RARE DISEASE
Isolated complex III deficiency
Isolated complex III deficiency
Isolated complex III deficiency
Synonyms: Isolated CoQ-cytochrome C reductase deficiency, Isolated coenzyme Q-cytochrome C reductase deficiency, Isolated mitochondrial respiratory chain complex III deficiency, Isolated ubiquinone-cytochrome C reductase deficiency
Synonyms: Isolated CoQ-cytochrome C reductase deficiency, Isolated coenzyme Q-cytochrome C reductase deficiency, Isolated mitochondrial respiratory chain complex III deficiency, Isolated ubiquinone-cytochrome C reductase deficiency
Synonyms: Isolated CoQ-cytochrome C reductase deficiency, Isolated coenzyme Q-cytochrome C reductase deficiency, Isolated mitochondrial respiratory chain complex III deficiency, Isolated ubiquinone-cytochrome C reductase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Mitochondrial complex III deficiency is a rare genetic disorder caused by mutations in genes such as MT-CYB (mitochondrial) or BCS1L (nuclear), impairing oxidative phosphorylation. Clinical manifestations vary from mild myopathy and exercise intolerance to severe multisystem dysfunction, including encephalopathy, cardiomyopathy, hepatopathy, renal tubulopathy, and lactic acidosis. Onset typically occurs in infancy or childhood, with prognosis correlating with disease severity [1][2][6].
Burden
High morbidity: Progressive neurologic decline, organ failure, and disability [9][12].
Diagnostic challenges: Genetic heterogeneity and overlapping symptoms with other mitochondrial disorders delay diagnosis [4][12].
Economic and psychosocial impact: Frequent hospitalizations, specialized care needs, and reduced quality of life for patients and caregivers [9][11].
Therapies
Supportive care: Management of metabolic crises (e.g., lactic acidosis), organ-specific complications (e.g., cardiomyopathy), and nutritional support [3][17].
Metabolic therapies: Coenzyme Q10, riboflavin, thiamine, and carnitine, though efficacy remains inconsistent [3][13][17].
Emerging approaches: Investigational agents targeting mitochondrial biogenesis, antioxidants (e.g., idebenone), and gene therapy trials [13][17].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
32 drug discovery papers about Isolated complex III deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
32 drug discovery papers about Isolated complex III deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-21 | Expanding the Clinical and Genetic Landscape of UQCRC2-related Mitochondrial Complex III Deficiency: A Case Report and Literature Review.
Mitochondrial oxidative phosphorylation (OXPHOS) defects are clinically heterogeneous and often challenging to diagnose. Complex III deficiency caused by UQCRC2 variants is exceptionally rare, with only a limited number of patients described worldwide. Reporting new cases is essential to expand the clinical and molecular landscape of this disorder and to provide insights into potential therapeutic strategies. We describe a female patient with UQCRC2-related complex III deficiency who experienced recurrent episodes of metabolic decompensation characterized by hypoglycemia, hyperlactatemia, and renal tubular dysfunction from early childhood. Brain magnetic resonance imaging revealed white matter lesions associated with mild neurological symptoms. During metabolic crises, management included intravenous glucose infusion and strict avoidance of prolonged fasting. At age 15, supplementation with coenzyme Q10 was introduced, followed by complete cessation of hospitalizations and a sustained clinical stabilization. Genetic testing identified compound heterozygosity for a known missense variant and a novel frameshift variant in UQCRC2. A literature review of previously reported cases confirmed the broad clinical variability, ranging from severe neonatal presentations to milder phenotypes with survival into adolescence. This case expands the phenotypic spectrum of UQCRC2-related complex III deficiency and suggests that targeted supplementation with coenzyme Q10 may contribute to improved longterm outcomes. Early recognition of metabolic crises, avoidance of fasting, and genetic confirmation are crucial for diagnosis and management. Further reports are needed to clarify genotype-phenotype correlations and to define the therapeutic role of coenzyme Q10 in this rare mitochondrial disorder.
2026-04-28 | Coenzyme Q10 and Idebenone Combination for Mitochondrial Electron Transport Chain Enhancement
Coenzyme Q10 enhances electron transport chain efficiency at Complex III, while idebenone acts as an alternative electron acceptor bypassing Complex I dysfunction secondary to LCHAD deficiency. This combination improves ATP synthesis efficiency and reduces accumulation of toxic long-chain 3-hydroxyacyl-CoA intermediates through enhanced mitochondrial respiratory capacity.
2026-04-27 | The Drp1-CoQ10-Coa6-ETC axis represents a therapeutic potential for working memory impairment caused by neuronal mitochondrial dysfunction
Abstract Background Coenzyme Q10 (CoQ10) is a key mitochondrial electron carrier and a widely used dietary supplement with potential neurological benefits. However, the mechanisms underlying its effect in ameliorating memory deficits caused by cerebellar injury are not fully understood. In this study, we investigated the effects of long-term CoQ10 supplementation on working memory and the underlying mechanisms. Methods Network pharmacology analysis was used to identify genetic targets of CoQ10 in cerebellar injury-related cognitive impairment. Purkinje cell (PC)-specific Drp1-deficient mice (PC-Drp1−/−) were generated to model mitochondrial dysfunction. Behavioral performance was evaluated using the eight-arm radial maze. Mitochondrial structure and respiratory chain complex levels were evaluated by morphological and biochemical assays. Molecular targets of CoQ10 were identified using integrated drug–target engagement approaches, and their functional relevance was tested by viral vector-mediated overexpression. Results The PC-Drp1−/− mice displayed progressive working memory impairment and decreased PC density, accompanied by disrupted mitochondrial morphology and reduced activities of electron transport chain complexes III–V. Long-term CoQ10 treatment significantly reduced working memory errors and preserved PC numbers in PC-Drp1−/− mice. Target engagement analyses identified cytochrome c oxidase assembly factor 6 (Coa6) as a direct binding target of CoQ10. Viral vector-mediated overexpression of Coa6 in PCs partially recapitulated the CoQ10-associated improvements in respiratory chain complex levels and working memory, whereas Coa6 knockdown attenuated these benefits. Conclusions CoQ10 directly interacts with Coa6 to enhance mitochondrial respiratory chain function and preserve PC integrity in the context of Drp1 deficiency. Our findings suggest a promising mechanistic pathway for CoQ10-based intervention in memory deficits associated with mitochondrial dysfunction.
2026-03-23 | Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model
ABSTRACT Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
2025-07-13 | Expanding the Clinical, Pathological, and Molecular Phenotypes of Tetratricopeptide 19 (TTC19) Gene Mutations: A Case Report from India.
Tetratricopeptide 19 gene (TTC19) is involved in mitochondrial respiratory chain (MRC) complex III function. Mutations cause developmental delay, Leigh syndrome, and spinocerebellar ataxia. In this report, we highlight the expanding phenotype of TTC19 gene variants. A 28-year-old man with intellectual disability presented with dysarthria, palatal tremors, and cerebellar ataxia of 5 months. After collecting clinical information and blood samples, clinical-exome sequencing was performed. Serum and cerebrospinal fluid lactate levels were elevated. Neuroimaging showed hypertrophic olivary degeneration, and MRC complex III deficiency was found on muscle biopsy. A novel variant of the TTC19 gene was identified, and the patient showed minimal symptomatic improvement with the mitochondrial cocktail. Mitochondrial complex III deficiency has varied ages of onset and multiaxial presentation. This novel variant in TTC19 gene indicated that palatal tremor, hypertrophic olivary degeneration, and axonal neuropathy might be unrecognized manifestations.
proteins
2025-07-11 | Evolutionarily conserved temperature dependency leads to loss of protein O-GlcNAc in mammalian hypothermia
Abstract O-N-acetylglucosaminylation (O-GlcNAcylation) is a conserved, non-canonical glycosylation of intracellular proteins suggested to regulate a wide spectrum of fundamental cell processes and stress responses. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove, respectively, O-GlcNAc on protein serines and threonines. O-GlcNAcylation is thought to be primarily regulated by the availability of its substrate, UDP-GlcNAc, produced by the hexosamine biosynthetic pathway (HBP). We observed a body-wide loss of O-GlcNAcylated proteins in Bcs1l mutant mice, a model of mitochondrial complex III deficiency. UDP-GlcNAc precursors glutamine, UTP and acetyl-CoA were decreased in the mutant liver but, surprisingly, UDP-GlcNAc was not consistently decreased in the organs that showed low O-GlcNAc. Neither N-acetylglucosamine supplementation nor overexpression of the HBP rate-limiting enzyme GFPT1 restored the protein O-GlcNAc levels. The Bcs1l mutant mice become hypothermic and, interestingly, earlier evidence suggest that O-GlcNAcylation depends on ambient temperature in Drosophila embryos. We found that temperature determined O-GlcNAc abundance also in adult flies of tropical and boreal Drosophila species, in the poikilothermic vertebrate zebrafish, and in cultured mammalian cells. In cultured cells, the OGT-OGA protein ratio coincided with temperature and O-GlcNAc level, providing a regulatory mechanism. Pharmacological OGA inhibition decoupled the O-GlcNAc temperature dependency in cultured cells, as did an OGA null allele in Drosophila . In Bcs1l mutant mice, O-GlcNAc levels strongly correlated with body temperature. Increasing the mouse body temperature through transgenic expression of the heat-generating mitochondrial alternative oxidase (AOX) or housing at 35°C prevented the loss of O-GlcNAc. Pharmacological restoration of O-GlcNAc in the Bcs1l mutant mice produced minimal effects, suggesting that the bulk of O-GlcNAc is dispensable in mild hypothermia. Our findings imply an evolutionarily ancient role of protein O-GlcNAcylation in temperature adaptation and, instead of protein function-specific roles, argue for a global role of O-GlcNAc in temperature control of proteostasis.
2023-04-26 | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
2017-04-15 | Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding gelsolin to modulate the oligomerization of VDAC complexes and cell survival
Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used two-dimensional difference gel electrophoresis analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patients' fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes.
1998-12-31 | Isolation of an Arabidopsis thaliana cDNA by complementation of a yeast abc1 deletion mutant deficient in complex III respiratory activity.
The yeast Abc1 protein acts as a chaperone-like protein essential for the proper conformation and efficient functioning of the respiratory complex III. By functional complementation of a yeast abc1 mutant, we have identified an Arabidopsis thaliana cDNA that corresponds to a single copy gene and encodes a protein sharing 45% similarity with the yeast Abc1p protein. Cytochrome spectra and respiratory activity measurements have shown that the plant protein allows a partial restoration of the complex III activity. No major difference in the steady-state level of ABC1At mRNA was observed in various plant tissues, suggesting that ABC1At is constitutively expressed in A. thaliana. Phylogenetic analysis revealed that the Abc1At protein belongs to a large family of proteins composed of two eukaryotic and one prokaryotic subgroups differing by their degree of similarity and probably by their function.
gene therapies
2026-05-07 | Mitochondrial complex III deficiency nuclear type 2: a case report and analysis of clinical onset age-related phenotypic features.
Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is a rare inherited neurometabolic disease. A 34-year-old male had neuropsychiatric episodes, progressive cerebellar degeneration, myopathy, polyneuropathy, and brain stem and basal ganglion lesions since childhood. Muscle biopsy revealed mitochondrial abnormalities. Two novel TTC19 pathogenic variants were detected. To analyze phenotypic characteristics of MC3DN2 related to clinical onset age, neurological presentation and brain MRI regarding infantile and childhood-onset (ICO) and adolescent and adult-onset (AAO) disease in a cohort composed of our patient and the cases reported in the literature were compared. It revealed that, clinically, cerebellar ataxia was common in both groups, nystagmus was more frequently noted in AAO patients, and psychiatric disturbances were more common in ICO patients. Regarding MRI findings, basal ganglion lesions were more prevalent in ICO patients, and inferior olive lesions were more frequent in AAO patients. These conspicuous phenotypic features of MC3DN2 may suggest diagnosis of this distinctive disease. The differences in clinical features and brain lesions associated with clinical onset age could provide crucial insights into the phenotypic landscape of MC3DN2.
2024-09-24 | Restoration of mitochondrial complex III function in hepatocytes highlights the liver as a key thermogenic organ independent of brown adipocyte activation
The liver is the key hub of systemic energy metabolism and growth, yet it is surprisingly rarely a major affected organ in mitochondrial diseases that compromise oxidative phosphorylation. Bcs1l p.S78G knock-in mice, carrying a respiratory complex III (CIII)-deficiency patient mutation, show juvenile-onset liver and kidney disease, growth restriction, lipodystrophy and premature death. To probe the as yet poorly understood systemic metabolic roles of the liver in mitochondrial diseases, we utilized this model and performed rAAV-based gene therapy using a hepatocyte-specific promoter to drive wild-type BCS1L expression. A single rAAV- Bcs1l intraperitoneal injection into presymptomatic 3-week-old mice transduced the liver, restored hepatic CIII assembly and activity, and prevented liver disease. Restoring CIII function in hepatocytes was sufficient to improve growth, prevent lethal hypoglycemia, and extend survival by 100%. Unexpectedly, the hepatocyte-specific gene replacement also prevented severe hypothermia. Mechanistically, the mutant mice lacked signs of thermogenic BAT activation, thermoneutral housing did not correct the hypothermia, and the mice exhibited impaired thermosensation, suggesting failure to respond to hypothermic cues. Immunostaining revealed grossly abnormal foot pad innervation, suggesting sensory neuropathy and impaired thermosensing. The rAAV- Bcs1l -treated mice maintained near-normal body temperature without induction of BAT thermogenesis, demonstrating that mitochondrial respiration in hepatocytes is both essential and sufficient for euthermia in juvenile mice. These findings emphasize the crucial role of the liver in thermoregulation, suggest sensory neuropathy as an unexpected cause of hypothermia, and demonstrate the therapeutic potential of tissue-specific gene therapy in a preclinical model of a multiorgan mitochondrial disease.
2020-04-17 | Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.
Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.
cell therapies
2025-10-01 | #2780 Mutant BCS1L patient urine derived renal epithelial cells: a personalised model of mitochondrial kidney tubule dysfunction
Abstract Background and Aims Biallelic, pathological mutations in BCS1L are one of the most common causes of mitochondrial Complex III deficiency. Affected individuals present with a spectrum of multisystemic disorders with variable onset. Among these, proximal renal-tubulopathies are commonly seen. Here, we set out to cultivate renal epithelial cells from a BCS1L mutant patient presenting primarily with renotubular-dysfunction, and to assess their potential as a model of mitochondrial and kidney specific features of their condition. Making use of the European Reference Network on Rare Kidney Diseases (ERKNet), we also aimed to establish a cohort of similar patients to confirm our own and previously published findings. Ultimately, we aim to establish a personalised disease model to further our aetiological understanding of the disease, and in which prospective therapeutics could be tested and affirmed. Method Exome sequencing was performed using the Twist Exome RefSeq capture method. Human urinary Renal Epithelial Cells (huREC) were isolated from fresh subject urine samples and cultivated as monolayers or in matrigel as 3D cystic structures termed tubuloids. Bulk-RNA-sequencing, Western blotting and immunofluorescence were conducted to assess the quantity and subcellular localisations of key mitochondrial markers. Live imaging of mitochondria with Rhodamine 123 was used to assess mitochondrial morphology. The Seahorse Cell Mito-stress test and mitochondrial complex assays were used to assess mitochondrial bioenergetics. Results In an adult female presenting with primary Fanconi Syndrome since the age of 4, exome sequencing identified two pathogenic BCS1L variants in compound heterozygosity (BCS1L NM_004328.5; variants c.-147A>G p.? and c.-166C>T p.(Arg56*)). The patient shows a full spectrum of tubular dysfunction including glycosuria, potassium, phosphate, bicarbonate, and urea wasting, plus low molecular weight protein loss and stage 3b CKD with an eGFR of 35 ml/min/1.73 m2 at 42 years of age. The patient has no cardiac or neurological sequelae. An ERKNet survey involving all 72 pediatric and adult reference centres across Europe, yielded identification of 4 additional patients carrying biallelic pathogenic variants in BCS1L, all of whom showed comparable phenotypic presentation with little to no neurological manifestation, but RTA (4/4), Fanconi Syndrome (4/4), and nephrocalcinosis (2/4). Western Blotting and immunofluorescence confirmed a BCS1L deficiency in patient-huRECs relative to age-sex matched controls. Concurrently, the Seahorse Mito Stress Test demonstrated that BCS1L-mutant huRECs possess reduced total respiratory capacity, relative to controls. Assessment of mitochondrial morphology, mitochondrial complex activities and exome wide gene expression changes are currently in process. 3D tubuloid cultures were also established from patient huRECs, a system that demonstrates enhanced cell polarity and trans-epithelial transport relative to monolayers, for which it is hypothesized respiratory deficiencies may be more pronounced due to enhanced energy requirements. Conclusion 2D- and 3D-cell cultures from a primary Fanconi patient with compound-heterozygous BCS1L-mutations were successfully established from non-invasively acquired urine samples. These cultures emulated key mitochondrial dysfunctions seen in the patient but not in huRECs from healthy controls. In the future, we intend to employ these cells for drug screening purposes against the mitochondrial phenotype. This study acts as a proof of concept for the use of huREC-derived cultures in modelling of rare kidney diseases and mitochondriopathies.
small molecules
2026-05-21 | Expanding the Clinical and Genetic Landscape of UQCRC2-related Mitochondrial Complex III Deficiency: A Case Report and Literature Review.
Mitochondrial oxidative phosphorylation (OXPHOS) defects are clinically heterogeneous and often challenging to diagnose. Complex III deficiency caused by UQCRC2 variants is exceptionally rare, with only a limited number of patients described worldwide. Reporting new cases is essential to expand the clinical and molecular landscape of this disorder and to provide insights into potential therapeutic strategies. We describe a female patient with UQCRC2-related complex III deficiency who experienced recurrent episodes of metabolic decompensation characterized by hypoglycemia, hyperlactatemia, and renal tubular dysfunction from early childhood. Brain magnetic resonance imaging revealed white matter lesions associated with mild neurological symptoms. During metabolic crises, management included intravenous glucose infusion and strict avoidance of prolonged fasting. At age 15, supplementation with coenzyme Q10 was introduced, followed by complete cessation of hospitalizations and a sustained clinical stabilization. Genetic testing identified compound heterozygosity for a known missense variant and a novel frameshift variant in UQCRC2. A literature review of previously reported cases confirmed the broad clinical variability, ranging from severe neonatal presentations to milder phenotypes with survival into adolescence. This case expands the phenotypic spectrum of UQCRC2-related complex III deficiency and suggests that targeted supplementation with coenzyme Q10 may contribute to improved longterm outcomes. Early recognition of metabolic crises, avoidance of fasting, and genetic confirmation are crucial for diagnosis and management. Further reports are needed to clarify genotype-phenotype correlations and to define the therapeutic role of coenzyme Q10 in this rare mitochondrial disorder.
2026-04-28 | Coenzyme Q10 and Idebenone Combination for Mitochondrial Electron Transport Chain Enhancement
Coenzyme Q10 enhances electron transport chain efficiency at Complex III, while idebenone acts as an alternative electron acceptor bypassing Complex I dysfunction secondary to LCHAD deficiency. This combination improves ATP synthesis efficiency and reduces accumulation of toxic long-chain 3-hydroxyacyl-CoA intermediates through enhanced mitochondrial respiratory capacity.
2026-04-27 | The Drp1-CoQ10-Coa6-ETC axis represents a therapeutic potential for working memory impairment caused by neuronal mitochondrial dysfunction
Abstract Background Coenzyme Q10 (CoQ10) is a key mitochondrial electron carrier and a widely used dietary supplement with potential neurological benefits. However, the mechanisms underlying its effect in ameliorating memory deficits caused by cerebellar injury are not fully understood. In this study, we investigated the effects of long-term CoQ10 supplementation on working memory and the underlying mechanisms. Methods Network pharmacology analysis was used to identify genetic targets of CoQ10 in cerebellar injury-related cognitive impairment. Purkinje cell (PC)-specific Drp1-deficient mice (PC-Drp1−/−) were generated to model mitochondrial dysfunction. Behavioral performance was evaluated using the eight-arm radial maze. Mitochondrial structure and respiratory chain complex levels were evaluated by morphological and biochemical assays. Molecular targets of CoQ10 were identified using integrated drug–target engagement approaches, and their functional relevance was tested by viral vector-mediated overexpression. Results The PC-Drp1−/− mice displayed progressive working memory impairment and decreased PC density, accompanied by disrupted mitochondrial morphology and reduced activities of electron transport chain complexes III–V. Long-term CoQ10 treatment significantly reduced working memory errors and preserved PC numbers in PC-Drp1−/− mice. Target engagement analyses identified cytochrome c oxidase assembly factor 6 (Coa6) as a direct binding target of CoQ10. Viral vector-mediated overexpression of Coa6 in PCs partially recapitulated the CoQ10-associated improvements in respiratory chain complex levels and working memory, whereas Coa6 knockdown attenuated these benefits. Conclusions CoQ10 directly interacts with Coa6 to enhance mitochondrial respiratory chain function and preserve PC integrity in the context of Drp1 deficiency. Our findings suggest a promising mechanistic pathway for CoQ10-based intervention in memory deficits associated with mitochondrial dysfunction.
2026-03-23 | Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model
ABSTRACT Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
2025-07-13 | Expanding the Clinical, Pathological, and Molecular Phenotypes of Tetratricopeptide 19 (TTC19) Gene Mutations: A Case Report from India.
Tetratricopeptide 19 gene (TTC19) is involved in mitochondrial respiratory chain (MRC) complex III function. Mutations cause developmental delay, Leigh syndrome, and spinocerebellar ataxia. In this report, we highlight the expanding phenotype of TTC19 gene variants. A 28-year-old man with intellectual disability presented with dysarthria, palatal tremors, and cerebellar ataxia of 5 months. After collecting clinical information and blood samples, clinical-exome sequencing was performed. Serum and cerebrospinal fluid lactate levels were elevated. Neuroimaging showed hypertrophic olivary degeneration, and MRC complex III deficiency was found on muscle biopsy. A novel variant of the TTC19 gene was identified, and the patient showed minimal symptomatic improvement with the mitochondrial cocktail. Mitochondrial complex III deficiency has varied ages of onset and multiaxial presentation. This novel variant in TTC19 gene indicated that palatal tremor, hypertrophic olivary degeneration, and axonal neuropathy might be unrecognized manifestations.
proteins
2025-07-11 | Evolutionarily conserved temperature dependency leads to loss of protein O-GlcNAc in mammalian hypothermia
Abstract O-N-acetylglucosaminylation (O-GlcNAcylation) is a conserved, non-canonical glycosylation of intracellular proteins suggested to regulate a wide spectrum of fundamental cell processes and stress responses. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove, respectively, O-GlcNAc on protein serines and threonines. O-GlcNAcylation is thought to be primarily regulated by the availability of its substrate, UDP-GlcNAc, produced by the hexosamine biosynthetic pathway (HBP). We observed a body-wide loss of O-GlcNAcylated proteins in Bcs1l mutant mice, a model of mitochondrial complex III deficiency. UDP-GlcNAc precursors glutamine, UTP and acetyl-CoA were decreased in the mutant liver but, surprisingly, UDP-GlcNAc was not consistently decreased in the organs that showed low O-GlcNAc. Neither N-acetylglucosamine supplementation nor overexpression of the HBP rate-limiting enzyme GFPT1 restored the protein O-GlcNAc levels. The Bcs1l mutant mice become hypothermic and, interestingly, earlier evidence suggest that O-GlcNAcylation depends on ambient temperature in Drosophila embryos. We found that temperature determined O-GlcNAc abundance also in adult flies of tropical and boreal Drosophila species, in the poikilothermic vertebrate zebrafish, and in cultured mammalian cells. In cultured cells, the OGT-OGA protein ratio coincided with temperature and O-GlcNAc level, providing a regulatory mechanism. Pharmacological OGA inhibition decoupled the O-GlcNAc temperature dependency in cultured cells, as did an OGA null allele in Drosophila . In Bcs1l mutant mice, O-GlcNAc levels strongly correlated with body temperature. Increasing the mouse body temperature through transgenic expression of the heat-generating mitochondrial alternative oxidase (AOX) or housing at 35°C prevented the loss of O-GlcNAc. Pharmacological restoration of O-GlcNAc in the Bcs1l mutant mice produced minimal effects, suggesting that the bulk of O-GlcNAc is dispensable in mild hypothermia. Our findings imply an evolutionarily ancient role of protein O-GlcNAcylation in temperature adaptation and, instead of protein function-specific roles, argue for a global role of O-GlcNAc in temperature control of proteostasis.
2023-04-26 | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
2017-04-15 | Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding gelsolin to modulate the oligomerization of VDAC complexes and cell survival
Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used two-dimensional difference gel electrophoresis analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patients' fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes.
1998-12-31 | Isolation of an Arabidopsis thaliana cDNA by complementation of a yeast abc1 deletion mutant deficient in complex III respiratory activity.
The yeast Abc1 protein acts as a chaperone-like protein essential for the proper conformation and efficient functioning of the respiratory complex III. By functional complementation of a yeast abc1 mutant, we have identified an Arabidopsis thaliana cDNA that corresponds to a single copy gene and encodes a protein sharing 45% similarity with the yeast Abc1p protein. Cytochrome spectra and respiratory activity measurements have shown that the plant protein allows a partial restoration of the complex III activity. No major difference in the steady-state level of ABC1At mRNA was observed in various plant tissues, suggesting that ABC1At is constitutively expressed in A. thaliana. Phylogenetic analysis revealed that the Abc1At protein belongs to a large family of proteins composed of two eukaryotic and one prokaryotic subgroups differing by their degree of similarity and probably by their function.
gene therapies
2026-05-07 | Mitochondrial complex III deficiency nuclear type 2: a case report and analysis of clinical onset age-related phenotypic features.
Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is a rare inherited neurometabolic disease. A 34-year-old male had neuropsychiatric episodes, progressive cerebellar degeneration, myopathy, polyneuropathy, and brain stem and basal ganglion lesions since childhood. Muscle biopsy revealed mitochondrial abnormalities. Two novel TTC19 pathogenic variants were detected. To analyze phenotypic characteristics of MC3DN2 related to clinical onset age, neurological presentation and brain MRI regarding infantile and childhood-onset (ICO) and adolescent and adult-onset (AAO) disease in a cohort composed of our patient and the cases reported in the literature were compared. It revealed that, clinically, cerebellar ataxia was common in both groups, nystagmus was more frequently noted in AAO patients, and psychiatric disturbances were more common in ICO patients. Regarding MRI findings, basal ganglion lesions were more prevalent in ICO patients, and inferior olive lesions were more frequent in AAO patients. These conspicuous phenotypic features of MC3DN2 may suggest diagnosis of this distinctive disease. The differences in clinical features and brain lesions associated with clinical onset age could provide crucial insights into the phenotypic landscape of MC3DN2.
2024-09-24 | Restoration of mitochondrial complex III function in hepatocytes highlights the liver as a key thermogenic organ independent of brown adipocyte activation
The liver is the key hub of systemic energy metabolism and growth, yet it is surprisingly rarely a major affected organ in mitochondrial diseases that compromise oxidative phosphorylation. Bcs1l p.S78G knock-in mice, carrying a respiratory complex III (CIII)-deficiency patient mutation, show juvenile-onset liver and kidney disease, growth restriction, lipodystrophy and premature death. To probe the as yet poorly understood systemic metabolic roles of the liver in mitochondrial diseases, we utilized this model and performed rAAV-based gene therapy using a hepatocyte-specific promoter to drive wild-type BCS1L expression. A single rAAV- Bcs1l intraperitoneal injection into presymptomatic 3-week-old mice transduced the liver, restored hepatic CIII assembly and activity, and prevented liver disease. Restoring CIII function in hepatocytes was sufficient to improve growth, prevent lethal hypoglycemia, and extend survival by 100%. Unexpectedly, the hepatocyte-specific gene replacement also prevented severe hypothermia. Mechanistically, the mutant mice lacked signs of thermogenic BAT activation, thermoneutral housing did not correct the hypothermia, and the mice exhibited impaired thermosensation, suggesting failure to respond to hypothermic cues. Immunostaining revealed grossly abnormal foot pad innervation, suggesting sensory neuropathy and impaired thermosensing. The rAAV- Bcs1l -treated mice maintained near-normal body temperature without induction of BAT thermogenesis, demonstrating that mitochondrial respiration in hepatocytes is both essential and sufficient for euthermia in juvenile mice. These findings emphasize the crucial role of the liver in thermoregulation, suggest sensory neuropathy as an unexpected cause of hypothermia, and demonstrate the therapeutic potential of tissue-specific gene therapy in a preclinical model of a multiorgan mitochondrial disease.
2020-04-17 | Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.
Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.
cell therapies
2025-10-01 | #2780 Mutant BCS1L patient urine derived renal epithelial cells: a personalised model of mitochondrial kidney tubule dysfunction
Abstract Background and Aims Biallelic, pathological mutations in BCS1L are one of the most common causes of mitochondrial Complex III deficiency. Affected individuals present with a spectrum of multisystemic disorders with variable onset. Among these, proximal renal-tubulopathies are commonly seen. Here, we set out to cultivate renal epithelial cells from a BCS1L mutant patient presenting primarily with renotubular-dysfunction, and to assess their potential as a model of mitochondrial and kidney specific features of their condition. Making use of the European Reference Network on Rare Kidney Diseases (ERKNet), we also aimed to establish a cohort of similar patients to confirm our own and previously published findings. Ultimately, we aim to establish a personalised disease model to further our aetiological understanding of the disease, and in which prospective therapeutics could be tested and affirmed. Method Exome sequencing was performed using the Twist Exome RefSeq capture method. Human urinary Renal Epithelial Cells (huREC) were isolated from fresh subject urine samples and cultivated as monolayers or in matrigel as 3D cystic structures termed tubuloids. Bulk-RNA-sequencing, Western blotting and immunofluorescence were conducted to assess the quantity and subcellular localisations of key mitochondrial markers. Live imaging of mitochondria with Rhodamine 123 was used to assess mitochondrial morphology. The Seahorse Cell Mito-stress test and mitochondrial complex assays were used to assess mitochondrial bioenergetics. Results In an adult female presenting with primary Fanconi Syndrome since the age of 4, exome sequencing identified two pathogenic BCS1L variants in compound heterozygosity (BCS1L NM_004328.5; variants c.-147A>G p.? and c.-166C>T p.(Arg56*)). The patient shows a full spectrum of tubular dysfunction including glycosuria, potassium, phosphate, bicarbonate, and urea wasting, plus low molecular weight protein loss and stage 3b CKD with an eGFR of 35 ml/min/1.73 m2 at 42 years of age. The patient has no cardiac or neurological sequelae. An ERKNet survey involving all 72 pediatric and adult reference centres across Europe, yielded identification of 4 additional patients carrying biallelic pathogenic variants in BCS1L, all of whom showed comparable phenotypic presentation with little to no neurological manifestation, but RTA (4/4), Fanconi Syndrome (4/4), and nephrocalcinosis (2/4). Western Blotting and immunofluorescence confirmed a BCS1L deficiency in patient-huRECs relative to age-sex matched controls. Concurrently, the Seahorse Mito Stress Test demonstrated that BCS1L-mutant huRECs possess reduced total respiratory capacity, relative to controls. Assessment of mitochondrial morphology, mitochondrial complex activities and exome wide gene expression changes are currently in process. 3D tubuloid cultures were also established from patient huRECs, a system that demonstrates enhanced cell polarity and trans-epithelial transport relative to monolayers, for which it is hypothesized respiratory deficiencies may be more pronounced due to enhanced energy requirements. Conclusion 2D- and 3D-cell cultures from a primary Fanconi patient with compound-heterozygous BCS1L-mutations were successfully established from non-invasively acquired urine samples. These cultures emulated key mitochondrial dysfunctions seen in the patient but not in huRECs from healthy controls. In the future, we intend to employ these cells for drug screening purposes against the mitochondrial phenotype. This study acts as a proof of concept for the use of huREC-derived cultures in modelling of rare kidney diseases and mitochondriopathies.
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