (generates 3 ATP vs FADH2’s 2), thus depending on the shuttle system used, complete oxidation of glucose may generate 36 or 38 ATP

69
Q

How is phosphate imported into the mito matrix?

A
  • antiport mechanism that simultaneously imports phosphate in form of H2PO4- and HPO2/4-, and exports hydroxide ion (OH-) or a molecule of malate
  • energy for antiport of phosphate and OH- is obtained from proton gradient (ΔpH)
70
Q

How are ATP and ADP exchanged for one another in the mito?

A
  • by ATP/ADP translocase
  • facilitates antiport of ATP and ADP
  • process is driven by low conc of ATP in intermembrane space, energy is provided by proton gradient (ΔpH) and membrane potential (Δφ)
  • because ADP has 3 negative charges and ATP has 4, their exchanges are energetically favored by proton gradient across inner mito membrane
71
Q

How is pyruvate transported into the mito matrix?

A
  • antiport with OH- going into inner mito membrane

:)

72
Q

Where is the NADH generated that is used in ETC, how is it transported into mito matrix if it is generated outside of this area?

A
  • derived mainly from TCA cycle (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase), from oxidative decarboxylation of pyruvate (pyruvate dehydrogenase), and from the oxidation of ketone bodies (β-hydroxybutyrate dehydrogenase)
  • NADH generated in cyto has electrons transferred to mito NAD+ or FAD by malate-aspartate or glycerol phosphate shuttles respectively
  • FADH2 (provides electrons to ubiquinone) can come from succinate dehydrogenase (complex II), glycerol phosphate shuttle, and fatty acyl CoA dehydrogenase
73
Q
  • first diagnosed mito dz
  • sx: perspiration, high fluid/caloric intake, asthenic, weakness
  • lab findings: increased BMR, normal thyroid function
  • uncoupling of ox phos in skeletal muscle, high levels of cytochrome-c oxidase, low levels of coenzyme Q10, high RNA in muscle homogenate (evidence of mito-protein syn)
  • electron microscopy: large accum of mito with variable size, paracrystalline inclusions
A

mitochondrial diseases (Luft’s disease specifically)

74
Q

What are the causes of mitochondrial diseases?

A
  • primary: defect in nuclear DNA encoding mito proteins; defect in mtDNA
  • secondary: ischemia, reperfusion, cardiovascular dz, renal failure, drugs, aging, alcohol, smoking, etc
75
Q

What are clinical features of mito dzs?

A
  • nervous system: seizures, ataxia, dementia, deafness, blindess
  • eyes: ptosis, external ophtalmoplegia, retinis pigmentosa w/ visual loss
  • skeletal muscle: muscle weakness, fatigue, myopathy, exercise intolerance, loss of coordination/balance
  • heart: cardiomyopathy
  • others: GI, liver failure, kidneys, pancreatic dz, diabetes
76
Q

What are metabolic features of mito dzs?

A
  • low energy production
  • increased free radical production
  • lactic acidosis

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