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Transcript
N-terminus
Thr-172
C-terminus
AMPK predicted
structure
• The cascade is activated in an ultrasensitive manner by
conditions (exercise, metabolic stress) that increase
AMP:ATP ratio.
• Ligases
ATP → AMP + PPi
• ATPases:
ATP → ADP + Pi
• Adenylate kinase:
2ADP ↔ ATP + AMP
• AMP allosterically activates the AMPK
• Exposition of Thr172 in the activation loop for
phosphorylation by AMPKK.
Respiratory chain
complex affected
subunits nDNA mtDNA
Complex I
39
7
Complex II
4
0
Complex III
Complex V
Complex IV
10
1
14
3
10
3
Clinical phenoype
MELAS, LHON, myopathy and exercise intolerance,
Parkinsonism, LHON/dystonia, Leigh's disease,
LHON/MELAS, exercise intolerant myoglobinuria,
eukodystrophy/myoclonic epilepsy
Extremely rare
Parkinsonism/MELAS, exercise intolerance,
cardiomyopathy, myopathy, exercise intolerance
myoglobinuria
Leigh's disease, NARP, NARP/MILS,
bilateral striatal necrosis
Sideroblastic anaemia, myoclonic ataxia, deafness,
myopathy, MELAS, exercise intolerance, mitochondrial
encephalomyopathy, motor neuron disease-like,
exercise-intolerant myoglobinuria
MELAS – mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MILS – maternally
inherited Leigh syndrome; LHON – Leber's hereditary optic neuropathy (Leber's disease); NARP –
neurogenic weakness ataxia and retinitis pigmentosa. Complex II are rarely affected (Rossignol et al.
2003).
Causes: Deleterious mutations in the mitochondrial genome
The mitochondrial tRNALeu(UUR) gene is the aetiological hot spot for
mtDNA mutations.
The A3243G transition in transfer RNALeu(UUR) gene is the common
point mutation that cause mitochondrial encephalomyopathy,
lactic acidosis with stroke-like episodes (MELAS) in approx. 80 % of the cases.
The A3243G transition alters a highly conserved dihydrouridine stem region in
tRNALeu(UUR) and possibly changes the stability and functioning of the tRNA
molecule.
the A8344G in the tRNALys gene in myoclonic epilepsy associated with ragged-red
fibres (MERRF)
The T8993G leads to neurogenic weakness, ataxia, and retinitis pigmentosa (NARP),
The G11778A culminates in Leber’s hereditary optic neuropathy (LHON)
T8993G or T8993C leads to Leigh syndrome.
Life Cycle of D. discoideum
N-terminus
Thr-172
C-terminus
AMPK predicted
structure
• The cascade is activated in an ultrasensitive manner by
conditions (exercise, metabolic stress) that increase
AMP:ATP ratio.
• Ligases
ATP → AMP + PPi
• ATPases:
ATP → ADP + Pi
• Adenylate kinase:
2ADP ↔ ATP + AMP
• AMP allosterically activates the AMPK
• Exposition of Thr172 in the activation loop for
phosphorylation by AMPKK.
Respiratory chain
complex affected
subunits nDNA mtDNA
Complex I
39
7
Complex II
4
0
Complex III
Complex V
Complex IV
10
1
14
3
10
3
Clinical phenoype
MELAS, LHON, myopathy and exercise intolerance,
Parkinsonism, LHON/dystonia, Leigh's disease,
LHON/MELAS, exercise intolerant myoglobinuria,
eukodystrophy/myoclonic epilepsy
Extremely rare
Parkinsonism/MELAS, exercise intolerance,
cardiomyopathy, myopathy, exercise intolerance
myoglobinuria
Leigh's disease, NARP, NARP/MILS,
bilateral striatal necrosis
Sideroblastic anaemia, myoclonic ataxia, deafness,
myopathy, MELAS, exercise intolerance, mitochondrial
encephalomyopathy, motor neuron disease-like,
exercise-intolerant myoglobinuria
MELAS – mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MILS – maternally
inherited Leigh syndrome; LHON – Leber's hereditary optic neuropathy (Leber's disease); NARP –
neurogenic weakness ataxia and retinitis pigmentosa. Complex II are rarely affected (Rossignol et al.
2003).
Causes: Deleterious mutations in the mitochondrial genome
The mitochondrial tRNALeu(UUR) gene is the aetiological hot spot for
mtDNA mutations.
The A3243G transition in transfer RNALeu(UUR) gene is the common
point mutation that cause mitochondrial encephalomyopathy,
lactic acidosis with stroke-like episodes (MELAS) in approx. 80 % of the cases.
The A3243G transition alters a highly conserved dihydrouridine stem region in
tRNALeu(UUR) and possibly changes the stability and functioning of the tRNA
molecule.
the A8344G in the tRNALys gene in myoclonic epilepsy associated with ragged-red
fibres (MERRF)
The T8993G leads to neurogenic weakness, ataxia, and retinitis pigmentosa (NARP),
The G11778A culminates in Leber’s hereditary optic neuropathy (LHON)
T8993G or T8993C leads to Leigh syndrome.