1. AMPK predicted structure C-terminus Thr-172 N-terminus

2. 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.

3. Table 1.3 Same respiratory chain complex activity defects cause divergent clinical phenotypes. Clinical phenoypesubunits nDNA mtDNARespiratory chain complex affected Complex I 39 7 MELAS, LHON, myopathy and exercise intolerance, Parkinsonism, LHON/dystonia, Leigh's disease, LHON/MELAS, exercise intolerant myoglobinuria, eukodystrophy/myoclonic epilepsy Complex II 4 0 Extremely rare Complex III 10 1 Parkinsonism/MELAS, exercise intolerance, cardiomyopathy, myopathy, exercise intolerance myoglobinuria Complex V 14 3 Leigh's disease, NARP, NARP/MILS, bilateral striatal necrosis Complex IV10 3 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).

4. the A8344G in the tRNALys gene in myoclonic epilepsy associated with ragged-red fibres (MERRF) Causes: Deleterious mutations in the mitochondrial genome 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 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. The mitochondrial tRNALeu(UUR) gene is the aetiological hot spot for mtDNA mutations.

5. Life Cycle of D. discoideum

6. AMPK predicted structure C-terminus Thr-172 N-terminus

7. 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.

8. Table 1.3 Same respiratory chain complex activity defects cause divergent clinical phenotypes. Clinical phenoypesubunits nDNA mtDNARespiratory chain complex affected Complex I 39 7 MELAS, LHON, myopathy and exercise intolerance, Parkinsonism, LHON/dystonia, Leigh's disease, LHON/MELAS, exercise intolerant myoglobinuria, eukodystrophy/myoclonic epilepsy Complex II 4 0 Extremely rare Complex III 10 1 Parkinsonism/MELAS, exercise intolerance, cardiomyopathy, myopathy, exercise intolerance myoglobinuria Complex V 14 3 Leigh's disease, NARP, NARP/MILS, bilateral striatal necrosis Complex IV10 3 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).

9. the A8344G in the tRNALys gene in myoclonic epilepsy associated with ragged-red fibres (MERRF) Causes: Deleterious mutations in the mitochondrial genome 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 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. The mitochondrial tRNALeu(UUR) gene is the aetiological hot spot for mtDNA mutations.