Transcript AMPK_PhD
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.