Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PT4024 > Mitochondrial Pharmacology > Flashcards

Mitochondrial Pharmacology Flashcards

1
Q

4 main compartments of mitochondria

A
  1. outer membrane
  2. inner membrane space
  3. inner membrane (folded into cristate, machinery for OXPHOS)
  4. matrix (location for metabolic reactions)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How many genes does mtDNA encode?

A

37

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

3 main roles of mitochondria

A
  1. Energy production by OXPHOS
  2. Central carbon metabolism
  3. Biosynthesis of intermediates for cell growth & function
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Primary Mitochondrial Diseases

A

A group of rare genetic metabolic disorders caused by mutations in nuclear or mitochondrial DNA, which result in malfunctioning mitochondria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Mutations in mtDNA only affect…

A

the integrity of the respiratory chain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Mutations in nuclear DNA disturb…

A

OXPHOS by impairing mitochondrial protein import, translation & assembly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

When do secondary mitochondrial diseases occur?

A

When other pathological processes negatively impact mitochondrial homeostasis (age-related conditions e.g. neurodegeneration, metabolic disorders, HF)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

OXPHOS can be divided into 2 basic parts

A
  1. The redox steps (ETC)
  2. The energy-generation events (chemiosmosis)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

The Main steps of oxidative phosphorylation

A
  • Delivery of electrons by NADH and FADH2
  • Electron transport and proton pumping
  • Splitting of oxygen to form water
  • ATP synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Complex I donates its electron (from NADH) to…

A

coenzyme A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

FADH2 donates its electron to…

A

Complex II

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Coenzyme A donates electrons to…

A

Complex III (cytochrome C oxidoreductase)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Oxygen collects electrons from…

A

Complex IV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Mitochondrial membrane potential is vital for…

A

maintaining the physiological function of the ETC to produce ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Significant loss in mitochondrial membrane potential results in…

A

depletion in cellular energy and subsequent cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Mitochondrial dysfunction causes significant changes in __ and __

A

cellular energy metabolism and ROS generation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Examples of harmful consequences of excessive mitochondrial ROS production

A
  • lipid oxidation
  • mtDNA/RNA damage
  • protein oxidation
  • Ca²⁺-dependent activation of MPTP
  • Cytochrome C release
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Cytochrome C release from mitochondria will induce..

A

apoptosis (via activation of the intrinsic pathway)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Mitochondrial homeostasis is preserved by the fine coordination between two opposing processes

A
  1. Generation of new mitochondria by mitochondrial biogenesis
  2. Removal of damaged mitochondria by mitophagy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the consequences of mitochondrial biogenesis?

A
  • Increased OXPHOS capacity
  • Diminishment of pathological oxidative stress
  • Repair of mitochondrial-associated dysfunction
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Important stimulant of mitochondrial biogenesis

A

PGC1α

22
Q

Mitochondrial dynamics

A

Fusion and fission

23
Q

Mitochondrial fusion is regulated by:

A

proteins such as mitofusins (MFN1 and MFN2) and optic atrophy protein 1 (OPA1)

24
Q

Mitochondrial fission is controlled by…

A

proteins such as dynamic-related protein (DRP1)

25
Q

Difference between mitochondrial fusion and fission

A

Fusion usually results if there are defective elements in each mitochondrion, which leads to replication of mtDNA during biogenesis. Whereas fission does not involve replication, mtDNA from each mitochondrion is used.

26
Q

Rationale for targeting mitochondria

A

Common patterns of how dysfunctional mitochondria contribute to pathogenesis of secondary diseases:
- Excessive ROS
- Disrupted Ca²⁺ homeostasis
- Defective mito biogenesis
- Disrupted mito dynamics
- Inappropriate apoptosis
- Reduced NAD⁺
- Alterations in mito signalling pathways

27
Q

6 potential therapeutic strategies for how small molecules can affect mitochondria (either directly or indirectly)

A
  1. OXPHOS modulators
  2. Repairing or preventing damage
  3. Inducing mitochondrial biogenesis
  4. Enhancing quality control by stimulating degradation of damaged mitochondria
  5. Co-opting mitochondrial function to induce cell death
  6. Altering mitochondrial signalling
28
Q

A widely used approach to target mitochondria is to utilise…

A

the mitochondrial membrane potential, which drives the accumulation of lipophilic cations within mitochondria

29
Q

Example of a lipophilic cation that’s able to pass through biological phospholipid bilayers

A

Triphenyl-phosphonium (TPP)

30
Q

By conjugation to TPP, bioactive molecules can be…

A

delivered into the mitochondrial matrix in vivo, provided they are not too polar

31
Q

Greatest focus of directly-targeted mitochondrial therapeutics

A

OXPHOS modulators

32
Q

Examples of OXPHOS modulators

A
  • Idebenone (Raxone)
  • Imeglimin
33
Q

What is Idebenone?

A
  • synthetic short chain analogue of coenzyme Q10 with enhanced solubility & PK
  • lipophilic electron carrier (predicted to act as an antioxidant in transfer of electrons from Complex II to III)
33
Q

Idebenone had disappointing results in clinical trials for which indications?

A

Alzheimer’s disease and Friedreich’s ataxia

34
Q

Idebenone has promising initial results for treatment of…

A

Leber’s hereditary optic neuropathy (LHON) - primary mito disease (vision loss due to mutations in mtDNA)

35
Q

Idebenone is under review by EMA for treatment of…

A

DMD patients who are not using glucocorticoids

36
Q

Preclinical evidence has shown that Imeglimin is…

A

a competitive inhibitor of Complex I and restores the hyperglycaemia-induced reduction in Complex III content and activity. This lowers reverse electron flow-associated ROS production and improves mitochondrial respiration

37
Q

Targeting mitochondrial pyruvate carrier (MPC) controls…

A

important of pyruvate into matrix from inner mitochondrial membrane, linking glycolysis to OXPHOS

38
Q

Dysregulated mitochondrial pyruvate uptake plays an important role in…

A

non-alcoholic fatty liver disease (NAFLD) - secondary mito disease

39
Q

Pharmacological inhibition of MPC is now being explored as a potential therapeutic to correct mitochondrial dysfunction in __

A

NAFLD

40
Q

__-sparing glitazone derivatives have been developed to improve the therapeutic effect of glitazone in non-alcoholic steatohepatitis (NASH) patients specifically through inhibition of MPC

A

PPAR𝛾

41
Q

A burst of __ from mitochondrial respiratory chain upon reperfusion initiates a cascade of tissue damage

A

superoxide

42
Q

Mitochondrial dysfunction is a key component of…

A

Heart Failure

43
Q

Mitochondrial antioxidants have had disappointing results in

A

Cardiovascular disease

44
Q

Drugs to protect mitochondria

A
  • Antioxidants to reduce oxidative damage
  • Replenish NAD⁺ stocks (nicotinamide)
  • Develop drugs to activate chaperones or proteases within mitochondria
45
Q

Drugs to induce mitochondrial biogenesis

A
  1. PPAR𝛾 can be activated directly by pioglitazone, which increases PGC1α expression
    - Pioglitazone metabolite, Leriglitazone, in Phase II/III trial for Friedreich’s ataxia
  2. Activation of AMPK can indirectly activate PGC1α
    - PXL770 (AMPK activator) in Phase II trial for NASH
46
Q

Cancer cells can evade death owing to defective induction of the mitochondrial __ pathway by over-expressing __ .

A

apoptotic
BCL-2

47
Q

Mitochondrial apoptosis is induced by…

A

mitochondrial outer membrane permeabilisation (MOMP) and the subsequent release of pro-apoptotic factors such as cytochrome C into the cytosol

48
Q

What pro-apoptotic proteins form the MOMP pore?

A

BCL-2 associated X (BAX) and BCL-2 homologous antagonist/killer (BAK)

49
Q

Example of a BH3-only pro-apoptotic protein

A

BID

PT4024 (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions