RARE DISEASE
Mitochondrial DNA-associated Leigh syndrome
Mitochondrial DNA-associated Leigh syndrome
Mitochondrial DNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is a maternally inherited neurodegenerative disorder caused by mtDNA mutations impairing oxidative phosphorylation. Typically presenting at 3-12 months after metabolic stressors, it features developmental regression, hypotonia, seizures, brainstem dysfunction (respiratory failure, dysphagia), and extraneurologic manifestations like cardiomyopathy. Diagnosis relies on clinical criteria, neuroimaging showing basal ganglia/brainstem lesions, and mtDNA variant identification. Prognosis is poor, with 50% mortality by age 3 and progressive multisystem decline [1][6][11].
Burden
Median survival: 3 years for early-onset; up to early 20s for later-onset forms [2][4]
42% develop severe functional impairment (mobility, feeding, communication) within 3 years [4][16]
High healthcare utilization: 85% require multidisciplinary care, 62% need gastrostomy, 33% develop cardiomyopathy [4][16]
Therapies
Supportive care: Sodium bicarbonate for acidosis, antiseizure medications, baclofen/dystonia management, respiratory support [1][8]
Metabolic support: Vitamin cocktails (CoQ10, thiamine), ketogenic diet for PDH deficiency [2][8]
Emerging therapies: EPI-743 (redox modulator), L-arginine for stroke-like episodes, gene-specific trials (e.g., MT-ATP6) [3][8][13]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
38 drug discovery papers about Mitochondrial DNA-associated Leigh syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
38 drug discovery papers about Mitochondrial DNA-associated Leigh syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-04-01 | Exploring of Recent pharmaceutical applications of Sildenafil in medicine: review article
Sildenafil (SIL), a phosphodiesterase enzyme 5 (PDE5) inhibitor, has become a prominent molecule for the erectile dysfunction (ED) treatment. It has assumed a major role in the treatment of this disease due to the demonstrated efficacy, ease of use, good tolerability, and positive impact on the quality of life of patients. SIL has multiple pharmacological actions that grasp the researchers’ attention due to its various pharmaceutical applications. In addition to its efficacy in treating erectile dysfunction (ED), SIL is extensively employed in the treatment of intrauterine growth retardation (IUGR), benign prostatic hypertrophy (BPH), Eisenmenger's syndrome and Mountain sickness, kidney diseases, pulmonary arterial hypertension. Furthermore, SIL also exhibits promise antiproliferative, anti-Alzheimer, and anti-inflammatory properties. Finally, the pharmacodynamics, pharmacokinetics, drug interactions, and SIL toxicity were investigated. The adequate pharmacokinetic properties of SIL and the diverse therapeutic applications have encouraged researchers to generate new applications that have either been approved by the FDA or are currently undergoing clinical trials like osteoarthritis (OA), COVID-19, female urinary incontinence (UI) and Maternally Inherited Leigh syndrome (MILS).
2020-03-10 | Downregulation of respiratory complex I mediates major signalling changes triggered by TOR activation
Mitochondrial dysfunctions belong amongst the most common metabolic diseases but the signalling networks that lead to the manifestation of a disease phenotype are often not well understood. We identified the subunits of respiratory complex I, III and IV as mediators of major signalling changes during Drosophila wing disc development. Their downregulation in larval wing disc leads to robust stimulation of TOR activity, which in turn orchestrates a complex downstream signalling network. Specifically, after downregulation of the complex I subunit ND-49 (mammalian NDUFS2), TOR activates JNK to induce cell death and ROS production essential for the stimulation of compensatory apoptosis-induced proliferation within the tissue. Additionally, TOR upregulates Notch and JAK/STAT signalling and it directs glycolytic switch of the target tissue. Our results highlight the central role of TOR signalling in mediating the complex response to mitochondrial respiratory dysfunction and they provide a rationale why the disease symptoms associated with respiratory dysfunctions are often alleviated by mTOR inhibitors.
2019-08-06 | Exploring mTOR inhibition as treatment for mitochondrial disease
Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.
2019-07-04 | Deregulating mitochondrial metabolite and ion transport has beneficial effects in yeast and human cellular models for NARP syndrome
Abstract The m.8993T>G mutation of the mitochondrial MT-ATP6 gene has been associated with numerous cases of neuropathy, ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome, which are diseases known to result from abnormalities affecting mitochondrial energy transduction. We previously reported that an equivalent point mutation severely compromised proton transport through the ATP synthase membrane domain (FO) in Saccharomyces cerevisiae and reduced the content of cytochrome c oxidase (Complex IV or COX) by 80%. Herein, we report that overexpression of the mitochondrial oxodicarboxylate carrier (Odc1p) considerably increases Complex IV abundance and tricarboxylic acid-mediated substrate-level phosphorylation of ADP coupled to conversion of α-ketoglutarate into succinate in m.8993T>G yeast. Consistently in m.8993T>G yeast cells, the retrograde signaling pathway was found to be strongly induced in order to preserve α-ketoglutarate production; when Odc1p was overexpressed, this stress pathway returned to an almost basal activity. Similar beneficial effects were induced by a partial uncoupling of the mitochondrial membrane with the proton ionophore, cyanide m-chlorophenyl hydrazone. This chemical considerably improved the glutamine-based, respiration-dependent growth of human cytoplasmic hybrid cells that are homoplasmic for the m.8993T>G mutation. These findings shed light on the interdependence between ATP synthase and Complex IV biogenesis, which could lay the groundwork for the creation of nutritional or metabolic interventions for attenuating the effects of mtDNA mutations.
gene therapies
2025-01-23 | Precise modelling of mitochondrial diseases using optimized mitoBEs.
The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
2023-10-30 | Beware of Leigh Syndrome Pedigrees with MT-ATP6 Mutation Whose Primary Diagnosis is Retinitis Pigmentosa
purpose:Maternally Inherited Leigh Syndrome (MILS) is a group of systemic diseases caused by defects in mitochondrial oxidative phosphorylation (OXPHOS). We aim to investigate the clinical and genetic characteristics of MILSpedigree with MT-ATP6 mutation who were first diagnosed with RP.Methods:This study included a family pedigree consisting of a proband with visual blurring symptoms, his mother with similar symptoms, and a father who was asymptomatic. The medical history was asked, and the best corrected visual acuity (BCVA), intraocular pressure, slit-lamp, wide-field fundus photography, optical coherence tomography (OCT), visual evoked potential (VEP) and whole exome sequencing were performed. In addition, brain Magnetic Resonance Imaging (MRI) and physical examination were performed for the mother and child.Results:Whole exon sequencing showed that the proband carried mitochondrial MT-ATP6 gene mutation. The proband's mother carried an 8993T>G heterozygous mutation, with a heterozygous mutation load of 86%, which was inherited from the proband's mother (heterozygous mutation load of 62%). This gene is the primary pathogenic gene of MILS. The patient was diagnosed with MILS after a complete physical examination and imaging examination.Conclusions:This study suggests that RP can be the cause of the first visit of MILS patients. Therefore, ophthalmologists should be alert to MILS when they find patients with clinical symptoms of the nervous system in the face of RP patients. MT-ATP6 mutation is one of the causes of RP, and its pathogenic mechanism has not been clearly explained. In the future, the research and intervention of MT-ATP6 mutation may provide a new direction for the diagnosis and treatment of MILS-related RP.
2023-01-03 | Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome.
Mitochondrial DNA (mtDNA)-associated Leigh syndrome is influenced by mutant pathogenicity and corresponding heteroplasmic loads; however, the manner in which heteroplasmic mutant load affects patient phenotypes and the relationship between mutant types and heteroplasmic mutant loads remain unknown. We aimed to investigate the distribution of the mutant load of different mtDNA mutations in a single-center cohort. We used next-generation sequencing to confirm mtDNA mutations in 31 patients with Leigh syndrome. Subsequently, we counted the number of mtDNA reads to quantitatively analyze the heteroplasmic mutant load and categorize the patients according to the mtDNA mutations they harbored. Confirmed cases of mtDNA-associated Leigh syndrome were classified according to the mutations observed in six genes and 10 nucleotides. Of the 31 patients with Leigh syndrome, 27 harbored known pathogenic mutations. We discovered that MT-ATP6 was the most commonly mutated gene (n = 13 patients), followed by MT-ND3 (n = 7) and MT-ND5 (n = 4). MT-ATP6 had a significantly higher mutant load than MT-ND3 and MT-ND5 (P < 0.001, each). By contrast, MT-ND5 had a significantly lower mutant load than MT-ND3 (P = 0.007). Notably, the mutation loads varied significantly among patients carrying the MT-ATP6, MT-ND3, and MT-ND5 mutations. Our study illustrated the heteroplasmic diversity and phenotypic expression threshold of mutated mitochondrial genes in mtDNA-associated Leigh syndrome. The results provide promising insights into the genotype-phenotype correlation in mtDNA-associated Leigh syndrome that are expected to guide the development of tailored treatments for Leigh syndrome.
2018-08-28 | Delivery of mtZFNs into Early Mouse Embryos
Mitochondrial diseases often result from mutations in the mitochondrial genome (mtDNA). In most cases, mutant mtDNA coexists with wild-type mtDNA, resulting in heteroplasmy. One potential future approach to treat heteroplasmic mtDNA diseases is the specific elimination of pathogenic mtDNA mutations, lowering the level of mutant mtDNA below pathogenic thresholds. Mitochondrially targeted zinc-finger nucleases (mtZFNs) have been demonstrated to specifically target and introduce double-strand breaks in mutant mtDNA, facilitating substantial shifts in heteroplasmy. One application of mtZFN technology, in the context of heteroplasmic mtDNA disease, is delivery into the heteroplasmic oocyte or early embryo to eliminate mutant mtDNA, preventing transmission of mitochondrial diseases through the germline. Here we describe a protocol for efficient production of mtZFN mRNA in vitro, and delivery of these into 0.5 dpc mouse embryos to elicit shifts of mtDNA heteroplasmy.
2016-09-04 | Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant.
We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, we report the stable allotopic expression, import and function of two mitochondria encoded genes, ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.
small molecules
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-04-01 | Exploring of Recent pharmaceutical applications of Sildenafil in medicine: review article
Sildenafil (SIL), a phosphodiesterase enzyme 5 (PDE5) inhibitor, has become a prominent molecule for the erectile dysfunction (ED) treatment. It has assumed a major role in the treatment of this disease due to the demonstrated efficacy, ease of use, good tolerability, and positive impact on the quality of life of patients. SIL has multiple pharmacological actions that grasp the researchers’ attention due to its various pharmaceutical applications. In addition to its efficacy in treating erectile dysfunction (ED), SIL is extensively employed in the treatment of intrauterine growth retardation (IUGR), benign prostatic hypertrophy (BPH), Eisenmenger's syndrome and Mountain sickness, kidney diseases, pulmonary arterial hypertension. Furthermore, SIL also exhibits promise antiproliferative, anti-Alzheimer, and anti-inflammatory properties. Finally, the pharmacodynamics, pharmacokinetics, drug interactions, and SIL toxicity were investigated. The adequate pharmacokinetic properties of SIL and the diverse therapeutic applications have encouraged researchers to generate new applications that have either been approved by the FDA or are currently undergoing clinical trials like osteoarthritis (OA), COVID-19, female urinary incontinence (UI) and Maternally Inherited Leigh syndrome (MILS).
2020-03-10 | Downregulation of respiratory complex I mediates major signalling changes triggered by TOR activation
Mitochondrial dysfunctions belong amongst the most common metabolic diseases but the signalling networks that lead to the manifestation of a disease phenotype are often not well understood. We identified the subunits of respiratory complex I, III and IV as mediators of major signalling changes during Drosophila wing disc development. Their downregulation in larval wing disc leads to robust stimulation of TOR activity, which in turn orchestrates a complex downstream signalling network. Specifically, after downregulation of the complex I subunit ND-49 (mammalian NDUFS2), TOR activates JNK to induce cell death and ROS production essential for the stimulation of compensatory apoptosis-induced proliferation within the tissue. Additionally, TOR upregulates Notch and JAK/STAT signalling and it directs glycolytic switch of the target tissue. Our results highlight the central role of TOR signalling in mediating the complex response to mitochondrial respiratory dysfunction and they provide a rationale why the disease symptoms associated with respiratory dysfunctions are often alleviated by mTOR inhibitors.
2019-08-06 | Exploring mTOR inhibition as treatment for mitochondrial disease
Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.
2019-07-04 | Deregulating mitochondrial metabolite and ion transport has beneficial effects in yeast and human cellular models for NARP syndrome
Abstract The m.8993T>G mutation of the mitochondrial MT-ATP6 gene has been associated with numerous cases of neuropathy, ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome, which are diseases known to result from abnormalities affecting mitochondrial energy transduction. We previously reported that an equivalent point mutation severely compromised proton transport through the ATP synthase membrane domain (FO) in Saccharomyces cerevisiae and reduced the content of cytochrome c oxidase (Complex IV or COX) by 80%. Herein, we report that overexpression of the mitochondrial oxodicarboxylate carrier (Odc1p) considerably increases Complex IV abundance and tricarboxylic acid-mediated substrate-level phosphorylation of ADP coupled to conversion of α-ketoglutarate into succinate in m.8993T>G yeast. Consistently in m.8993T>G yeast cells, the retrograde signaling pathway was found to be strongly induced in order to preserve α-ketoglutarate production; when Odc1p was overexpressed, this stress pathway returned to an almost basal activity. Similar beneficial effects were induced by a partial uncoupling of the mitochondrial membrane with the proton ionophore, cyanide m-chlorophenyl hydrazone. This chemical considerably improved the glutamine-based, respiration-dependent growth of human cytoplasmic hybrid cells that are homoplasmic for the m.8993T>G mutation. These findings shed light on the interdependence between ATP synthase and Complex IV biogenesis, which could lay the groundwork for the creation of nutritional or metabolic interventions for attenuating the effects of mtDNA mutations.
gene therapies
2025-01-23 | Precise modelling of mitochondrial diseases using optimized mitoBEs.
The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
2023-10-30 | Beware of Leigh Syndrome Pedigrees with MT-ATP6 Mutation Whose Primary Diagnosis is Retinitis Pigmentosa
purpose:Maternally Inherited Leigh Syndrome (MILS) is a group of systemic diseases caused by defects in mitochondrial oxidative phosphorylation (OXPHOS). We aim to investigate the clinical and genetic characteristics of MILSpedigree with MT-ATP6 mutation who were first diagnosed with RP.Methods:This study included a family pedigree consisting of a proband with visual blurring symptoms, his mother with similar symptoms, and a father who was asymptomatic. The medical history was asked, and the best corrected visual acuity (BCVA), intraocular pressure, slit-lamp, wide-field fundus photography, optical coherence tomography (OCT), visual evoked potential (VEP) and whole exome sequencing were performed. In addition, brain Magnetic Resonance Imaging (MRI) and physical examination were performed for the mother and child.Results:Whole exon sequencing showed that the proband carried mitochondrial MT-ATP6 gene mutation. The proband's mother carried an 8993T>G heterozygous mutation, with a heterozygous mutation load of 86%, which was inherited from the proband's mother (heterozygous mutation load of 62%). This gene is the primary pathogenic gene of MILS. The patient was diagnosed with MILS after a complete physical examination and imaging examination.Conclusions:This study suggests that RP can be the cause of the first visit of MILS patients. Therefore, ophthalmologists should be alert to MILS when they find patients with clinical symptoms of the nervous system in the face of RP patients. MT-ATP6 mutation is one of the causes of RP, and its pathogenic mechanism has not been clearly explained. In the future, the research and intervention of MT-ATP6 mutation may provide a new direction for the diagnosis and treatment of MILS-related RP.
2023-01-03 | Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome.
Mitochondrial DNA (mtDNA)-associated Leigh syndrome is influenced by mutant pathogenicity and corresponding heteroplasmic loads; however, the manner in which heteroplasmic mutant load affects patient phenotypes and the relationship between mutant types and heteroplasmic mutant loads remain unknown. We aimed to investigate the distribution of the mutant load of different mtDNA mutations in a single-center cohort. We used next-generation sequencing to confirm mtDNA mutations in 31 patients with Leigh syndrome. Subsequently, we counted the number of mtDNA reads to quantitatively analyze the heteroplasmic mutant load and categorize the patients according to the mtDNA mutations they harbored. Confirmed cases of mtDNA-associated Leigh syndrome were classified according to the mutations observed in six genes and 10 nucleotides. Of the 31 patients with Leigh syndrome, 27 harbored known pathogenic mutations. We discovered that MT-ATP6 was the most commonly mutated gene (n = 13 patients), followed by MT-ND3 (n = 7) and MT-ND5 (n = 4). MT-ATP6 had a significantly higher mutant load than MT-ND3 and MT-ND5 (P < 0.001, each). By contrast, MT-ND5 had a significantly lower mutant load than MT-ND3 (P = 0.007). Notably, the mutation loads varied significantly among patients carrying the MT-ATP6, MT-ND3, and MT-ND5 mutations. Our study illustrated the heteroplasmic diversity and phenotypic expression threshold of mutated mitochondrial genes in mtDNA-associated Leigh syndrome. The results provide promising insights into the genotype-phenotype correlation in mtDNA-associated Leigh syndrome that are expected to guide the development of tailored treatments for Leigh syndrome.
2018-08-28 | Delivery of mtZFNs into Early Mouse Embryos
Mitochondrial diseases often result from mutations in the mitochondrial genome (mtDNA). In most cases, mutant mtDNA coexists with wild-type mtDNA, resulting in heteroplasmy. One potential future approach to treat heteroplasmic mtDNA diseases is the specific elimination of pathogenic mtDNA mutations, lowering the level of mutant mtDNA below pathogenic thresholds. Mitochondrially targeted zinc-finger nucleases (mtZFNs) have been demonstrated to specifically target and introduce double-strand breaks in mutant mtDNA, facilitating substantial shifts in heteroplasmy. One application of mtZFN technology, in the context of heteroplasmic mtDNA disease, is delivery into the heteroplasmic oocyte or early embryo to eliminate mutant mtDNA, preventing transmission of mitochondrial diseases through the germline. Here we describe a protocol for efficient production of mtZFN mRNA in vitro, and delivery of these into 0.5 dpc mouse embryos to elicit shifts of mtDNA heteroplasmy.
2016-09-04 | Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant.
We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, we report the stable allotopic expression, import and function of two mitochondria encoded genes, ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.
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