RARE DISEASE
Mitochondrial disease
Mitochondrial disease
Mitochondrial disease
Drug discovery
5
drugs
With orphan designations
Overview
Mitochondrial diseases are inherited disorders of oxidative phosphorylation caused by mutations in nuclear or mitochondrial DNA, leading to cellular energy deficits. They manifest with multisystem involvement, predominantly affecting high-energy-demand organs (brain, heart, muscles) and presenting with symptoms ranging from myopathy to metabolic strokes, seizures, and organ failure [1][5][9].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
3,097 drug discovery papers about Mitochondrial disease, with 8 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,097 drug discovery papers about Mitochondrial disease, with 8 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Case Report: Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease
We present a case of a 21-year-old adult female with a history of chronic focal epilepsy and a learning disability presumed to be secondary to a traumatic brain injury due to shaken baby syndrome. She had a previous admission to a district general hospital with refractory status epilepticus precipitated by an infection, which was complicated by an apparent thalamic infarct. On this occasion she presented with super-refractory status epilepticus precipitated by a chest infection. Seizure control required use of multiple anaesthetic agents combined with six anti-epileptic drugs. Multiple refractory status presentations precipitated by infection, imaging and EEG findings raised the suspicion of mitochondrial disease. Urgent genetic testing was undertaken which revealed a homozygous Polymerase g ( POLG ) pathogenic variant, not known previously, consistent with a diagnosis of a POLG -related mitochondrial disorder. Antiepileptic therapy was optimized while avoiding hepatotoxic agents, resulting in substantially improved seizure control. This case highlights the importance of considering POLG variants as a cause of chronic focal-onset epilepsy, with refractory and super-refractory epilepsy presentations, even when there are apparent alternative explanations for seizures. Characteristic EEG and imaging findings involving posterior brain regions should further raise suspicion of POLG -related mitochondrial disease. This case also underlines the utility of rapid genetic testing in unwell adults, not only for diagnosis, but to guide anti-epileptic therapy and prognosis in patients with refractory and super-refractory status epilepticus.
2026-08-05 | Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined. Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis. POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I-V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs. These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.
2026-08-04 | A young male with kidney damage from genetic mitochondrial disease: case report and literature review
The most familiar ear and kidney syndrome is Alport syndrome for a nephrologist. Mutations in the mitochondrial gene MT-TL1 , which encodes UUR, can also cause renal dysfunction and hearing loss. In this study, we reported a young Chinese male presented with proteinuria and renal dysfunction with a morphological presentation of focal segmental glomerulosclerosis (FSGS) with m.3243 A > G mutation in the mitochondria in the mitochondrial gene MT-TL1 . We conducted a systematic literature review to summarize previously reported cases. A 17-year-old male was admitted to our hospital due to foamy urine that had persisted for three months after an upper respiratory tract infection. He also complained of weakness in both lower extremities, particularly the calves. He had progressive hearing loss and body hair growth in the last two years.His urinalysis revealed 2 + proteinuria and 24-hour urine protein of 0.85 g.His blood tests revealed increased serum creatinine of 2.1 mg/dl, blood urea nitrogen of 36.1 mg/dl, and uric acid of 12.5 mg/dl. His fasting blood glucose was within the normal range of 99 mg/dl. Renal biopsy pathology revealed changes consistent with FSGS.High-power microscopy demonstrated swollen podocytes and an increased number of dysmorphic mitochondria within renal tubular epithelial cells. Consequently, whole-exome sequencing was performed, confirming that both the patient and her mother harbor the m.3243 A > G mutation in the mitochondrial MT-TL1 gene.We provide patients with treatments to improve mitochondrial energy synthesis, reduce creatinine production, promote creatinine excretion, and lower uric acid levels.After a 23-month follow-up, renal function remained stable. The UUR gene is an important tRNA gene in mtDNA. Its mutation can lead to mitochondrial dysfunction and cause a variety of diseases.The family history of patients with concurrent ear and renal diseases should be assessed in detail.
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Case Report: Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease
We present a case of a 21-year-old adult female with a history of chronic focal epilepsy and a learning disability presumed to be secondary to a traumatic brain injury due to shaken baby syndrome. She had a previous admission to a district general hospital with refractory status epilepticus precipitated by an infection, which was complicated by an apparent thalamic infarct. On this occasion she presented with super-refractory status epilepticus precipitated by a chest infection. Seizure control required use of multiple anaesthetic agents combined with six anti-epileptic drugs. Multiple refractory status presentations precipitated by infection, imaging and EEG findings raised the suspicion of mitochondrial disease. Urgent genetic testing was undertaken which revealed a homozygous Polymerase g ( POLG ) pathogenic variant, not known previously, consistent with a diagnosis of a POLG -related mitochondrial disorder. Antiepileptic therapy was optimized while avoiding hepatotoxic agents, resulting in substantially improved seizure control. This case highlights the importance of considering POLG variants as a cause of chronic focal-onset epilepsy, with refractory and super-refractory epilepsy presentations, even when there are apparent alternative explanations for seizures. Characteristic EEG and imaging findings involving posterior brain regions should further raise suspicion of POLG -related mitochondrial disease. This case also underlines the utility of rapid genetic testing in unwell adults, not only for diagnosis, but to guide anti-epileptic therapy and prognosis in patients with refractory and super-refractory status epilepticus.
2026-08-05 | Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined. Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis. POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I-V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs. These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.
2026-08-04 | A young male with kidney damage from genetic mitochondrial disease: case report and literature review
The most familiar ear and kidney syndrome is Alport syndrome for a nephrologist. Mutations in the mitochondrial gene MT-TL1 , which encodes UUR, can also cause renal dysfunction and hearing loss. In this study, we reported a young Chinese male presented with proteinuria and renal dysfunction with a morphological presentation of focal segmental glomerulosclerosis (FSGS) with m.3243 A > G mutation in the mitochondria in the mitochondrial gene MT-TL1 . We conducted a systematic literature review to summarize previously reported cases. A 17-year-old male was admitted to our hospital due to foamy urine that had persisted for three months after an upper respiratory tract infection. He also complained of weakness in both lower extremities, particularly the calves. He had progressive hearing loss and body hair growth in the last two years.His urinalysis revealed 2 + proteinuria and 24-hour urine protein of 0.85 g.His blood tests revealed increased serum creatinine of 2.1 mg/dl, blood urea nitrogen of 36.1 mg/dl, and uric acid of 12.5 mg/dl. His fasting blood glucose was within the normal range of 99 mg/dl. Renal biopsy pathology revealed changes consistent with FSGS.High-power microscopy demonstrated swollen podocytes and an increased number of dysmorphic mitochondria within renal tubular epithelial cells. Consequently, whole-exome sequencing was performed, confirming that both the patient and her mother harbor the m.3243 A > G mutation in the mitochondrial MT-TL1 gene.We provide patients with treatments to improve mitochondrial energy synthesis, reduce creatinine production, promote creatinine excretion, and lower uric acid levels.After a 23-month follow-up, renal function remained stable. The UUR gene is an important tRNA gene in mtDNA. Its mutation can lead to mitochondrial dysfunction and cause a variety of diseases.The family history of patients with concurrent ear and renal diseases should be assessed in detail.
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Drug Discovery Landscape
5 orphan drug designations for Mitochondrial disease.
5 orphan drug designations for Mitochondrial disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Methyl 4-{[2-(acetamino)ethyl]sulfanyl}-4-oxobutanoate | small molecules | FDA | 2023-04-14 | — | Pharming Technologies BV |
zagociguat | small molecules | FDA | 2023-03-23 | — | Tisento Therapeutics, Inc. |
vatiquinone | small molecules | FDA | 2020-08-10 | — | PTC Therapeutics, Inc. |
uridine triacetate | small molecules | FDA | 2009-09-03 | — | Pharma Cinq, LLC |
2',3',5'-tri-o-acetyluridine | small molecules | FDA | 2003-01-13 | — | Repligen Corporation |
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