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Metabolism > Mitochondrial function and dysfunction > Flashcards

Mitochondrial function and dysfunction Flashcards

1
Q

functions of mitochondria

A
  • oxidation of fat, protein and CHO for energy
  • steroid hormones and neurotransmitter synthesis
  • nucleotide synthesis
  • calcium buffering
  • growth and proliferation
  • apoptosis and cell growth
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2
Q

anatomy of mitochondrion

A
  • outer membrane
  • intermembrane space
  • innermembrane
  • matrix
  • cristae junction
  • F0, F1 complexes
  • DNA
  • ribosomes
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3
Q

what is the mitochondria inner membrane permeable to

A

O2, CO2 and H2O

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4
Q

what is the mitochondria outer membrane permeable to

A

<5000 Da

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5
Q

3 stages of cellular respiration

A
  • production of acetyl CoA (link reaction)
  • oxidation of acetyl Coa
    = TCA cycle
  • electron transport and chemiosmosis
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6
Q

how is acetyl CoA produced

A

from pyruvate in the link reaction

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7
Q

TCA Cycle

A
  1. Acetyl CoA (from link)
  2. citric acid
  3. isocitric acid
  4. alpha-ketoglutaric acid
  5. succinyl CoA
  6. Succinate
  7. Fumarate
  8. Malate
  9. oxaloacetate
  10. acetyl CoA
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8
Q

where in TCA is NADH produced

A
  • isocitric acid -> alpha-ketoglutaric acid
  • alpha-ketoglutaric acid -> succinyl CoA
  • malate -> oxaloacetate

= 3 x NADH

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9
Q

Where in TCA is FADH2 produced

A
  • succinate -> fumarate

= 1 x FADH2

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10
Q

Where is CO2 produced in the TCA cycle

A
  • isocitric acid -> alpha-ketoglutaric acid
  • alpha-ketoglutaric acid -> succinyl CoA

= 2 x CO2

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11
Q

where is ATP produced in the TCA cycle

A
  • succinyl CoA -> succinate

= 1 x ATP

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12
Q

reduced NAD

A

NADH

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13
Q

Steps of ETC

A
  1. Complex I takes 2e- from NADH. Energy released is used to pump 4H+ across the membrane
  2. complex II takes 2e- from FADH2. No H+ is pumpd across the membrane
  3. Ubiquinone (Q) takes 2e- from complex I and II and transfers to complex III
  4. Complex III accepts these 2e- from Q. Energy released is used to pump H+ across the membrane
  5. Cyt C takes e- from complex III and transfers to complex IV
  6. Complex IV accepts e- from Cyt C
  7. cycle repeats and Complex IV accumulates 4e-
  8. 4e- used to reduce molecular oxygen to water
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14
Q

what transfers electrons from Complex I and II to complex III

A

ubiquinone (Q)

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15
Q

what does ubiquinone do in ETC

A

transfers e- from Complex I and II to complex III

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16
Q

Where does complex I take it 2e- from

A

NADH

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17
Q

Where does complex Ii take it 2e- from

A

FADH2

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18
Q

Where does complex III get its 2e- from

A

Ubiquinione, Q

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19
Q

what does Cyt C do

A

takes e- from complex III to complex IV

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20
Q

where does complex IV get its e- from

A

Cyt c, from complex IV

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21
Q

What happens when complex IV accumulates 4e-

A

4e- used to reduce molecular oxygen to water

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22
Q

which complexes pump H across membrane

A

I, III and IV

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23
Q

where to pumped protons go

A

enter ATPase to produce ATP via chemiosmosis

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24
Q

where is Q

A

inner mitochondrial membrane

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25
Q

where is Cyt C

A

intermembrane space

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26
Q

where is Complex I

A

inner mitochondrial membrane

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27
Q

where is complex II

A

mitochondrial matrix

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28
Q

where is complex III

A

inner mitochondrial membrane

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29
Q

where is complex IV

A

inner mitochondrial membrane

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30
Q

where is ATPase

A

inner mitochondrial membrane through to matrix

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31
Q

list electron carriers

A
  • NAD+
  • flavoprotens
  • iron-sulphur clusters
  • Ubiquinone
  • cytochromes
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32
Q

NAD+ as electron carrier

A
  • accepts 2e- and one H+ = NADH
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33
Q

flavoproteins as electron carriers

A

accept 1e- in semiquinone form or 2e-, and 2 H+

  • FAD -> FADH2
  • FMN -> FMNH2
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34
Q

iron sulphur clusters as electron carriers

A
  • Fe-S accept and release one e- at a time

non haem prosthetic group associated with flavin enzymes.
Fe2+ or Fe3+ ; net charge is somewhere inbetween as electrons are dispersed amount Fe

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35
Q

uniquinone as electron carrier

A

aka coenzyme Q10

  • only electron carrier not bound to protein complex
  • freely diffusable in the non-polar interior of the IMM
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36
Q

cytochromes as electron carrier

A

c1, c, a and a3

  • capable of absorbing visible light due to haem group
  • haem prosthetic group oscialte between Fe2+ and Fe3+ after acceptin an electron
  • cytochromes carry one e-
  • cyt c is mobile
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37
Q

what is complex I

A

NADH dehydrogenase

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38
Q

role of complex I

A
  • oxidises NADH from TCA cycle, glycolysis and FA oxidation
  • reduces Q for rest of ETC
  • transports H+ across IMM to support ATP synthesis
  • major contributor to cellular reactive oxygen species productive and oxidative stress
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39
Q

structure of complex I

A 
NADH dehydrogenase
integral membrane enzyme composed of:
- 9 redox cofactors
- 44 different subunits 
has a membrane arm and a matrix arm 
- many iron-sulphur centres
- FMN containing flavoprotein
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40
Q

how does complex I transfer electrons from NADH to Q

A
  • FMN in the matrix arm accepts 2e- from NADH converting it to reduced form FMNH2
  • Fe-S clusters in the matrix arm transfer 2e- protein N2 in membrane arm, one at a time
  • electrons transfer from N2 through membrane arm to Q
  • Q is reduced to QH2
  • 2H+ are pulled from the matrix
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41
Q

function of complex I in ETC

A

catalyses two simultaneous and coupled processes

  • takes 2e- from NADH and passes them to Q, pulling 2H+ from matrix to generate QH2
  • transfers 4H+ from matrix to intermembrane
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42
Q

what is complex III

A

cytochrome c oxidoreductase

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43
Q

where does QH2 go

A

complex III

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44
Q

Structure of Complex III

A
  • cytochrome c oxidoreductase
  • membrane protein
  • dimer of identical monomers
  • each monomer has 11 different subunits
  • Cyt C1 and Rieske of Complex III project into the IMS and interact with CytC
  • has 2 distinct binding sites of QH2
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45
Q

examples of some of the different subunits found in each monomer of complex III

A
  • cytochrome b, with 2 haem groups
  • rieske, Fe2S2 protein
  • cytochrome C1, with heam group
46
Q

what are the two binding sites on complex III for QH2

A

QN and QP

47
Q

summary equation of the Q cycle

A

QH2 + 2Cytc (Fe3+) + 2H+ (m) -> Q + 4H+ (ims) + 2Cytc (Fe2+)

QH2 + 2H+ -> Q + 2e- + 4H+

48
Q

what is the Q cycle

A

Oxidation of QH2 by Cytochrome C, catalysed by complex III. Protons are also pumped across the IMM

49
Q

Structure of Cytochrome C

A
  • small
  • single haem group and single e-
  • 12kDa
  • 104 amino acids
50
Q

what does leakage of cytochrome C out of mitochondrial memebrane trigger

A

apoptosis

51
Q

what is complex IV

A

cytochrome C oxidase

52
Q

structure of complex IV

A

cytochome C oxidase

  • 14 protein subunits
  • 2 catalytic subunits
  • 2 haems: Cyt a and Cyt a3
  • 2 copper centres: CuA and CuB
53
Q

what is sepcial about complex IV

A

it reduces oxygen without generating superoxide // free radicals

54
Q

process of complex IV actions

A
  1. two molecules of reduced Cyt C each donate an e- to CuA
  2. first e- passes through haem group of subnits 1 to the Fe-CuB centre to reduce copper
  3. second e- stops at haem a3, reducing Fe3+ to Fe2+
  4. oxygen now recruited, forming haem a3-oxygen complex
  5. proximity of reduced Cu to the haem complex reduces it to copper peroxied which bridges haem and Cu
  6. Cyt C delivers 3rd e- which cleaves O-O peroxide bond, with help of 2 matirix H+ = generation of Fe4+ with haem a3
  7. Cyt c delivers final e- which reduces Fe4+ to Fe3+
  8. 2 more H+ release 2 molecules of water and reset the system
  9. Complex IV also pumps 4H+ into IMM
55
Q

overall reaction at complex IV

A

4cyt c (reduced) + 8H+ + O2 -> 4Cyt c (oxidised) + 2H2O + 4H+

56
Q

How many H+ does complex IV remove from the matrix

A

8

  • removes 4 by chemical reaction to form water
  • pumps 4 across membrane into IMM
57
Q

What is compelx II

A

succinate dehydrogenase

58
Q

how many protons does complex II pump

A

none

59
Q

which complex pumps no protons

A

complex II

60
Q

structure of complex II

A 
succinate dehydrogenase, has 4 subunits
- SDH-A : FAD as a proton acceptor
- SDH-B: 3 Fe-S clusters
- SDH-C: cytochrome b
- SDH-D: cytochrome b
also has Q binding site
61
Q

role of Complex II

A

Involved in production of FADH2, via TCA cycle

takes 2e- from FADH2 to give to Q

62
Q

what is the overall purpose of thee ETC

A

to generate proton gradient to drive ATP synthase

63
Q

what powers the ETC

A

Redox reactions

- simultaneous reduction and oxidation resulting in transfer of electrons

64
Q

what is a redox potential

A

the measure of ease with which a molecule will accepy protons
- more positive the redox potential, the more readily a molecule is reduced

65
Q

why does ETC happen via lots of small reactions

A

lots of little reactions each produce a small amount of energy.
this is favourable becuase it is easier to control than one large sum of energy that would be produced if reaction went straight from NADH -> O2

66
Q

PMF

A

proton motive force

67
Q

what forces are involved in the electrochemical gradient of H+ across the IMM

A
  • large force due to membrane potential

- smaller force due to [H+] gradient

68
Q

what is complex V

A

F1F0 ATP synthase

69
Q

structure of complex V

A

F1F0ATP synthase

  • 500kDa complex which makes use of electrochemical gradient
  • F0 is hydrophobic unit in membrane with 10 identical subunits
  • F1 is hydrophillic catalytic unit with 3 identical alpha beta subunits
70
Q

what drives complex V

A

spins at 150 Hz

  • flow of H+ down electrochemical grad drives the F0 roto that lies in the membrane
  • H+ bind to empty F0 subunits
  • once protonated F0 subunits complete a full circle, protons exit the matrix
71
Q

what is the energy conversion at complex V

A

energy stored in proton gradient is converted to rotational energy

72
Q

rotatory catalysis model

A
  • when F1 is in the open state, ADP and P enter the active site
  • protein then closes around ADP and P and binds them loosely
  • protein undergoes another conformational change forcing ADP and P closer together
    = AS is now in a T-state to produce ATP with very high affinity
  • AS goes back to open which releases the ATP and binds more ADP and P for next cycle
73
Q

what happens if F1 doesnt have ADP and P attached

A

F1 will not allow F0 and stalk to rotate

- very important for respiratory control

74
Q

total ATP made from oxidative phosphorylation

A

26-28

  • 3-5 from glycolysis (via NADH)
  • 5 from link reaction (via NADH)
  • 18 from TCA cycle (via NADH and FADH2)
75
Q

types of mitochondrial dysfunction

A
  1. impairment of ETC and ATPsynthesis machinery
  2. inadequate no. of mitochondria
  3. accumulation of damaged mitochondria
76
Q

what causes impairment of ETC and ATPsynthesis machinery

A

single enzme disorder or ROS/RNS

77
Q

RNS and ROS

A

reactive nitrogen species

reactive oxygen species

78
Q

what causes inadequate no. of mitochondria

A

imparied mitochondrial dynamics / biogenesis

79
Q

what causes accumulation of damaged mitochondria

A

impaired mitophagy

80
Q

what is the most common single enzyme mitochondrial disorder

A

complex I disorder

81
Q

complex I disorder

A
  • most common single enzyme mitochondrial disorder
  • mutations discovered in 26/44 genes, 7mtDNA and 21nDNA
  • range of symptons and severity
    • 50% fatal under 2yo
    • 75% fatal under 10yo
82
Q

what does complex I disorder causes

A
  • lactic acidosis which is fatal bc of sever inhibiton of ETC
  • mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
  • Leigh syndrome
83
Q

MELAS

A

mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes

84
Q

what is heteroplasmy

A

presence of >1 type of mitochondrial genome

  • multiple copies of mtDNA per cell and not segregated like nuclear genome
  • proprtion of mutant DNA vary between indivuduals and tissues
  • bottleneck at myosis - few mitochondria transmitted so variable mutaton burden in offspring
85
Q

how does diabetes affect mitochondria metabolism

A
  • causes marked inhibition of mitochondrial metabolism in pancreatic beta cells
  • mitochondrially-generated ATP stimulates insulin secretion and senses glucose
  • mouse model of T2D showed reduced mitochondrial metabolism and ATP function
86
Q

what are the major source of ROS

A

mitochondria

87
Q

what are the most likely origins of ROS in intact cells

A

complex I and III

88
Q

how are ROS produced

A

leak of e- as they progress from donor redox centres to molecular oxygen (ETC)
- premature single e- reduction of molecualr oxygen earier in the ETC forms superoxide radical

89
Q

ROS production

A

highlight reactive •OH generated from O2•- and H2O

  • initiates formation of lipid radicals and lipid peroxyl radiocals
  • mitochondria are also exposed to RNS (NO•) which can react with O2•- to form peroxynitrate ONOO-
90
Q

Superoxide anion

A

O2•-

91
Q

what do O2•- and NO• form

A

peroxynitrate ONOO-

92
Q

how many types of DNA to mitochondria have

A

2

  • nuclear DNA
  • mitochondrial DNA
93
Q

mitochondrial DNA

A
  • maternally inherited
  • multiple copies per mitochondrion
  • located in The matrix
  • encodes critical subunits of the ETC
94
Q

what do ROS do to mitochondrial DNA

A

cause base pari lesions which accumulate with age

  • H2O2 forms reactive •OH which causes formation of 8-oxoG from purines
  • produces G-T inversions on replication
95
Q

Mitochondrial maintenace

A

methods of minimising dysfunction

  • fusion and fission
  • ROS scavenging
  • mitophagy
96
Q

ROS scavenging

A

removal of ROS

O2•- is converted to H2O2 by superoxide dismutase

97
Q

mitochondrial dynamics

A

fission and fusion

fission: required for cell division, increased itochondrial number and segregation of damaged mitochondrial
fusion: allows mitochondria contents to mix and may inrease ATP production

98
Q

Fission

A

required for cell division, increased itochondrial number and segregation of damaged mitochondrial

99
Q

Fusion

A

allows mitochondria contents to mix and may inrease ATP production

100
Q

steps of fission

A
  • cystolic Drp1 is phosphorylated
  • Drp1 recruited to mitochondria and binds receptors
  • forms cuff around mitochondria which constricts the organelle
  • constriction severs both membranes
  • new mitochondria generated
101
Q

steps of fusion

A
  • Mfn1 and 2 localise o the outer membranes and dock the two mitochondrion together by fusion of outer membrane
  • OPA 1 localised on inner membrane, responsible for fusing the two inner membranes together
  • shares content of mitochondria and dilutes the effects of any damage
102
Q

what is OPA 1 used for

A

localised on he inner membrane of mitochondria to fuse the two inner membranes together during fusion

103
Q

where else is OPA 1 critical

A

ETC function and apoptosis

  • OPA1 bridges the entrance to the cristae within the mitochondrion
  • disruption of OPA1 bridge disrupts the ETC and releases CytC
  • Cyc C escapes the mitochondrion and promotes apoptosis
104
Q

quality control of mitochondria

A

mitophagy

105
Q

mitophagy

A

quality control of mitochondria

  • selective mitochondrial degradation/recycling
  • usually upregulated in response to stress
106
Q

healthy mitochondria

A

PINK1 degraded by proteomsomes

107
Q

Depolarised mitochondria

A

PINK1 and parkin act on the outer MM proteins to recruit them into autophagosomes for recycling

108
Q

pathologies of mitochondiral dysfunction

A

Complex II : huntington’s
Complex IV: Alzheimer’s
PINK1/Parkin: parkinson;s
ROS: autism

chronic fatigue, diabetes, epilipsy, cerebral palsy, muscular dystrophy, cardiomyopathy and more

109
Q

where is cytochrome c reoxidised

A

Complex IV of the Electron Transport Chain

110
Q

Which components of the Electron Transport Chain are the most likely producers of Reactive Oxygen Species (ROS) in mitochondria

A

Complexes I and III

Metabolism (11 decks)

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