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PT4024 > Mitochondrial Pharmacology > Flashcards

Mitochondrial Pharmacology Flashcards

(50 cards)

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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)
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2
Q

How many genes does mtDNA encode?

A

37

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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
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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

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5
Q

Mutations in mtDNA only affect…

A

the integrity of the respiratory chain

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6
Q

Mutations in nuclear DNA disturb…

A

OXPHOS by impairing mitochondrial protein import, translation & assembly

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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)

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8
Q

OXPHOS can be divided into 2 basic parts

A
  1. The redox steps (ETC)
  2. The energy-generation events (chemiosmosis)
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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
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10
Q

Complex I donates its electron (from NADH) to…

A

coenzyme A

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11
Q

FADH2 donates its electron to…

A

Complex II

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12
Q

Coenzyme A donates electrons to…

A

Complex III (cytochrome C oxidoreductase)

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13
Q

Oxygen collects electrons from…

A

Complex IV

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14
Q

Mitochondrial membrane potential is vital for…

A

maintaining the physiological function of the ETC to produce ATP

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15
Q

Significant loss in mitochondrial membrane potential results in…

A

depletion in cellular energy and subsequent cell death

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16
Q

Mitochondrial dysfunction causes significant changes in __ and __

A

cellular energy metabolism and ROS generation

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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
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18
Q

Cytochrome C release from mitochondria will induce..

A

apoptosis (via activation of the intrinsic pathway)

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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
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20
Q

What are the consequences of mitochondrial biogenesis?

A
  • Increased OXPHOS capacity
  • Diminishment of pathological oxidative stress
  • Repair of mitochondrial-associated dysfunction
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21
Q

Important stimulant of mitochondrial biogenesis

22
Q

Mitochondrial dynamics

Study These Flashcards
A

Fusion and fission

23
Q

Mitochondrial fusion is regulated by:

Study These Flashcards
A

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

24
Q

Mitochondrial fission is controlled by…

Study These Flashcards
A

proteins such as dynamic-related protein (DRP1)

25
Difference between mitochondrial fusion and fission
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
Rationale for targeting mitochondria
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
6 potential therapeutic strategies for how small molecules can affect mitochondria (either directly or indirectly)
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
A widely used approach to target mitochondria is to utilise…
the mitochondrial membrane potential, which drives the accumulation of lipophilic cations within mitochondria
29
Example of a lipophilic cation that’s able to pass through biological phospholipid bilayers
Triphenyl-phosphonium (TPP)
30
By conjugation to TPP, bioactive molecules can be…
delivered into the mitochondrial matrix in vivo, provided they are not too polar
31
Greatest focus of directly-targeted mitochondrial therapeutics
OXPHOS modulators
32
Examples of OXPHOS modulators
* Idebenone (Raxone) * Imeglimin
33
What is Idebenone?
* 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
Idebenone had disappointing results in clinical trials for which indications?
Alzheimer’s disease and Friedreich’s ataxia
34
Idebenone has promising initial results for treatment of...
Leber’s hereditary optic neuropathy (LHON) - primary mito disease (vision loss due to mutations in mtDNA)
35
Idebenone is under review by EMA for treatment of…
DMD patients who are not using glucocorticoids
36
Preclinical evidence has shown that Imeglimin is…
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
Targeting mitochondrial pyruvate carrier (MPC) controls…
important of pyruvate into matrix from inner mitochondrial membrane, linking glycolysis to OXPHOS
38
Dysregulated mitochondrial pyruvate uptake plays an important role in…
non-alcoholic fatty liver disease (NAFLD) - secondary mito disease
39
Pharmacological inhibition of MPC is now being explored as a potential therapeutic to correct mitochondrial dysfunction in __
NAFLD
40
__-sparing glitazone derivatives have been developed to improve the therapeutic effect of glitazone in non-alcoholic steatohepatitis (NASH) patients specifically through inhibition of MPC
PPAR𝛾
41
A burst of __ from mitochondrial respiratory chain upon reperfusion initiates a cascade of tissue damage
superoxide
42
Mitochondrial dysfunction is a key component of...
Heart Failure
43
Mitochondrial antioxidants have had disappointing results in
Cardiovascular disease
44
Drugs to protect mitochondria
* Antioxidants to reduce oxidative damage * Replenish NAD⁺ stocks (nicotinamide) * Develop drugs to activate chaperones or proteases within mitochondria
45
Drugs to induce mitochondrial biogenesis
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
Cancer cells can evade death owing to defective induction of the mitochondrial __ pathway by over-expressing __ .
apoptotic BCL-2
47
Mitochondrial apoptosis is induced by…
mitochondrial outer membrane permeabilisation (MOMP) and the subsequent release of pro-apoptotic factors such as cytochrome C into the cytosol
48
What pro-apoptotic proteins form the MOMP pore?
BCL-2 associated X (BAX) and BCL-2 homologous antagonist/killer (BAK)
49
Example of a BH3-only pro-apoptotic protein
BID

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