nemoci-sympt/METABOLISMUS/mitochondrie/podpora-mitochondrialni-funkce
Terapie mitochondriálních poruch obecně
Generalist” strategies
- Applied to a wide spectrum of different disease conditions
Disease-tailored strategies
Regulation/activation of mitochondrial biogenesis
Regulation/activation of mitochondrial autophagy
Inhibition of mitochondrial apoptosis
Scavenging of toxic compounds in specific diseases
Bypass of electron transfer chain defects
Nuclear transfer
Supplementation of nucleotides
Gene- and cell-replacement therapies
Terapie mitochondriálních poruch obecně
Generalist” strategies
- Applied to a wide spectrum of different disease conditions
Disease-tailored strategies
Regulation/activation of mitochondrial biogenesis
Regulation/activation of mitochondrial autophagy
Inhibition of mitochondrial apoptosis
Scavenging of toxic compounds in specific diseases
Bypass of electron transfer chain defects
Nuclear transfer
Supplementation of nucleotides
Gene- and cell-replacement therapies
Fermented wheat germ extract (FWGE) is a dietary supplement used to treat cancer and to slow ageing. The mode of action of FWGE is a mitochondrial restoration agent as it modulates the activity of the pyruvate dehydrogenase (PDH) complex to support the production of ATP from mitochondria128. Also, FWGE inhibits LDH and reduces the NAD+ levels128. Moreover, it shows promising action as an anti-cytokine storm drug
MAG-DHA and MAG-EPA
- Drastically decreased the mitochondrial oxygen consumption compensating for the proton leak
- Fatty acid composition of mitochondrial membranes
- Important determinant of proton leak
- Membranes with higher PUFA levels are associated with higher rates of proton leak
- Incorporation of DHA and EPA into mitochondrial membranes after supplementation in muscles of healthy men
- Theoretically cause an increase of proton leak
- Not consistent with results
- Supplementation of n-3 PUFA (mix of DHA and EPA)
- Reduced proton leak in muscles of old men and women
- Proton leak may serve to decrease ROS production
- Especially in ectotherms
- H2O2 production was reduced by 20–25% after 4 months of n-3 PUFA consumption in muscles of older adults
- Some studies have reported increased proton leak during aging
- Others showed a general decrease of proton leak with aging
- mitochondrial oxidative capacities of different substrates
- Generally decreasing at 45 days old
- More pronounced in flies fed the SD and was apparent at younger ages
- MAG-DHA does not increase mitochondrial oxidative capacities
- Flies fed MAG-EPA displayed higher mitochondrial oxygen consumption at almost all ages
- Compared to those fed the SD.
- Same trend was observed for the non-coupled respiration
- Overall capacity to transfer electrons from one complex to another inside the inner mitochondrial membrane is higher when flies are fed MAG-EPA
- EPA but not DHA
- Restores muscle mitochondrial oxidative capacities of old mice
- In healthy young men, fish oil supplementation (mix of EPA and DHA)
- Did not change mitochondrial respiratory functions
- Improved mitochondrial ADP kinetics
- Oral supplementation of n-3 PUFA monoacylglycerides
- Increase the plasma concentration and bioavailability of these n-3 PUFAs in rodents
- Compared to other forms
- Drosophila after chill coma
- Higher mitochondrial capacities
- Improved climbing abilities with arachidonic acid
- Shorter recovery time with docosahexaenoic acid
- Lifespan was decreased with arachidonic acid
- Only arachidonic acid and ALA were detected in the flies
- After exposure to the diet with arachidonic acid
- Lifespan effect detected should be specific to EPA and/or DHA
- Combination of
- Decreased proton leak with n-3 PUFAs
- Increased CI-OXPHOS with MAG-EPA
- Led to significantly higher mitochondrial coupling than SD for both MAG-DHA and MAG-EPA
- Aging tends to decrease this coupling ratio
- mitochondrial coupling efficiency
- Respiratory control ratio
- Expected decrease was observed with the SD
- Less apparent with either MAG-DHA or MAG-EPA
- Coupling ratio
- Restored in old mice supplemented with EPA but not with DHA
- Both n-3 PUFAs increased the coupling ratio at all ages
- Maintain this coupling during aging
- mitochondrial functions are improved when flies are fed MAG-EPA
- Quantitative (more mitochondria) rather than a qualitative ?
- MAG-EPA and to a lesser extend MAG-DHA
- Had protective effects against oxidative damages during aging
- But do not affect anti-oxidant capacities at younger ages
- Drosophila exposed to paraquat (a well-known inducer of oxidative stress)
- EPA/DHA supplements restored mitochondrial functions and inhibit H2O2 production [52].
- MAG-EPA have more potent effects than MAG-DHA
- Increased mitochondrial oxidative capacities
- Better protection against oxidative damages in old flies
- Could explain the increased lifespan observed in Drosophila
- Minor effects were also detected with MAG-DHA
- Oxidation of DHA to EPA
Acetyl-L-Carnitine
- 250 – 1000 mg per day
Acetyl-L-Carnitine
- 250 – 1000 mg per day
Adeno-associated viral (AAVs) vectors
- Gene therapy
- AAVs belong to the parvoviridae family
- Not associated with any disease in humans or animals
- Remain episomic in the cells for prolonged time
- Reducing the risk of insertional mutagenesis
- Several serotypes with different cellular specificity have been selected
- Specific targeting of several organs and tissues [9]
- AAV2 local injections to correct the myopathy associated with Ant1-/-mice [9]
- 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 [9]
- AAV2/8-mediated gene therapy
- Correcting liver-specific mitochondrial dysfunction in Mpv17-/-mouse
- Small protein of unknown function embedded in the inner mitochondrial membrane
- Is mutated in patients affected by hepato-cerebral forms of severe mtDNA depletion syndrome
- Including Navajo neuro-hepatopathy
- Profound decrease of mtDNA copy number in the liver
- Liver steatosis evolving into cirrhosis associated with fatal liver failure is produced in Mpv17-/-exposed to keto diet !!! [9]
- An AAV2/8 viral vector expressing human MPV17wt
- Fully rescued the mtDNA depletion
- Prevented the KD-induced cirrhosis in Mpv17-/-mice, when the treatment was initiated before starting the KD regime
- The same treatment significantly delayed but not arrested disease progression when initiated after starting KD [9]
- New serotypes efficiently and selectively targeting the liver - AAV5
- Possibility to repeat the injection well after the first administration without incurring in immunological neutralization [9]
- AAV2 vector used to re-express AIF in the eye of the Harlequin mouse
- Correction of complex I deficiency
- Long-lasting protection of retinal ganglion cells and optic nerve from degeneration [9]
- Great potential of AAV-mediated gene therapy
- Development of suitable strategies to effectively target extra-hepatic, critical organs such as skeletal muscle, heart and brain [9]
Allotopic expression
- Recoded wild type gene
- Transfected to the nucleus
- Expresses a recombinant protein containing a mitochondrial targeting sequence (MTS), to address it to mitochondria
- A 3'-UTR signal is usually added in yeast
- Then translated by a local pool of ribosomes into proteins
- Can promptly be imported into the organelle [9]
- Attempted in fibroblasts carrying mutations in ND1, ND4 and ATP6 genes, in a rat model of LHON
- Conflicting data have been obtained by different groups [9]
Protein nucleic acids (PNAs) as an “antigenomic” device
- PNAs are synthetic DNA-like molecules
- Pyrimidine and purine residues are linked to an aminoethyl (pseudopeptide) backbone
- Not charged at physiological pH
- PNA binds its complementary DNA with greater affinity than natural nucleic acids
- PNA–DNA hybrids are more stable than DNA–DNA hybrids [9]
- PNAs complementary to
- MtDNA stretch containing the 8344A>G MERRF mutation in mt-tRNALys
- Breakpoint junction associated with the mtDNA common deletion [9]
- Imported into mitochondria
- Inhibited the replication of mutant but not wild type mtDNA [9]
- no such effect was demonstrated in cell lines [9]
Synthetic N-terminal signal
- Used to introduce oligonucleotides complementary to mtDNA into the mitochondrial matrix
- Antigenomic effect was not demonstrated [9]
Target allotopically expressed tRNAs and mRNAs to the mitochondria
- RNase P, a ribonucleoprotein involved in the processing of mitochondrial transcripts
- Is imported into mitochondria through a specialized system (PNPase)
- Specifically recognizes its RNA component (H1 RNA) [9]
- Fusing the gene of interest with a 20-ribonucleotide stem-loop sequence from the H1 RNA
- Correction of mt-tRNA and COII gene mutations in cell lines [9]
Adeno-associated viral (AAVs) vectors
- Gene therapy
- AAVs belong to the parvoviridae family
- Not associated with any disease in humans or animals
- Remain episomic in the cells for prolonged time
- Reducing the risk of insertional mutagenesis
- Several serotypes with different cellular specificity have been selected
- Specific targeting of several organs and tissues [9]
- AAV2 local injections to correct the myopathy associated with Ant1-/-mice [9]
- 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 [9]
- AAV2/8-mediated gene therapy
- Correcting liver-specific mitochondrial dysfunction in Mpv17-/-mouse
- Small protein of unknown function embedded in the inner mitochondrial membrane
- Is mutated in patients affected by hepato-cerebral forms of severe mtDNA depletion syndrome
- Including Navajo neuro-hepatopathy
- Profound decrease of mtDNA copy number in the liver
- Liver steatosis evolving into cirrhosis associated with fatal liver failure is produced in Mpv17-/-exposed to keto diet !!! [9]
- An AAV2/8 viral vector expressing human MPV17wt
- Fully rescued the mtDNA depletion
- Prevented the KD-induced cirrhosis in Mpv17-/-mice, when the treatment was initiated before starting the KD regime
- The same treatment significantly delayed but not arrested disease progression when initiated after starting KD [9]
- New serotypes efficiently and selectively targeting the liver - AAV5
- Possibility to repeat the injection well after the first administration without incurring in immunological neutralization [9]
- AAV2 vector used to re-express AIF in the eye of the Harlequin mouse
- Correction of complex I deficiency
- Long-lasting protection of retinal ganglion cells and optic nerve from degeneration [9]
- Great potential of AAV-mediated gene therapy
- Development of suitable strategies to effectively target extra-hepatic, critical organs such as skeletal muscle, heart and brain [9]
Allotopic expression
- Recoded wild type gene
- Transfected to the nucleus
- Expresses a recombinant protein containing a mitochondrial targeting sequence (MTS), to address it to mitochondria
- A 3'-UTR signal is usually added in yeast
- Then translated by a local pool of ribosomes into proteins
- Can promptly be imported into the organelle [9]
- Attempted in fibroblasts carrying mutations in ND1, ND4 and ATP6 genes, in a rat model of LHON
- Conflicting data have been obtained by different groups [9]
Protein nucleic acids (PNAs) as an “antigenomic” device
- PNAs are synthetic DNA-like molecules
- Pyrimidine and purine residues are linked to an aminoethyl (pseudopeptide) backbone
- Not charged at physiological pH
- PNA binds its complementary DNA with greater affinity than natural nucleic acids
- PNA–DNA hybrids are more stable than DNA–DNA hybrids [9]
- PNAs complementary to
- MtDNA stretch containing the 8344A>G MERRF mutation in mt-tRNALys
- Breakpoint junction associated with the mtDNA common deletion [9]
- Imported into mitochondria
- Inhibited the replication of mutant but not wild type mtDNA [9]
- no such effect was demonstrated in cell lines [9]
Synthetic N-terminal signal
- Used to introduce oligonucleotides complementary to mtDNA into the mitochondrial matrix
- Antigenomic effect was not demonstrated [9]
Target allotopically expressed tRNAs and mRNAs to the mitochondria
- RNase P, a ribonucleoprotein involved in the processing of mitochondrial transcripts
- Is imported into mitochondria through a specialized system (PNPase)
- Specifically recognizes its RNA component (H1 RNA) [9]
- Fusing the gene of interest with a 20-ribonucleotide stem-loop sequence from the H1 RNA
- Correction of mt-tRNA and COII gene mutations in cell lines [9]
AICAR
- Alternative pathway to induce PGC-1 alpha dependent mitochondriogenesis
- Activation of the AMP-dependent kinase (AMPK) [9]
- AMPK agonist AICAR
- Robust induction of OXPHOS-related gene transcription
- Increase of respiratory chain complex activities in:
- Three models of COX deficiency
- Surf1 constitutive knockout mouse (Surf1-/-)
- Sco2 knockout/knockin (Sco2KOKI) mouse
- Muscle-specific Cox15(ACTA-Cox15-/-) mouse [9]
- Striking improvement of motor endurance
- In the Sco2KOKI
- But not in ACTA-Cox15-/-mice (more severe clinical phenotype)
- PGC-1 alpha delayed, but did not arrest, the disease progression [9]
- AICAR was the most effective compound in inducing mitochondrial biogenesis in complex I deficient cells [9]
- AICAR widely used in experimental work
- Short half-life after intravenous administration (1.4–2.2 h)
- Poor bioavailability after oral ingestion (less than 5%)
- Causes increased blood levels of
- Lactic acid
- uric acid [9]
- =poor candidate for long-term use [9]
AICAR
- Alternative pathway to induce PGC-1 alpha dependent mitochondriogenesis
- Activation of the AMP-dependent kinase (AMPK) [9]
- AMPK agonist AICAR
- Robust induction of OXPHOS-related gene transcription
- Increase of respiratory chain complex activities in:
- Three models of COX deficiency
- Surf1 constitutive knockout mouse (Surf1-/-)
- Sco2 knockout/knockin (Sco2KOKI) mouse
- Muscle-specific Cox15(ACTA-Cox15-/-) mouse [9]
- Striking improvement of motor endurance
- In the Sco2KOKI
- But not in ACTA-Cox15-/-mice (more severe clinical phenotype)
- PGC-1 alpha delayed, but did not arrest, the disease progression [9]
- AICAR was the most effective compound in inducing mitochondrial biogenesis in complex I deficient cells [9]
- AICAR widely used in experimental work
- Short half-life after intravenous administration (1.4–2.2 h)
- Poor bioavailability after oral ingestion (less than 5%)
- Causes increased blood levels of
- Lactic acid
- uric acid [9]
- =poor candidate for long-term use [9]
Alpha-lipoic acid
Alpha-lipoic acid
Mitochondria-targeted antioxidants (MTAs)
- Antioxidant group linked to a mitochondria-targeted moiety
- Widely used in experiments for evaluating the impact of mitochondria on different pathological processes involving oxidative stress
- Alleviate mitochondrial oxidative damage
- Improve the outcome of the pathology [1]
Tocopherol
Lipoic acid
Spin traps
Peroxidase mimetic Ebselen
Quaternary ammonium (QACs) and phosphonium (QPCs) compounds
- Used as antiseptics and disinfectants since the 1930-ies [1]
triphenylphosphonium (TPP+) cation
- Inhibitory effect of alkyl triphenyl phosphonium cations (Cn-TPP) and SkQ1 on the growth of the Gram-positive bacterium B. subtilis
- Effect increased with growing lipophilicity of Cn-TPP
- Gram-negative bacterium E. coli was insensitive to Cn-TPP and SkQ1
- Different permeability of bacterial cell envelopes for Cn-TPP and SkQ1 [1]
TPP+-conjugated ubiquinone (MitoQ)
Plastoquinone (SkQ1) - decyltriphenyl phosphonium cation conjugated to a quinone moiety
- Hydrophobic cations with delocalized charge, like SkQ1
- Exert protonophore-like activity in artificial and mitochondrial membranes in the presence of fatty acids [1]
- Known to alleviate mitochondrial oxidative damage
- Exhibited strong antibacterial activity in submicromolar and micromolar concentrations
- Gram-positive Bacillus subtilis
- Mycobacterium sp.
- Staphylococcus aureus
- Gram-negative Photobacterium phosphoreum
- Rhodobacter sphaeroides [1]
- Less antibiotic activity towards
- Escherichia coli
- Highly effective multidrug resistance pump AcrAB-TolC [1]
- Lowering of the bacterial membrane potential by SkQ1
- Might be involved in the mechanism of its bactericidal action [1]
- No significant cytotoxic effect on mammalian cells was observed at bacteriotoxic concentrations of SkQ1 [1]
- Human immortalized HeLa cells culture
- 0.01–3?µM concentration range
- A significant cytotoxic effect of SkQ1 on HeLa cells was not detected
- Reduction of cell viability did not exceed 10% for 21–24?hours
- SkQ1 could serve as an antibiotic suitable for treating bacterial infections in humans [1]
- SkQ1 is a unique artificial substrate that is recognized only by AcrAB-TolC
- Is not expelled by other transporters
- Antioxidant moiety targeting mitochondrial reactive oxygen species
- Can be used in the course of treatment of bacteria-induced pyelonephritis
- Protecting mitochondrial integrity and lowering kidney damage
- Some quinone derivatives
- Demonstrated antimicrobial activity towards clinical isolates of Gram-negative and Gram-positive bacteria
- Can be reasonably considered as a “hybrid” antibiotic [1]
Mitochondria-targeted antioxidants (MTAs)
- Antioxidant group linked to a mitochondria-targeted moiety
- Widely used in experiments for evaluating the impact of mitochondria on different pathological processes involving oxidative stress
- Alleviate mitochondrial oxidative damage
- Improve the outcome of the pathology [1]
Tocopherol
Lipoic acid
Spin traps
Peroxidase mimetic Ebselen
Quaternary ammonium (QACs) and phosphonium (QPCs) compounds
- Used as antiseptics and disinfectants since the 1930-ies [1]
triphenylphosphonium (TPP+) cation
- Inhibitory effect of alkyl triphenyl phosphonium cations (Cn-TPP) and SkQ1 on the growth of the Gram-positive bacterium B. subtilis
- Effect increased with growing lipophilicity of Cn-TPP
- Gram-negative bacterium E. coli was insensitive to Cn-TPP and SkQ1
- Different permeability of bacterial cell envelopes for Cn-TPP and SkQ1 [1]
TPP+-conjugated ubiquinone (MitoQ)
Plastoquinone (SkQ1) - decyltriphenyl phosphonium cation conjugated to a quinone moiety
- Hydrophobic cations with delocalized charge, like SkQ1
- Exert protonophore-like activity in artificial and mitochondrial membranes in the presence of fatty acids [1]
- Known to alleviate mitochondrial oxidative damage
- Exhibited strong antibacterial activity in submicromolar and micromolar concentrations
- Gram-positive Bacillus subtilis
- Mycobacterium sp.
- Staphylococcus aureus
- Gram-negative Photobacterium phosphoreum
- Rhodobacter sphaeroides [1]
- Less antibiotic activity towards
- Escherichia coli
- Highly effective multidrug resistance pump AcrAB-TolC [1]
- Lowering of the bacterial membrane potential by SkQ1
- Might be involved in the mechanism of its bactericidal action [1]
- No significant cytotoxic effect on mammalian cells was observed at bacteriotoxic concentrations of SkQ1 [1]
- Human immortalized HeLa cells culture
- 0.01–3?µM concentration range
- A significant cytotoxic effect of SkQ1 on HeLa cells was not detected
- Reduction of cell viability did not exceed 10% for 21–24?hours
- SkQ1 could serve as an antibiotic suitable for treating bacterial infections in humans [1]
- SkQ1 is a unique artificial substrate that is recognized only by AcrAB-TolC
- Is not expelled by other transporters
- Antioxidant moiety targeting mitochondrial reactive oxygen species
- Can be used in the course of treatment of bacteria-induced pyelonephritis
- Protecting mitochondrial integrity and lowering kidney damage
- Some quinone derivatives
- Demonstrated antimicrobial activity towards clinical isolates of Gram-negative and Gram-positive bacteria
- Can be reasonably considered as a “hybrid” antibiotic [1]
Beta -carotene
- 10,000 IU; every other day to daily
Beta -carotene
- 10,000 IU; every other day to daily
Bezafibrate
- PPAR pan agonist
- Widely used to treat metabolic syndrome and diabetes
- Activate the PPAR-PGC-1 alpha axis [6]
- Bezafibrate gave highly variable and poorly reproducible results [9]
- Fibroblasts from patients with different mitochondrial diseases with bezafibrate
- Improvement in the defective activities of the respiratory chain complexes, dependent on the induction of PGC-1 alpha activity [9]
- Muscle-specific PGC-1 alpha transgenic mouse and bezafibrate
- Improve the motor performance of a muscle-specific knockout mouse for Cox10, a farnesyltransferase
- Involved in the biosynthesis of COX-specific heme a.
- Effect was not due to restoration of COX activity in isolated mitochondria but to increased mitochondrial content
- Overall increase in ATP availability in the muscle fibers [9]
- A single report showed that bezafibrate can rescue the COX-defect of SCO2 mutant fibroblasts
- Fibroblast cell line from a SCO2 mutant patient and in Sco2KOKI MEFs
- Analysis of OxPhos activities + Seahorse oxygen consumption
- Failed to show any beneficial effect [9]
- CPT2-mutant patients
- Increase of OXPHOS markers in bezafibrate-treated [9]
Bezafibrate
- PPAR pan agonist
- Widely used to treat metabolic syndrome and diabetes
- Activate the PPAR-PGC-1 alpha axis [6]
- Bezafibrate gave highly variable and poorly reproducible results [9]
- Fibroblasts from patients with different mitochondrial diseases with bezafibrate
- Improvement in the defective activities of the respiratory chain complexes, dependent on the induction of PGC-1 alpha activity [9]
- Muscle-specific PGC-1 alpha transgenic mouse and bezafibrate
- Improve the motor performance of a muscle-specific knockout mouse for Cox10, a farnesyltransferase
- Involved in the biosynthesis of COX-specific heme a.
- Effect was not due to restoration of COX activity in isolated mitochondria but to increased mitochondrial content
- Overall increase in ATP availability in the muscle fibers [9]
- A single report showed that bezafibrate can rescue the COX-defect of SCO2 mutant fibroblasts
- Fibroblast cell line from a SCO2 mutant patient and in Sco2KOKI MEFs
- Analysis of OxPhos activities + Seahorse oxygen consumption
- Failed to show any beneficial effect [9]
- CPT2-mutant patients
- Increase of OXPHOS markers in bezafibrate-treated [9]
Biotin
- 2.5 – 10 mg a day
Biotin
- 2.5 – 10 mg a day
Bypassing the block of the respiratory chain
- By-pass the block of OXPHOS due to mutations affecting the RCcomplexes
- Using the “alternative” enzymes
- NADH dehydrogenase/CoQ reductase (Ndi1)
- CoQ/O2 alternative oxidase (AOX) [9]
- Single-peptide enzymes
- In the mitochondrial inner membrane
- Transfer electrons to (Ndi1) and from (AOX) CoQ
- Without pumping protons across the membrane [9]
- Ndi1
- Substitutes complex I in yeast mitochondria [9]
- AOX
- Alternative electron transport system present in lower eukaryotes, plants and several invertebrates
- By-passes the complex III + IV segment of the respiratory chain
- AOX-expressing mice have recently been created
- Be viable and fertile models of complex III or IV deficiency [9]
- Expression of these proteins
- Is well tolerated in mammalian cells, flies and mice
- Has successfully been exploited to by-pass complex I or complex III/IV defects in human cells and Drosophila models
- Capacity of these enzymes to restore the electron flow through the quinone pool
- Preventing accumulation of reduced intermediates and oxidative damage [9]
- Not accompanied by restoration of proton translocation across the inner mitochondrial membrane
- Does not directly increase ATPproduction
- Restoration of the electron flow can reactivate the unaffected RC complexes
- Indirectly promoting
- Rebuilding of the proton gradient
- The reactivation of OXPHOS [9]
Bypassing the block of the respiratory chain
- By-pass the block of OXPHOS due to mutations affecting the RCcomplexes
- Using the “alternative” enzymes
- NADH dehydrogenase/CoQ reductase (Ndi1)
- CoQ/O2 alternative oxidase (AOX) [9]
- Single-peptide enzymes
- In the mitochondrial inner membrane
- Transfer electrons to (Ndi1) and from (AOX) CoQ
- Without pumping protons across the membrane [9]
- Ndi1
- Substitutes complex I in yeast mitochondria [9]
- AOX
- Alternative electron transport system present in lower eukaryotes, plants and several invertebrates
- By-passes the complex III + IV segment of the respiratory chain
- AOX-expressing mice have recently been created
- Be viable and fertile models of complex III or IV deficiency [9]
- Expression of these proteins
- Is well tolerated in mammalian cells, flies and mice
- Has successfully been exploited to by-pass complex I or complex III/IV defects in human cells and Drosophila models
- Capacity of these enzymes to restore the electron flow through the quinone pool
- Preventing accumulation of reduced intermediates and oxidative damage [9]
- Not accompanied by restoration of proton translocation across the inner mitochondrial membrane
- Does not directly increase ATPproduction
- Restoration of the electron flow can reactivate the unaffected RC complexes
- Indirectly promoting
- Rebuilding of the proton gradient
- The reactivation of OXPHOS [9]
Caloric restriction
Caloric restriction
Cell division and renewal
Cell division and renewal
CO releasing molecules
CO releasing molecules
Coenzyme Q10
- mitochondrial targeted antioxidants/peptides
- Generally accepted effective therapy
- May not ultimately be effective for an individual patient [5]
Coenzyme Q10
- mitochondrial targeted antioxidants/peptides
- Generally accepted effective therapy
- May not ultimately be effective for an individual patient [5]
Cold exposure
Cold exposure
Cyclosporine A (CsA)
- Known to inhibit the PTP
- Through a cyclophilin-D dependent mechanism
- Used in patients with Bethlem/Ullrich congenital muscular dystrophy
- Allelic conditions
- Mutations in the gene encoding collagen VI
- Mitochondrial dysfunction and proneness to apoptosis in skeletal muscle documented in both syndromes
- CsA treatment for one month corrected these phenomena [9]
Cyclosporine A (CsA)
- Known to inhibit the PTP
- Through a cyclophilin-D dependent mechanism
- Used in patients with Bethlem/Ullrich congenital muscular dystrophy
- Allelic conditions
- Mutations in the gene encoding collagen VI
- Mitochondrial dysfunction and proneness to apoptosis in skeletal muscle documented in both syndromes
- CsA treatment for one month corrected these phenomena [9]
Deoxyribonucleotides
Deoxyribonucleotides
Endurance exercise
- John Holloszy in the 1960s
- Physical endurance training induced higher mitochondrial content levels
- Greater glucose uptake by muscles [7]
- Aerobic exercise [7]
- Trigger mitochondrial biogenesis
- Delay the effects of aging in mice
- Activation of:
- PGC-1alpha
- PGC-1beta
- AMPK
- P38 gamma
- MAPK
- Hypoxia inducible factors (HIFs) [9]
- Double PGC-1 alpha and -1beta knockout mice:
- Reduced respiration
- Decrease of respiratory capacity
- Effect of the system in setting OxPhos proficiency [9]
- But normal mitochondrial content and morphology
- Normal muscle fibers composition
- Normal endurance performance
- This work challenges the central role of PGC-1 proteins in regulating mitochondrial content [9]
- Irrespective of the molecular mechanism, endurance exercise has been reported as beneficial and safe in patients affected by:
- mitochondrial myopathy
- In muscle-specific Cox10 knockout mice
- In mtDNA mutator mice
- Appears to rescue progeroid aging
- Beneficial effects were not limited to skeletal muscle but also involved other organs, including the brain [9]
Endurance exercise
- John Holloszy in the 1960s
- Physical endurance training induced higher mitochondrial content levels
- Greater glucose uptake by muscles [7]
- Aerobic exercise [7]
- Trigger mitochondrial biogenesis
- Delay the effects of aging in mice
- Activation of:
- PGC-1alpha
- PGC-1beta
- AMPK
- P38 gamma
- MAPK
- Hypoxia inducible factors (HIFs) [9]
- Double PGC-1 alpha and -1beta knockout mice:
- Reduced respiration
- Decrease of respiratory capacity
- Effect of the system in setting OxPhos proficiency [9]
- But normal mitochondrial content and morphology
- Normal muscle fibers composition
- Normal endurance performance
- This work challenges the central role of PGC-1 proteins in regulating mitochondrial content [9]
- Irrespective of the molecular mechanism, endurance exercise has been reported as beneficial and safe in patients affected by:
- mitochondrial myopathy
- In muscle-specific Cox10 knockout mice
- In mtDNA mutator mice
- Appears to rescue progeroid aging
- Beneficial effects were not limited to skeletal muscle but also involved other organs, including the brain [9]
eNOS activators
- AVE compounds
eNOS activators
- AVE compounds
Erythropoietin
Erythropoietin
Fenofibrate
Fenofibrate
Folic Acid
- 1 – 10 mg a day
Folic Acid
- 1 – 10 mg a day
Small GSK-3 inhibitors
SB216763
ZLN005
Small GSK-3 inhibitors
SB216763
ZLN005
High fat diet (HFD)
- Protective effect on fibroblasts with complex I deficiency
- Effective in delaying the neurological symptoms of the Harlequin mouse, a model of partial complex I defect associated with a homozygous mutation of AIFM1,
- Encoding the mitochondrial apoptosis inducing factor [9]
High fat diet (HFD)
- Protective effect on fibroblasts with complex I deficiency
- Effective in delaying the neurological symptoms of the Harlequin mouse, a model of partial complex I defect associated with a homozygous mutation of AIFM1,
- Encoding the mitochondrial apoptosis inducing factor [9]
Imidazol[1,2-b]thiazole
Imidazol[1,2-b]thiazole
Levo-carnitine
- (Carnitor)
- Variable
- Starting dose of 30 mg/kg/day, typical maximum of 100 mg/kg/day
Levo-carnitine
- (Carnitor)
- Variable
- Starting dose of 30 mg/kg/day, typical maximum of 100 mg/kg/day
Ketogenic diet (KD)
- High-fat, low-carbohydrate diet
- Proposed to stimulate mitochondrial beta-oxidation
- Provide ketones
- Alternative energy source for the brain, heart and skeletal muscle [9]
- Ketone bodies
- Metabolized to acetyl-CoA
- Enters the Krebs cycle
- Oxidized to feed the RC
- Ultimately generate ATP via OXPHOS [9]
- Partially bypasses complex I
- Via increased synthesis of succinate
- Which donates electrons to the respiratory chain via complex II [9]
- Increased ketone bodies
- Associated with increased expression of OXPHOS genes
- Via a starvation-like response
- Stressing condition to the cell
- Activation of many transcription factors and cofactors
- Including SIRT1, AMPK, and PGC-1 alpha
- Increase mitochondrial biogenesis [9]
- KD
- Reduced the mutation load of a heteroplasmic mtDNA deletion in a cybrid cell line from a Kearns–Sayre syndrome patient
- Increase the expression levels of uncoupling proteins
- Increase mitochondrial biogenesis in the hippocampus of mice and rats
- Increased mitochondrial GSH levels in rat brain
- Could contribute to explain the anticonvulsant effects of KD [9]
- Slowed the progression of mitochondrial myopathy
- Other reports showed that KD can have the opposite effect, and worsens the mitochondrial defect invivo
- Mterf2-/-
- Mpv17–/-mouse models [9]
Ketogenic diet (KD)
- High-fat, low-carbohydrate diet
- Proposed to stimulate mitochondrial beta-oxidation
- Provide ketones
- Alternative energy source for the brain, heart and skeletal muscle [9]
- Ketone bodies
- Metabolized to acetyl-CoA
- Enters the Krebs cycle
- Oxidized to feed the RC
- Ultimately generate ATP via OXPHOS [9]
- Partially bypasses complex I
- Via increased synthesis of succinate
- Which donates electrons to the respiratory chain via complex II [9]
- Increased ketone bodies
- Associated with increased expression of OXPHOS genes
- Via a starvation-like response
- Stressing condition to the cell
- Activation of many transcription factors and cofactors
- Including SIRT1, AMPK, and PGC-1 alpha
- Increase mitochondrial biogenesis [9]
- KD
- Reduced the mutation load of a heteroplasmic mtDNA deletion in a cybrid cell line from a Kearns–Sayre syndrome patient
- Increase the expression levels of uncoupling proteins
- Increase mitochondrial biogenesis in the hippocampus of mice and rats
- Increased mitochondrial GSH levels in rat brain
- Could contribute to explain the anticonvulsant effects of KD [9]
- Slowed the progression of mitochondrial myopathy
- Other reports showed that KD can have the opposite effect, and worsens the mitochondrial defect invivo
- Mterf2-/-
- Mpv17–/-mouse models [9]
Coenzyme Q10
Coenzyme Q10
Lipoic Acid
- A -lipoate
- 60 – 200 mg; 3 times a day
Lipoic Acid
- A -lipoate
- 60 – 200 mg; 3 times a day
Manipulating mtDNA heteroplasmy
- Mutations of mtDNA are often heteroplasmic
- Behave as “recessive-like” mutations
- Eliminating or reducing the amount of mutated DNA below the threshold at which the disease manifests
- Targeting to mitochondria:
- Recombinant restriction endonucleases
- Zinc finger-endonucleases
- TALENs [9]
Mitochondrially targeted restriction enzymes
- Used in a variety of systems to induce a shift in heteroplasmy [9]
- 8399T>G NARP mutations forms a unique CCCGGG restriction site in mtDNA
- Specific to the restriction endonuclease SmaI (the wild type sequence is CCCGTG)
- A mitochondrially targeted recombinant SmaI variant
- Decrease the 8399T>G mutation load in heteroplasmic mutant cybrids
- Repopulation of cells with wild-type mtDNA
- Restoration to normal of mitochondrial membrane potential and increase of intracellular ATP levels [9]
- PstI endonuclease
- Restriction site is present in human and mouse but not rat mtDNA
- Targeted to human mitochondria
- Degraded mtDNA
- Determined a shift towards the rat haplotype in a hybrid cell line harboring both mouse and rat mtDNA
- In NZB/BalbC heteroplasmic mice in which AAV1,2 vectors expressing a mitochondrially-targeted restriction endonuclease ApaLI were injected locally into muscle or brain [9]
- Can be used therapeutically only if a unique restriction site is created by an mtDNA mutation
- Case of the 8993T>G NARP
- Exceptionally rare event [9]
- Zinc-finger nuclease
- Chimeric enzymes [9]
- MitoTALENs
- Proven to eliminate heteroplasmic mutant mtDNA in cybrid cells
- M.8483_13459del4977 common mtDNA deletion
- M.14459G>A LHON/Dystonia mutation in the MT-ND6 gene
- Transient decrease in total mtDNA levels occurred
- Repopulation with wild type mtDNA up to normal values [9]
- Mitochondrially targeted ZFNs (mtZFNs)
- Successfully used in heterolasmic cybrids to cleave mtDNA harboring
- Heteroplasmic m.8993T>G NARP mutation
- Common deletion [9]
- TALENS and restriction enzymes
- MtZFNs led to a reduction in mutant mtDNA haplotype load
- Subsequent repopulation of wild-type mtDNA
- Restoration of mitochondrial respiration [9]
Manipulating mtDNA heteroplasmy
- Mutations of mtDNA are often heteroplasmic
- Behave as “recessive-like” mutations
- Eliminating or reducing the amount of mutated DNA below the threshold at which the disease manifests
- Targeting to mitochondria:
- Recombinant restriction endonucleases
- Zinc finger-endonucleases
- TALENs [9]
Mitochondrially targeted restriction enzymes
- Used in a variety of systems to induce a shift in heteroplasmy [9]
- 8399T>G NARP mutations forms a unique CCCGGG restriction site in mtDNA
- Specific to the restriction endonuclease SmaI (the wild type sequence is CCCGTG)
- A mitochondrially targeted recombinant SmaI variant
- Decrease the 8399T>G mutation load in heteroplasmic mutant cybrids
- Repopulation of cells with wild-type mtDNA
- Restoration to normal of mitochondrial membrane potential and increase of intracellular ATP levels [9]
- PstI endonuclease
- Restriction site is present in human and mouse but not rat mtDNA
- Targeted to human mitochondria
- Degraded mtDNA
- Determined a shift towards the rat haplotype in a hybrid cell line harboring both mouse and rat mtDNA
- In NZB/BalbC heteroplasmic mice in which AAV1,2 vectors expressing a mitochondrially-targeted restriction endonuclease ApaLI were injected locally into muscle or brain [9]
- Can be used therapeutically only if a unique restriction site is created by an mtDNA mutation
- Case of the 8993T>G NARP
- Exceptionally rare event [9]
- Zinc-finger nuclease
- Chimeric enzymes [9]
- MitoTALENs
- Proven to eliminate heteroplasmic mutant mtDNA in cybrid cells
- M.8483_13459del4977 common mtDNA deletion
- M.14459G>A LHON/Dystonia mutation in the MT-ND6 gene
- Transient decrease in total mtDNA levels occurred
- Repopulation with wild type mtDNA up to normal values [9]
- Mitochondrially targeted ZFNs (mtZFNs)
- Successfully used in heterolasmic cybrids to cleave mtDNA harboring
- Heteroplasmic m.8993T>G NARP mutation
- Common deletion [9]
- TALENS and restriction enzymes
- MtZFNs led to a reduction in mutant mtDNA haplotype load
- Subsequent repopulation of wild-type mtDNA
- Restoration of mitochondrial respiration [9]
MCT oleje
Omezit tuky - dlouhé MK
Medium chain triglycerides
- In some patients, adding fat in the form of medium chain triglycerides (MCT), may be helpful.
- 8 to 10 carbons long
- Easier to metabolize (turn into energy) than the longer ( 12-18 carbons)
- Do not require carnitine to be transported into the mitochondria
- MCT Oil© is mainly made of 8 and 10 carbon triglycerides
- Does not occur in nature
- Made from coconut oil [5]
MCT oleje
Omezit tuky - dlouhé MK
Medium chain triglycerides
- In some patients, adding fat in the form of medium chain triglycerides (MCT), may be helpful.
- 8 to 10 carbons long
- Easier to metabolize (turn into energy) than the longer ( 12-18 carbons)
- Do not require carnitine to be transported into the mitochondria
- MCT Oil© is mainly made of 8 and 10 carbon triglycerides
- Does not occur in nature
- Made from coconut oil [5]
Metformin
Metformin
Methylene Blue
- Oldest of synthetic drugs even before aspirin
- Heinrich Carro manufactured it in 1876 for the German firm BASF
- Methylene blue is a simple molecule.
- Fusion of two benzene rings with one nitrogen and one sulphur atom leads to a tricyclic aromatic compound
- Complex pharmacology and multiple clinical indications.
- Stabilising effect on mitochondria
- Inhibits the replication of SARS-CoV-2136
- Reported a cohort of patients treated for cancer by Methylene Blue in cases without SARS-CoV-2
- www.tandfonline.com/doi/full/10.1080/14756366.2021.1937144
MitoQ10
MitoQ10
N-acetylcysteine (NAC)
N-acetylcysteine (NAC)
Niacin (B3)
- 50 – 100 mg a day
Niacin (B3)
- 50 – 100 mg a day
Nicotinamide riboside (NR)
- NR is a natural compound
- Part of vitamin B3 [9]
- Enriched in maternal milk [9]
- NAD+ pool can be increased by
- Diet supplementation natural precursor nicotinamide riboside (NR) [9]
- NAD+ higher pool lead to
- Activation of Sirt1 (and other sirtuins)
- Boost mitochondrial respiration
- By inducing OXPHOS genes
- Via the PGC-1? axis [9]
- Sco2KOKI mice
- Improved motor performance up to normal values
- NR was also effective in delaying the disease progression of the deletor mouse [9]
- mitochondrial myopathy due to expression of a mutant variant of Twinkle, the mtDNA helicase
- NR induced robust mitochondrial biogenesis
- Corrected abnormalities of mitochondrial ultrastructure
- Prevented the generation of multiple mtDNA rearrangements [9]
- Both studies showed that
- NR also induced the mitochondrial unfolded protein response (UPRmt)
- UPRmt is a stress response
- Activates transcription of mitochondrial chaperones to preserve protein homeostasis within the organelle
- Suggest the involvement of UPRmt in the protective effects provided by NR [9]
Nicotinamide riboside (NR)
- NR is a natural compound
- Part of vitamin B3 [9]
- Enriched in maternal milk [9]
- NAD+ pool can be increased by
- Diet supplementation natural precursor nicotinamide riboside (NR) [9]
- NAD+ higher pool lead to
- Activation of Sirt1 (and other sirtuins)
- Boost mitochondrial respiration
- By inducing OXPHOS genes
- Via the PGC-1? axis [9]
- Sco2KOKI mice
- Improved motor performance up to normal values
- NR was also effective in delaying the disease progression of the deletor mouse [9]
- mitochondrial myopathy due to expression of a mutant variant of Twinkle, the mtDNA helicase
- NR induced robust mitochondrial biogenesis
- Corrected abnormalities of mitochondrial ultrastructure
- Prevented the generation of multiple mtDNA rearrangements [9]
- Both studies showed that
- NR also induced the mitochondrial unfolded protein response (UPRmt)
- UPRmt is a stress response
- Activates transcription of mitochondrial chaperones to preserve protein homeostasis within the organelle
- Suggest the involvement of UPRmt in the protective effects provided by NR [9]
NO donors
NO donors
Stabilizing mutant mt-tRNA
- More than 50% of the mtDNA mutations are localized in tRNA genes
- Wide range of syndromes
- MELAS or MERRF [9]
- Aminoacyl-tRNA synthetases (aaRSs)
- Ubiquitously expressed
- Essential enzymes performing the attachment of amino acids to their cognate tRNA molecules
- First step of protein synthesis
- Overexpressing cognate mt-aaRS
- Can attenuate the detrimental effects of mt-tRNA point mutations [9]
- Overexpression of mt-leucyl-tRNA synthetase (mt-LeuRS)
- Corrects the respiratory chain deficiency of transmitochondrial cybrids harboring the MELAS mutation in the mt-tRNALeu(UUR) gene (MTTL1) [9]
- Overexpressing the cognate mt-valyl-tRNA synthetase (mt-ValRS)
- Restored, at least in part, steady-state levels of mutated mt-tRNAVal in cybrid cell lines [9]
- Constitutive high levels of mt-isoleucyl-tRNA synthetase (mt-IleRS)
- Associated with reduced penetrance of the homoplasmic m.4277T>C mt-tRNAIle mutation
- Hypertrophic cardiomyopathy [9]
- Overexpression of either human mt-LeuRS or mt-ValRS
- Able of rescuing the pathological phenotype associated with mutations in both the cognate and the non-cognate mt-tRNA
- Carboxy-terminal domain of mt-LeuRS
- Necessary and sufficient to determine this phenomenon
- Probably via a chaperone-like stabilizing effect [9]
- TRNA mutations in mtDNA
- May in principle be complemented by expressing a xenotopic nDNA-encoded yeast mitochondrial tRNA from the mammalian nucleus
- Attempted for the treatment of human cells harboring the tRNALys nucleotide 8344A>G mutation using the yeast tRNALys nDNA gene
- Partially restored the mitochondrial dysfunction associated with the mitochondrial protein-synthesis defect [9]
- Leishmania mitochondrial RNA import complex
- Exploited to introduce the human cytosolic tRNALys into human cybrids harboring the tRNALys 8344A>G mtDNA mutation by a caveolin-1-dependent pathway,
- Significant restoration of mitochondrial function [9]
Stabilizing mutant mt-tRNA
- More than 50% of the mtDNA mutations are localized in tRNA genes
- Wide range of syndromes
- MELAS or MERRF [9]
- Aminoacyl-tRNA synthetases (aaRSs)
- Ubiquitously expressed
- Essential enzymes performing the attachment of amino acids to their cognate tRNA molecules
- First step of protein synthesis
- Overexpressing cognate mt-aaRS
- Can attenuate the detrimental effects of mt-tRNA point mutations [9]
- Overexpression of mt-leucyl-tRNA synthetase (mt-LeuRS)
- Corrects the respiratory chain deficiency of transmitochondrial cybrids harboring the MELAS mutation in the mt-tRNALeu(UUR) gene (MTTL1) [9]
- Overexpressing the cognate mt-valyl-tRNA synthetase (mt-ValRS)
- Restored, at least in part, steady-state levels of mutated mt-tRNAVal in cybrid cell lines [9]
- Constitutive high levels of mt-isoleucyl-tRNA synthetase (mt-IleRS)
- Associated with reduced penetrance of the homoplasmic m.4277T>C mt-tRNAIle mutation
- Hypertrophic cardiomyopathy [9]
- Overexpression of either human mt-LeuRS or mt-ValRS
- Able of rescuing the pathological phenotype associated with mutations in both the cognate and the non-cognate mt-tRNA
- Carboxy-terminal domain of mt-LeuRS
- Necessary and sufficient to determine this phenomenon
- Probably via a chaperone-like stabilizing effect [9]
- TRNA mutations in mtDNA
- May in principle be complemented by expressing a xenotopic nDNA-encoded yeast mitochondrial tRNA from the mammalian nucleus
- Attempted for the treatment of human cells harboring the tRNALys nucleotide 8344A>G mutation using the yeast tRNALys nDNA gene
- Partially restored the mitochondrial dysfunction associated with the mitochondrial protein-synthesis defect [9]
- Leishmania mitochondrial RNA import complex
- Exploited to introduce the human cytosolic tRNALys into human cybrids harboring the tRNALys 8344A>G mtDNA mutation by a caveolin-1-dependent pathway,
- Significant restoration of mitochondrial function [9]
Oxazolo[4,4-b]pyridine
Oxazolo[4,4-b]pyridine
PARP-inhibitors
- Partially improved COX deficiency also in the brain
- Raising the possibility for their use to target neurological defects [9]
- Several PARPis are currently under clinical trial as anticancer therapeutic agents [9]
- Potential mutagenic effects of PARPis in non-cancer patients
- Still to be adequately investigated
- Suggest limited genomic toxicity:
- Long-term study in mouse models of diet-induced obesity [9]
- Patients treated with Olaparib (AZD-2281) [9]
PARP-inhibitors
- Partially improved COX deficiency also in the brain
- Raising the possibility for their use to target neurological defects [9]
- Several PARPis are currently under clinical trial as anticancer therapeutic agents [9]
- Potential mutagenic effects of PARPis in non-cancer patients
- Still to be adequately investigated
- Suggest limited genomic toxicity:
- Long-term study in mouse models of diet-induced obesity [9]
- Patients treated with Olaparib (AZD-2281) [9]
Pioglitazone
Pioglitazone
Sodium pyruvate
Sodium pyruvate
Rapamycin
- Chronic treatment with rapamycin
- Activates autophagy
- Significantly delayed
- Disease progression and fatal outcome of a Ndufs4-/-mouse
- Lacks the 18 kDa Ndufs4 subunit of complex I [9]
Rapamycin
- Chronic treatment with rapamycin
- Activates autophagy
- Significantly delayed
- Disease progression and fatal outcome of a Ndufs4-/-mouse
- Lacks the 18 kDa Ndufs4 subunit of complex I [9]
Resveratrol (RSV)
- Activation of AMPK [6]
- Reported to trigger mitochondrial biogenesis in several animal models
- Caenorhabditis elegans
- Drosophila melanogaster
- Mus musculus
- Idea that RSV operates via direct activation of Sirt1 has been recently challenged by showing that in fact RSV inhibits phosphodiesterase IV
- Consequent raise in cAMP levels
- Triggers a Ca2 +–calmodulin–kinase–kinase–beta signaling pathway
- Activation of AMPK [9]
- Some evidence that RSV can correct complex I and IV defects in human fibroblasts
- Via Sirt1- and AMPK-independent mechanisms involve:
- RSV and metformin
- Both stabilize mitochondrial respiratory chain supercomplexes
- Without increasing mitochondrial protein content in cells [9]
Resveratrol (RSV)
- Activation of AMPK [6]
- Reported to trigger mitochondrial biogenesis in several animal models
- Caenorhabditis elegans
- Drosophila melanogaster
- Mus musculus
- Idea that RSV operates via direct activation of Sirt1 has been recently challenged by showing that in fact RSV inhibits phosphodiesterase IV
- Consequent raise in cAMP levels
- Triggers a Ca2 +–calmodulin–kinase–kinase–beta signaling pathway
- Activation of AMPK [9]
- Some evidence that RSV can correct complex I and IV defects in human fibroblasts
- Via Sirt1- and AMPK-independent mechanisms involve:
- RSV and metformin
- Both stabilize mitochondrial respiratory chain supercomplexes
- Without increasing mitochondrial protein content in cells [9]
Retinoic acid
- Stimulace retinoid X receptor-alpha (RXRalpha)
- Correct the OXPHOS defects in cybrid cells containing different loads of the 3243A>G MELAS mutation
- Possibly by increasing the RXRA–PGC-1alpha interaction [9]
Retinoic acid
- Stimulace retinoid X receptor-alpha (RXRalpha)
- Correct the OXPHOS defects in cybrid cells containing different loads of the 3243A>G MELAS mutation
- Possibly by increasing the RXRA–PGC-1alpha interaction [9]
Riboflavin (B2)
- 100 – 400 mg a day
Riboflavin (B2)
- 100 – 400 mg a day
Rosiglitazone
Rosiglitazone
Selenium
- 25 – 50 micrograms a day
Selenium
- 25 – 50 micrograms a day
Sirt1 agonists
Quercetin
Resveratrol
Sirt1 agonists
Quercetin
Resveratrol
Somatic nuclear transfer
- Prenatal or pre-implantation genetic diagnosis
- Nowadays the best option available to women carrying pathogenic mtDNA mutations
- Can only be applied to subjects with low levels of mtDNA mutations in oocytes
- Technically challenging
- Way to replace the mutated maternal mtDNA with that obtained from a healthy woman
- Transferring either the spindle-chromosomal complex of mature oocytes or pronuclei during the pre-zygotic stage of fertilized egg
- In order to minimize the amount of mutant mtDNA carried over into the recipient ooplasm
- Child born by these procedures will carry the nuclear genes of the affected mother (and healthy father) but the healthy mitochondrial genes of the donor [9]
Somatic nuclear transfer
- Prenatal or pre-implantation genetic diagnosis
- Nowadays the best option available to women carrying pathogenic mtDNA mutations
- Can only be applied to subjects with low levels of mtDNA mutations in oocytes
- Technically challenging
- Way to replace the mutated maternal mtDNA with that obtained from a healthy woman
- Transferring either the spindle-chromosomal complex of mature oocytes or pronuclei during the pre-zygotic stage of fertilized egg
- In order to minimize the amount of mutant mtDNA carried over into the recipient ooplasm
- Child born by these procedures will carry the nuclear genes of the affected mother (and healthy father) but the healthy mitochondrial genes of the donor [9]
SRT1460
SRT1460
SRT1720
SRT1720
SRT2183
SRT2183
Thiamine (B1)
- 50 – 100 mg a day
Thiamine (B1)
- 50 – 100 mg a day
Triheptaoin
- Other compounds that release succinate in mitochondria (similar to ketogenic and high fat diet)
- Anaplerotic compound
- Inducing a rapid increase of plasmatic C4- and C5-ketone bodies
- C5 bodies is precursor of propionyl-CoA
- Converted into succinyl-CoA
- Dramatically improve cardiomyopathy in patients with VLCAD deficiency and myopathic symptoms in CPT2 deficiency patients [9]
Triheptaoin
- Other compounds that release succinate in mitochondria (similar to ketogenic and high fat diet)
- Anaplerotic compound
- Inducing a rapid increase of plasmatic C4- and C5-ketone bodies
- C5 bodies is precursor of propionyl-CoA
- Converted into succinyl-CoA
- Dramatically improve cardiomyopathy in patients with VLCAD deficiency and myopathic symptoms in CPT2 deficiency patients [9]
Triterpenoids
Triterpenoids
Vitamin B
Vitamin B
Vitamin C
- 100 – 500 mg; 1 – 3 times a day
Vitamin C
- 100 – 500 mg; 1 – 3 times a day
Vitamin E
- 200 – 400 IU; 1 – 3 times a day
Vitamin E
- 200 – 400 IU; 1 – 3 times a day
