nemoci-sympt/METABOLISMUS/mitochondrie/mitochondrialni-nemoci
Mitochonodrialni nemoci obecně
- Primary mitochondrial diseases - two major categories
Mitochondrial genome (od matky)
Heteroplasmic point mutations
- Found in all mitochondrial genes
- Lead to different clinical phenotypes
- mitochondrial encephalomyopathy
- With lactic acidosis
- Stroke-like episodes (MELAS)
- Myoclonic epilepsy with ragged red fibers (MERRF)
- Neurogenic weakness, ataxia and retinitis pigmentosa (NARP)
- Leigh syndrome (LS) [9]
Homoplasmic mtDNA point mutations
- Leber's hereditary optic neuropathy (LHON) [9]
Rearrangements (single deletions or duplications) of mtDNA
- Sporadic progressive external ophthalmoplegia (PEO)
- Kearns–Sayre syndrome (KSS)
- Pearson's syndrome [9]
Nuclear genome mutations
- In a huge number of genes directly or indirectly related to the
- Respiratory chain
- proteins involved in mtDNA maintenance
- Replication machinery
- Structural subunits of the respiratory chain complexes
- Assembly factors of the respiratory complexes
- Components of the translation apparatus
- proteins of the execution pathways
- Fission/fusion
- Apoptosis ...etc. an exhaustive list... [9]
Clinical outcomes
- Primary coenzyme Q deficiency
- From encephalomyopathy, multisystem disease, cerebellar ataxia, isolated myopathy and nephrotic syndrome
- Only 20% of the patients respond to CoQ10, the only available therapy [9]
- Slow pharmacokinetics of CoQ10 can explain the different responses observed in humans [9]
- Mutations in genes encoding FMN- or FAD-dependent proteins such as NDUFV1 (the FMN binding subunit of complex I), AIFM1, ACAD9 [12,13], and SDHA (the FAD binding subunit of complex II)
- riboflavin is effective only in some cases [9]
Mitochonodrialni nemoci obecně
- Primary mitochondrial diseases - two major categories
Mitochondrial genome (od matky)
Heteroplasmic point mutations
- Found in all mitochondrial genes
- Lead to different clinical phenotypes
- mitochondrial encephalomyopathy
- With lactic acidosis
- Stroke-like episodes (MELAS)
- Myoclonic epilepsy with ragged red fibers (MERRF)
- Neurogenic weakness, ataxia and retinitis pigmentosa (NARP)
- Leigh syndrome (LS) [9]
Homoplasmic mtDNA point mutations
- Leber's hereditary optic neuropathy (LHON) [9]
Rearrangements (single deletions or duplications) of mtDNA
- Sporadic progressive external ophthalmoplegia (PEO)
- Kearns–Sayre syndrome (KSS)
- Pearson's syndrome [9]
Nuclear genome mutations
- In a huge number of genes directly or indirectly related to the
- Respiratory chain
- proteins involved in mtDNA maintenance
- Replication machinery
- Structural subunits of the respiratory chain complexes
- Assembly factors of the respiratory complexes
- Components of the translation apparatus
- proteins of the execution pathways
- Fission/fusion
- Apoptosis ...etc. an exhaustive list... [9]
Clinical outcomes
- Primary coenzyme Q deficiency
- From encephalomyopathy, multisystem disease, cerebellar ataxia, isolated myopathy and nephrotic syndrome
- Only 20% of the patients respond to CoQ10, the only available therapy [9]
- Slow pharmacokinetics of CoQ10 can explain the different responses observed in humans [9]
- Mutations in genes encoding FMN- or FAD-dependent proteins such as NDUFV1 (the FMN binding subunit of complex I), AIFM1, ACAD9 [12,13], and SDHA (the FAD binding subunit of complex II)
- riboflavin is effective only in some cases [9]
Mitochondrial dysfunction
- Abnormality in
- Generation of ATP by OXPHOS
- ROS production
- Regulation of apoptosis
- Regulation of cytoplasmic and mitochondrial matrix calcium
- Synthesis and catabolism of metabolites
- mitochondrial trafficking (Brand and Nicholls, 2011) [154]
- A decrease in maximal respiration indicates a mitochondrial dysfunction (Brand and Nicholls, 2011)
- Impairment of the respiratory chain leads to
- An increased glycolysis
- Supporting tumor cell growth, and proliferation (Warburg, 1956)
- Increased mitochondrial membrane potential
- Termed mitochondrial hyperpolarization
- Prevents apoptosis (Michelakis, 2008)
- Cells need to metabolically adapt to hypoxia
- By switching the metabolism from oxidative phosphorylation (OXPHOS) to anaerobic glycolysis to maintain ATP supply
- Mitochondria mediate innate immune responses at different levels
- By supporting cellular metabolic reprogramming
- The cytosolic immune signaling cascades (Monlun et al., 2016)
- Activation of macrophages and dendritic cells by pro-inflammatory stimuli
- Causes a metabolic switch away from OXPHOS toward glycolysis (Kelly and O'Neill, 2015) [154]
Alzheimer´s Disease
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Alzheimer´s Disease
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Ataxia
Ataxia
Cardiac pathologies
- Hypertrophied or failing heart [8]
Cardiac pathologies
- Hypertrophied or failing heart [8]
Chronic progressive external ophthalmoplegia (CPEO)
Chronic progressive external ophthalmoplegia (CPEO)
Cytochrome c oxidase deficiency - complex IV deficiency
Příčiny
- Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency
- Subunit proteins of enzyme complex cytochrome c oxidase
- Can affect several parts of the body
- Skeletal muscles
- Heart
- Brain
- Liver [5]
- Last step in oxidative phosphorylation before the generation of ATP
- Lack of functional cytochrome c oxidase
- Disrupts the last step of oxidative phosphorylation
- Decrease in ATP production
- Can lead to cell death in tissues that require large amounts of energy [5]
- The severity of cytochrome c oxidase deficiency varies widely [5]
- Cytochrome c oxidase deficiency is caused by mutations
- One of at least 14 genes
- Most cases by mutations in genes found within nuclear DNA
- Rare in genes located within mtDNA
- Alter proteins that assemble the holoenzymes - partially assembled or not assembled at all [5]
Symptomy
- Mildly affected
- Muscle weakness (myopathy)
- Poor muscle tone (hypotonia)
- no other health problems [5]
- More severely affected
- Myopathy along
- Severe brain dysfunction (encephalomyopathy)
- 25% with cytochrome c oxidase deficiency
- Hypertrophic cardiomyopathy
- Enlarged liver
- Až liver failure
- Lactic acidosis
- Can cause nausea
- Irregular heart rate
- Can be life-threatening [5]
- Specific group of features known as Leigh syndrome
- Loss of mental function
- Movement problems
- Hypertrophic cardiomyopathy
- Eating difficulties
- Brain abnormalities
- Cytochrome c oxidase deficiency is one of the many causes of Leigh syndrome [5]
- Cytochrome c oxidase deficiency
- Frequently fatal in childhood
- Some individuals with mild signs and symptoms survive into adolescence or adulthood [5]
Cytochrome c oxidase deficiency - complex IV deficiency
Příčiny
- Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency
- Subunit proteins of enzyme complex cytochrome c oxidase
- Can affect several parts of the body
- Skeletal muscles
- Heart
- Brain
- Liver [5]
- Last step in oxidative phosphorylation before the generation of ATP
- Lack of functional cytochrome c oxidase
- Disrupts the last step of oxidative phosphorylation
- Decrease in ATP production
- Can lead to cell death in tissues that require large amounts of energy [5]
- The severity of cytochrome c oxidase deficiency varies widely [5]
- Cytochrome c oxidase deficiency is caused by mutations
- One of at least 14 genes
- Most cases by mutations in genes found within nuclear DNA
- Rare in genes located within mtDNA
- Alter proteins that assemble the holoenzymes - partially assembled or not assembled at all [5]
Symptomy
- Mildly affected
- Muscle weakness (myopathy)
- Poor muscle tone (hypotonia)
- no other health problems [5]
- More severely affected
- Myopathy along
- Severe brain dysfunction (encephalomyopathy)
- 25% with cytochrome c oxidase deficiency
- Hypertrophic cardiomyopathy
- Enlarged liver
- Až liver failure
- Lactic acidosis
- Can cause nausea
- Irregular heart rate
- Can be life-threatening [5]
- Specific group of features known as Leigh syndrome
- Loss of mental function
- Movement problems
- Hypertrophic cardiomyopathy
- Eating difficulties
- Brain abnormalities
- Cytochrome c oxidase deficiency is one of the many causes of Leigh syndrome [5]
- Cytochrome c oxidase deficiency
- Frequently fatal in childhood
- Some individuals with mild signs and symptoms survive into adolescence or adulthood [5]
- Type 2 diabetes with peripheral insulin resistance
- Hypothesis of mitochondrial dysfunction
- Impaired (mitochondrial) oxidative capacity of the cell or tissue
- Widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes [6]
- Type 2 diabetes with peripheral insulin resistance
- Hypothesis of mitochondrial dysfunction
- Impaired (mitochondrial) oxidative capacity of the cell or tissue
- Widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes [6]
Ethylmalonic encephalopathy (EE)
- EE is a devastating, multisystem disease of infancy due to mutations in ETHE1
- Gene encoding a mitochondrial sulfur dioxygenase (SDO)
- Involved in the disposal of H2S
- H2S - Hydrogen sulfide - is produced by the
- Catabolism of sulfurated amino acids in tissues
- By the anaerobic bacterial flora in the large intestine
- Concentrations above nanomolar is highly toxic
- Profound inhibition of:
- The terminal segment of fatty acids beta oxidation
- COX
- Direct damage to endothelial lining of small vessels [9]
- Accumulation of H2S then causes
- Generalized microvasculopathy
- COX deficiency, with multiple organ damage
- Brain
- Skin (with petechial purpura and orthostatic acrocyanosis)
- Skeletal muscle
- Large intestine
- First step of H2S metabolism
- Catalyzed by sulfide:quinone oxido-reductase (SQOR) to form thiosulfate (SSO32 -)
- Using sulfite (SO32 -) as an acceptor for the sulfur sulfane (HS-) moiety of H2S (H2S + SO32 - + 2e- - > SSO32 -)
- Thiosulfate is the substrate of thiosulfate:sulfur transferase (TST)
- Uses reduced glutathione (GSH) to transfer its sulfane sulphur to form glutathione persulfide (GSS-)
- Rest of the molecule generates sulfite - recycled (SSO32 - + GS- -> GSS- + SO32 -)
- GSS-persulfide is then oxidized by the sulfur dioxygenase activity (SDO) encoded by ETHE1
- To produce sulfite and reduced glutathione (GSS- + O2 + H2O -> GS- + SO32 -)
- SO32
- Oxidized to sulfate (SO42 -) through the sulfite oxidase (SO) (in the liver)
- Recycled through SQOR (in extrahepatic tissues)
N-acetylcysteine (NAC) and metronidazole
- To dump high levels of hydrogen sulfide (H2S)
- NAC is a cell-permeable precursor of GSH
- Can act as an intracellular H2S buffer
- Metronidazole is an antibiotic specifically active against H2S-producing anaerobic bacteria and protozoa
- Administration of NAC and metronidazole
- Significantly prolonged the lifespan and clinical conditions of an Ethe1-/-mouse model
- Also effective in a cohort of EE patients, ameliorating some of the clinical hallmarks of the disease
- Chronic diarrhea
- Diffuse microvasculopathy with acrocyanosis
- Some signs of CNS involvement - increased alertness and wakefulness, decreased number and duration of epileptic seizures [9]
Hepatotropic AAV2/8 serotype
- Recombinant construct expressing human Ethe1wt could be targeted to the liver using a hepatotropic AAV2/8 serotype
- 1012 viral genomes/kg were injected in three-week old Ethe1-/-mice
- Ethe1-associated SDO activity was completely recovered in liver
- Efficient clearance of H2S from the bloodstream
- Associated with
- Significant rescue of the profound COX deficiency due to the inhibitory effect of H2S
- Correction of the other biomarkers of the disease
- High plasma and urine levels of ethylmalonate, lactate and thiosulfate [9]
- Remarkable clinical improvement
- Marked prolongation of the lifespan
- Few weeks in untreated animals x over 8 months in AAV-treated littermates [9]
- Administration of the AAV2/8 construct in two doses at P1 and P21 is even more effective
- Prolongation of the lifespan to over 1.5 years [9]
Ethylmalonic encephalopathy (EE)
- EE is a devastating, multisystem disease of infancy due to mutations in ETHE1
- Gene encoding a mitochondrial sulfur dioxygenase (SDO)
- Involved in the disposal of H2S
- H2S - Hydrogen sulfide - is produced by the
- Catabolism of sulfurated amino acids in tissues
- By the anaerobic bacterial flora in the large intestine
- Concentrations above nanomolar is highly toxic
- Profound inhibition of:
- The terminal segment of fatty acids beta oxidation
- COX
- Direct damage to endothelial lining of small vessels [9]
- Accumulation of H2S then causes
- Generalized microvasculopathy
- COX deficiency, with multiple organ damage
- Brain
- Skin (with petechial purpura and orthostatic acrocyanosis)
- Skeletal muscle
- Large intestine
- First step of H2S metabolism
- Catalyzed by sulfide:quinone oxido-reductase (SQOR) to form thiosulfate (SSO32 -)
- Using sulfite (SO32 -) as an acceptor for the sulfur sulfane (HS-) moiety of H2S (H2S + SO32 - + 2e- - > SSO32 -)
- Thiosulfate is the substrate of thiosulfate:sulfur transferase (TST)
- Uses reduced glutathione (GSH) to transfer its sulfane sulphur to form glutathione persulfide (GSS-)
- Rest of the molecule generates sulfite - recycled (SSO32 - + GS- -> GSS- + SO32 -)
- GSS-persulfide is then oxidized by the sulfur dioxygenase activity (SDO) encoded by ETHE1
- To produce sulfite and reduced glutathione (GSS- + O2 + H2O -> GS- + SO32 -)
- SO32
- Oxidized to sulfate (SO42 -) through the sulfite oxidase (SO) (in the liver)
- Recycled through SQOR (in extrahepatic tissues)
N-acetylcysteine (NAC) and metronidazole
- To dump high levels of hydrogen sulfide (H2S)
- NAC is a cell-permeable precursor of GSH
- Can act as an intracellular H2S buffer
- Metronidazole is an antibiotic specifically active against H2S-producing anaerobic bacteria and protozoa
- Administration of NAC and metronidazole
- Significantly prolonged the lifespan and clinical conditions of an Ethe1-/-mouse model
- Also effective in a cohort of EE patients, ameliorating some of the clinical hallmarks of the disease
- Chronic diarrhea
- Diffuse microvasculopathy with acrocyanosis
- Some signs of CNS involvement - increased alertness and wakefulness, decreased number and duration of epileptic seizures [9]
Hepatotropic AAV2/8 serotype
- Recombinant construct expressing human Ethe1wt could be targeted to the liver using a hepatotropic AAV2/8 serotype
- 1012 viral genomes/kg were injected in three-week old Ethe1-/-mice
- Ethe1-associated SDO activity was completely recovered in liver
- Efficient clearance of H2S from the bloodstream
- Associated with
- Significant rescue of the profound COX deficiency due to the inhibitory effect of H2S
- Correction of the other biomarkers of the disease
- High plasma and urine levels of ethylmalonate, lactate and thiosulfate [9]
- Remarkable clinical improvement
- Marked prolongation of the lifespan
- Few weeks in untreated animals x over 8 months in AAV-treated littermates [9]
- Administration of the AAV2/8 construct in two doses at P1 and P21 is even more effective
- Prolongation of the lifespan to over 1.5 years [9]
Neuropathy, ataxia, and retinitis pigmentosa
Age-related hearing loss
- Jen málo případů dědičné hluchoty je způsobeno mutací v mtDNA.
Age-related hearing loss
- Jen málo případů dědičné hluchoty je způsobeno mutací v mtDNA.
Huntington´s Disease
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Huntington´s Disease
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Kearns-Sayre syndrome
- Ketogenic diet
- Reduced the mutation load of a heteroplasmic mtDNA deletion in a cybrid cell line from a Kearns–Sayre syndrome patient [9]
Kearns-Sayre syndrome
- Ketogenic diet
- Reduced the mutation load of a heteroplasmic mtDNA deletion in a cybrid cell line from a Kearns–Sayre syndrome patient [9]
Lactic acidosis
Lactic acidosis
Leber hereditary optic neuropathy
- Náhlá a rychlá nekróza optického nervu
- S preogresivní ztrátou zraku
- Vedoucí k úplné slepotě
- Zejména u mužů a to mezi 16 - 25 lety věku
- Bioenergetics defects
- Decreased ATP synthesis
- Interventions aimed at increasing the ATP levels available to cells may be beneficial
- Manifest when the residual activity of the defective gene product, either mitochondrial or nuclear encoded, falls below a critical threshold
- Even partial restoration of the activity may be sufficient to rescue / ameliorate the phenotype [9]
- mitochondrial biogenesis is critical to determine the phenotypic outcome of disease
- Increased mitochondrial content protects non-manifesting carriers of the LHON mutations
- Explain the incomplete penetrance of the disease
- Opens the possibility to stimulate mitochondrial biogenesis as a therapeutic strategy for LHON [9]
- AAV-mediated allotopic expression of mtDNA genes for LHON
- Currently recruiting patients (https://clinicaltrial.gov) [9]
- AAV2 construct has been proposed to express the wild type ND4 gene in LHON mutant cybrids and in a transgenic rat model of LHON
- AAV2 capsid protein VP2 has been engineered by adding an MTS
- To promote the internalization of the viral particle into mitochondria [9]
Leber hereditary optic neuropathy
- Náhlá a rychlá nekróza optického nervu
- S preogresivní ztrátou zraku
- Vedoucí k úplné slepotě
- Zejména u mužů a to mezi 16 - 25 lety věku
- Bioenergetics defects
- Decreased ATP synthesis
- Interventions aimed at increasing the ATP levels available to cells may be beneficial
- Manifest when the residual activity of the defective gene product, either mitochondrial or nuclear encoded, falls below a critical threshold
- Even partial restoration of the activity may be sufficient to rescue / ameliorate the phenotype [9]
- mitochondrial biogenesis is critical to determine the phenotypic outcome of disease
- Increased mitochondrial content protects non-manifesting carriers of the LHON mutations
- Explain the incomplete penetrance of the disease
- Opens the possibility to stimulate mitochondrial biogenesis as a therapeutic strategy for LHON [9]
- AAV-mediated allotopic expression of mtDNA genes for LHON
- Currently recruiting patients (https://clinicaltrial.gov) [9]
- AAV2 construct has been proposed to express the wild type ND4 gene in LHON mutant cybrids and in a transgenic rat model of LHON
- AAV2 capsid protein VP2 has been engineered by adding an MTS
- To promote the internalization of the viral particle into mitochondria [9]
Leber hereditary optic neuropathy
- Náhlá a rychlá nekróza optického nervu
- S preogresivní ztrátou zraku
- Vedoucí k úplné slepotě
- Zejména u mužů a to mezi 16 - 25 lety věku
Leigh syndrome
- Importance of ROS overproduction in the pathogenesis of cI-related Leigh syndrome
- Potential therapeutic target in cI-related disorders in cell models [9]
- Mutations of NDUFS4
- Associated with autosomal recessive, severe infantile Leigh disease in humans
- Rapidly progressive, early fatal neurological failure in the Ndufs4-/-mouse model
- Effect of rapamycin seems to be exquisitely metabolic
- no increase in complex I activity or amount was detected
- Metabolomic analysis of Ndufs4-/-brains
- Accumulation of:
- Pyruvate
- Lactate
- Glycolytic intermediates
- Reduced:
- Free amino acids
- Free fatty acids
- Nucleotides
- Products of nucleotide catabolism
- Increased:
- Oxidative stress markers
- Reduced
- Levels of GABA
- Dopamine
- Rapamycin treatment
- Corrected several of these abnormal metabolic biomarkers [9]
Leigh syndrome
- Importance of ROS overproduction in the pathogenesis of cI-related Leigh syndrome
- Potential therapeutic target in cI-related disorders in cell models [9]
- Mutations of NDUFS4
- Associated with autosomal recessive, severe infantile Leigh disease in humans
- Rapidly progressive, early fatal neurological failure in the Ndufs4-/-mouse model
- Effect of rapamycin seems to be exquisitely metabolic
- no increase in complex I activity or amount was detected
- Metabolomic analysis of Ndufs4-/-brains
- Accumulation of:
- Pyruvate
- Lactate
- Glycolytic intermediates
- Reduced:
- Free amino acids
- Free fatty acids
- Nucleotides
- Products of nucleotide catabolism
- Increased:
- Oxidative stress markers
- Reduced
- Levels of GABA
- Dopamine
- Rapamycin treatment
- Corrected several of these abnormal metabolic biomarkers [9]
Maternally inherited diabetes and deafness
Maternally inherited diabetes and deafness
MELAS
- Mitochondrial Encephalo-myopathy, Lactic acidosis, Stroke-like episodes
Symptomy
- Affects many of the body's systems
- Particularly the
- Brain and nervous system (encephalo-)
- Muscles (myopathy)
- Most often appear in childhood following a period of normal development
- Can begin at any age
- Early symptoms
- Muscle weakness and pain
- Recurrent headaches
- Loss of appetite, vomiting, and seizures
- Most affected individuals
- Stroke-like episodes beginning before age 40
- Often involve temporary muscle weakness on one side of the body (hemiparesis)
- Altered consciousness
- Vision abnormalities
- Seizures
- Severe headaches resembling migraines
- Repeated stroke-like episodes can
- Progressively damage the brain (dementia)
- Vision loss
- Problems with movement
- Most people with MELAS have
- Lactic acidosis
- Increased acidity in the blood can lead to
- Vomiting
- Abdominal pain
- Extreme tiredness (fatigue)
- Muscle weakness
- Difficulty breathing
- Less commonly, people with MELAS may experience
- Involuntary muscle spasms (myoclonus)
- Impaired muscle coordination (ataxia)
- Hearing loss
- Heart and kidney problems
- Diabetes
- Hormonal imbalances
Biochemie
- Can result from mutations in one of several mitoch. genes
- MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV
- proteins involved in normal mitochondrial function
- Part of a large enzyme complex in mitochondria that helps convert oxygen, fats, and simple sugars to energy
- Transfer RNAs (tRNAs)
MELAS
- Mitochondrial Encephalo-myopathy, Lactic acidosis, Stroke-like episodes
Symptomy
- Affects many of the body's systems
- Particularly the
- Brain and nervous system (encephalo-)
- Muscles (myopathy)
- Most often appear in childhood following a period of normal development
- Can begin at any age
- Early symptoms
- Muscle weakness and pain
- Recurrent headaches
- Loss of appetite, vomiting, and seizures
- Most affected individuals
- Stroke-like episodes beginning before age 40
- Often involve temporary muscle weakness on one side of the body (hemiparesis)
- Altered consciousness
- Vision abnormalities
- Seizures
- Severe headaches resembling migraines
- Repeated stroke-like episodes can
- Progressively damage the brain (dementia)
- Vision loss
- Problems with movement
- Most people with MELAS have
- Lactic acidosis
- Increased acidity in the blood can lead to
- Vomiting
- Abdominal pain
- Extreme tiredness (fatigue)
- Muscle weakness
- Difficulty breathing
- Less commonly, people with MELAS may experience
- Involuntary muscle spasms (myoclonus)
- Impaired muscle coordination (ataxia)
- Hearing loss
- Heart and kidney problems
- Diabetes
- Hormonal imbalances
Biochemie
- Can result from mutations in one of several mitoch. genes
- MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV
- proteins involved in normal mitochondrial function
- Part of a large enzyme complex in mitochondria that helps convert oxygen, fats, and simple sugars to energy
- Transfer RNAs (tRNAs)
Mitochondrial complex III deficiency
Mitochondrial complex III deficiency
Mitochondrial encephalomyopathy
Mitochondrial encephalomyopathy
Mitochondrial neuro-gastro-intestinal encephalomyopathy, MNGIE
Synonyma
- MEPOP
- Mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction
- Mitochondrial neurogastrointestinal encephalopathy syndrome
- MNGIE disease
- MNGIE syndrome
- Myoneurogastrointestinal encephalopathy syndrome
- Oculogastrointestinal muscular dystrophy
- OGIMD
- POLIP
- Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction
- Thymidine phosphorylase deficiency [11]
Popis
- Mutations in human TYMP1, encoding TP
- MtDNA depletion
- Severe, autosomal recessive mitochondrial disorder of early adulthood
- Can appear anytime from infancy to adulthood
- Signs and symptoms most often begin by age 20 [11]
- Painful gastrointestinal dysmotility
- Chronic diarrhea
- Leading to cachexia [9]
- Progressive external ophthalmoplegia
- With mitochondrial myopathy
- Severe sensory-motor peripheral neuropathy
- Patients usually die of complications due to their critical nutritional status
- Average age at death of 37 years [9]
- Abnormalities of the digestive system are among the most common and severe features of MNGIE disease
- Almost all affected people have a condition known as gastrointestinal dysmotility
- Muscles and nerves of the digestive system do not move food through the digestive tract efficiently
- Feelings of fullness (satiety) after eating only a small amount
- Trouble swallowing (dysphagia)
- Nausea and vomiting after eating
- Episodes of abdominal pain, diarrhea, and intestinal blockage
- Lead to extreme weight loss and reduced muscle mass (cachexia) [11]
- Abnormalities of the nervous system
- Tingling, numbness, and weakness in their limbs (peripheral neuropathy)
- Particularly in the hands and feet [11]
- Can include droopy eyelids (ptosis)
- Weakness of the muscles that control eye movement (ophthalmoplegia)
- Hearing loss [11]
- Leukoencephalopathy
- Deterioration of white matter
- Can be seen with magnetic resonance
- Usually do not cause symptoms in people with this disorder [11]
- TP is a cytosolic enzyme catalyzing the first step of thymidine (dThd) and deoxyuridine (dUrd) catabolism
- Consequence of TP dysfunction
- MNGIE patients accumulate dThd and dUrd systemically
- Imbalances of the mitochondrial pool of deoxyribonucleoside triphosphates (dNTPs) [9]
- Measured invitro and invivo
- Increased deoxythymidine triphosphate (dTTP)
- Decreased deoxycytidine triphosphate (dCTP)
- DNTP imbalance is mutagenic for mitochondrial DNA (mtDNA)
- Depletion, multiple deletions, and point mutations accumulating in post-mitotic organs
- Notably intestinal smooth muscle
- Skeletal muscle
- Nervous system
- Cause progressive mitochondrial deficiency and organ failure [9]
Supplementation of deoxyribonucleotides
- Can effectively correct mtDNA depletion in patients' fibroblasts carrying mutations in enzymes involved in:
- The control of the mitochondrial nucleotide pools
- Deoxynucleotide pools
- Deoxy-guanosine kinase
- DGK
- Thymidine phosphorylase
- TP [9]
- Encoded by the DGUOK and TYMP genes respectively [9]
- MtDNA depletion
- Corrected in vivo
- Treating a Tymp knockout mouse model with either dCtd or tetrahydrouridine
- An inhibitor of nucleotide catabolism [9]
- Thymidine Kinase 2 (Tk2) H126N knockin mouse reproducing a pathological mutation found in patients.
- Gene for the mitochondrial thymidine kinase
- Phosphorylates thymidine and deoxycytidine pyrimidine nucleosides to generate
- Deoxythymidine monophosphate (dTMP)
- Deoxycytidine monophosphate (dCMP)
- Absence of Tk2 determines an imbalance of dNTP pools
- Leading to mtDNA instability and depletion
- The Tk2 H126N reproduces a human disease
- Characterized by early-onset fatal encephalomyopathy due to mtDNA depletion and multiple RC defects
- Treatment with 200 or 400 mg/kg/day leads to increased dNTP concentrations and mtDNA content
- Rescuing the RC defects
- Significantly prolonging lifespan from 13 to 34 days [9]
Liver-specific AAV2/8 vector to treat a mouse model for MNGIE
- Although the Tymp-/-mouse displays hardly any clinical sign, it is characterized by markedly abnormal dNTP pools, similar to MNGIE patients
- Intra-venous injection of AAV2/8 particles expressing human wt TYMP (1012–1013 viral DNA/kg)
- Normalized dCTP and dTTP levels in plasma and tissues for up to 8 months of age
- Anon-invasive and safe procedure of systemic administration of suitably engineered AAV vectors [9]
Bone marrow transplantation
- Current standard treatment for MNGIE relies on
- More than 50% post-graft mortality due to poor clinical conditions of the recipient patients [9]
Mitochondrial neuro-gastro-intestinal encephalomyopathy, MNGIE
Synonyma
- MEPOP
- Mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction
- Mitochondrial neurogastrointestinal encephalopathy syndrome
- MNGIE disease
- MNGIE syndrome
- Myoneurogastrointestinal encephalopathy syndrome
- Oculogastrointestinal muscular dystrophy
- OGIMD
- POLIP
- Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction
- Thymidine phosphorylase deficiency [11]
Popis
- Mutations in human TYMP1, encoding TP
- MtDNA depletion
- Severe, autosomal recessive mitochondrial disorder of early adulthood
- Can appear anytime from infancy to adulthood
- Signs and symptoms most often begin by age 20 [11]
- Painful gastrointestinal dysmotility
- Chronic diarrhea
- Leading to cachexia [9]
- Progressive external ophthalmoplegia
- With mitochondrial myopathy
- Severe sensory-motor peripheral neuropathy
- Patients usually die of complications due to their critical nutritional status
- Average age at death of 37 years [9]
- Abnormalities of the digestive system are among the most common and severe features of MNGIE disease
- Almost all affected people have a condition known as gastrointestinal dysmotility
- Muscles and nerves of the digestive system do not move food through the digestive tract efficiently
- Feelings of fullness (satiety) after eating only a small amount
- Trouble swallowing (dysphagia)
- Nausea and vomiting after eating
- Episodes of abdominal pain, diarrhea, and intestinal blockage
- Lead to extreme weight loss and reduced muscle mass (cachexia) [11]
- Abnormalities of the nervous system
- Tingling, numbness, and weakness in their limbs (peripheral neuropathy)
- Particularly in the hands and feet [11]
- Can include droopy eyelids (ptosis)
- Weakness of the muscles that control eye movement (ophthalmoplegia)
- Hearing loss [11]
- Leukoencephalopathy
- Deterioration of white matter
- Can be seen with magnetic resonance
- Usually do not cause symptoms in people with this disorder [11]
- TP is a cytosolic enzyme catalyzing the first step of thymidine (dThd) and deoxyuridine (dUrd) catabolism
- Consequence of TP dysfunction
- MNGIE patients accumulate dThd and dUrd systemically
- Imbalances of the mitochondrial pool of deoxyribonucleoside triphosphates (dNTPs) [9]
- Measured invitro and invivo
- Increased deoxythymidine triphosphate (dTTP)
- Decreased deoxycytidine triphosphate (dCTP)
- DNTP imbalance is mutagenic for mitochondrial DNA (mtDNA)
- Depletion, multiple deletions, and point mutations accumulating in post-mitotic organs
- Notably intestinal smooth muscle
- Skeletal muscle
- Nervous system
- Cause progressive mitochondrial deficiency and organ failure [9]
Supplementation of deoxyribonucleotides
- Can effectively correct mtDNA depletion in patients' fibroblasts carrying mutations in enzymes involved in:
- The control of the mitochondrial nucleotide pools
- Deoxynucleotide pools
- Deoxy-guanosine kinase
- DGK
- Thymidine phosphorylase
- TP [9]
- Encoded by the DGUOK and TYMP genes respectively [9]
- MtDNA depletion
- Corrected in vivo
- Treating a Tymp knockout mouse model with either dCtd or tetrahydrouridine
- An inhibitor of nucleotide catabolism [9]
- Thymidine Kinase 2 (Tk2) H126N knockin mouse reproducing a pathological mutation found in patients.
- Gene for the mitochondrial thymidine kinase
- Phosphorylates thymidine and deoxycytidine pyrimidine nucleosides to generate
- Deoxythymidine monophosphate (dTMP)
- Deoxycytidine monophosphate (dCMP)
- Absence of Tk2 determines an imbalance of dNTP pools
- Leading to mtDNA instability and depletion
- The Tk2 H126N reproduces a human disease
- Characterized by early-onset fatal encephalomyopathy due to mtDNA depletion and multiple RC defects
- Treatment with 200 or 400 mg/kg/day leads to increased dNTP concentrations and mtDNA content
- Rescuing the RC defects
- Significantly prolonging lifespan from 13 to 34 days [9]
Liver-specific AAV2/8 vector to treat a mouse model for MNGIE
- Although the Tymp-/-mouse displays hardly any clinical sign, it is characterized by markedly abnormal dNTP pools, similar to MNGIE patients
- Intra-venous injection of AAV2/8 particles expressing human wt TYMP (1012–1013 viral DNA/kg)
- Normalized dCTP and dTTP levels in plasma and tissues for up to 8 months of age
- Anon-invasive and safe procedure of systemic administration of suitably engineered AAV vectors [9]
Bone marrow transplantation
- Current standard treatment for MNGIE relies on
- More than 50% post-graft mortality due to poor clinical conditions of the recipient patients [9]
Myoclonic epilepsy with ragged-red fibers
- Stimulation of mitochondrial biogenesis caused by genetic or pharmacological induction of PGC-1alpha
- Seems more effective than that spontaneously occurring in pathological conditions such as for instance, ragged-red fibers
- Mitochondriogenic pathway is activated only in highly mutated, bioenergetically spent mitochondria clustering in ragged red fibers
- Pharmacological modulation of PGC-1alpha is generalized
- Involves also OXPHOS proficient mitochondria
- Can then exert effective functional complementation along the entire muscle fiber [9]
- PGC-1alpha activation switch towards oxidative fiber types
- Increases the energetic efficiency of the tissue [9]
Myoclonic epilepsy with ragged-red fibers
- Stimulation of mitochondrial biogenesis caused by genetic or pharmacological induction of PGC-1alpha
- Seems more effective than that spontaneously occurring in pathological conditions such as for instance, ragged-red fibers
- Mitochondriogenic pathway is activated only in highly mutated, bioenergetically spent mitochondria clustering in ragged red fibers
- Pharmacological modulation of PGC-1alpha is generalized
- Involves also OXPHOS proficient mitochondria
- Can then exert effective functional complementation along the entire muscle fiber [9]
- PGC-1alpha activation switch towards oxidative fiber types
- Increases the energetic efficiency of the tissue [9]
Cancers
Cancers
NARP
Neurodegenerative diseases
Neurodegenerative diseases
Neuropathy, ataxia, and retinitis pigmentosa - NARP
Neuropathy, ataxia, and retinitis pigmentosa - NARP
Nonsyndromic hearing loss
Nonsyndromic hearing loss
Parkinson´s Disease (PD)
- Very good example of this important mitochondrial component on neurodegenerative diseases
- Gene mutations in important genes such as DJ-1, ?-syn, parkin, PINK1 or LRRK2
- May cause defects in mitochondrial dynamics
- Fission/fusion,
- Biogenesis,
- Trafficking in retrograde and anterograde directions
- Mitophagy
- Dual effect of PGC-1? expression on PD prognosis
- Modest expression of this transcriptional co-activator
- Positive effects
- Moderate to substantial overexpession
- Deleterious consequences
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Most remarkable effects in clinical trials
- Creatine
- Coenzyme Q10
- mitochondrial targeted antioxidants/peptides [6]
Strategie možná
- Activate Sirt1 with
- resveratrol
- Use PPAR agonists such as
- Pioglitazone,
- Rosiglitazone,
- Fenofibrate
- Bezafibrate [6]
- Triggering of Nrf2/antioxidant response element (ARE) pathway by
- Triterpenoids (derivatives of oleanolic acid)
- By Bacopa monniera [6]
- Enhancement of ATP production by
- Carnitine
- Alpha-lipoic acid [6]
Parkinson´s Disease (PD)
- Very good example of this important mitochondrial component on neurodegenerative diseases
- Gene mutations in important genes such as DJ-1, ?-syn, parkin, PINK1 or LRRK2
- May cause defects in mitochondrial dynamics
- Fission/fusion,
- Biogenesis,
- Trafficking in retrograde and anterograde directions
- Mitophagy
- Dual effect of PGC-1? expression on PD prognosis
- Modest expression of this transcriptional co-activator
- Positive effects
- Moderate to substantial overexpession
- Deleterious consequences
- Impaired function or expression of PGC-1?
- Master regulator of mitochondrial biogenesis [6]
Most remarkable effects in clinical trials
- Creatine
- Coenzyme Q10
- mitochondrial targeted antioxidants/peptides [6]
Strategie možná
- Activate Sirt1 with
- resveratrol
- Use PPAR agonists such as
- Pioglitazone,
- Rosiglitazone,
- Fenofibrate
- Bezafibrate [6]
- Triggering of Nrf2/antioxidant response element (ARE) pathway by
- Triterpenoids (derivatives of oleanolic acid)
- By Bacopa monniera [6]
- Enhancement of ATP production by
- Carnitine
- Alpha-lipoic acid [6]
Pearson marrow-pancreas syndrome
- Severe condition
- X development of blood cells
- X function of the pancreas and other organs
- Often fatal in infancy or early childhood
- Deletion of mitochondrial DNA
- Size and location vary
- Usually ranging from 1,000 to 10,000 nucleotides
- Cca 20 % of affected individuals have a deletion of 4,997 nucleotides
- Also common in Kearns-Sayre syndrome
- Loss of mitochondrial DNA impairs oxidative phosphorylation
- Reduces the energy available to cells
- Not clear why the same deletion can result in different signs and symptoms
- Tissues in which the mitochondrial DNA deletions are found determine which features develop
Pearson marrow-pancreas syndrome
- Severe condition
- X development of blood cells
- X function of the pancreas and other organs
- Often fatal in infancy or early childhood
- Deletion of mitochondrial DNA
- Size and location vary
- Usually ranging from 1,000 to 10,000 nucleotides
- Cca 20 % of affected individuals have a deletion of 4,997 nucleotides
- Also common in Kearns-Sayre syndrome
- Loss of mitochondrial DNA impairs oxidative phosphorylation
- Reduces the energy available to cells
- Not clear why the same deletion can result in different signs and symptoms
- Tissues in which the mitochondrial DNA deletions are found determine which features develop
