Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism.

Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine ß-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.

Cardiomyopathy and altered integrin-actin signaling in Fhl1 mutant female mice.

X-linked scapuloperoneal myopathy (X-SM), one of Four-and-a-half LIM 1 (FHL1) related diseases, is an adult-onset slowly progressive myopathy, often associated with cardiomyopathy. We previously generated a knock-in mouse model that has the same mutation (c.365 G > C, p.W122S) as human X-SM patients. The mutant male mouse developed late-onset slowly progressive myopathy without cardiomyopathy. In this study, we observed that heterozygous (Het) and homozygous (Homo) female mice did not show alterations of skeletal muscle function or histology. In contrast, 20-month-old mutant female mice showed signs of cardiomyopathy on echocardiograms with increased systolic diameter [wild-type (WT): 2.74 ± 0.22 mm, mean ± standard deviation (SD); Het: 3.13 ± 0.11 mm, P < 0.01; Homo: 3.08 ± 0.37 mm, P < 0.05) and lower fractional shortening (WT: 31.1 ± 4.4%, mean ± SD; Het: 22.7 ± 2.5%, P < 0.01; Homo: 22.4 ± 6.9%, P < 0.01]. Histological analysis of cardiac muscle revealed frequent extraordinarily large rectangular nuclei in mutant female mice that were also observed in human cardiac muscle from X-SM patients. Western blot demonstrated decreased Fhl1 protein levels in cardiac muscle, but not in skeletal muscle, of Homo mutant female mice. Proteomic analysis of cardiac muscle from 20-month-old Homo mutant female mice indicated abnormalities of the integrin signaling pathway (ISP) in association with cardiac dysfunction. The ISP dysregulation was further supported by altered levels of a subunit of the ISP downstream effectors Arpc1a in Fhl1 mutant mice and ARPC1A in X-SM patient muscles. This study reveals the first mouse model of FHL1-related cardiomyopathy and implicates ISP dysregulation in the pathogenesis of FHL1 myopathy.

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine-sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.

Regulatory environment for novel therapeutic development in mitochondrial diseases.

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.

A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis.

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of 'virtual hypoglycosis' induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

Growth differentiation factor-15 as a biomarker of strength and recovery in survivors of acute respiratory failure.

Muscle mitochondrial dysfunction is implicated in intensive care unit-acquired weakness, but there is no serum biomarker of muscle mitochondrial function for critical illness survivors. Higher serum growth differentiation factor-15 (GDF-15) is a biomarker of inherited mitochondrial myopathy disease and is associated with mortality in several age-related diseases. Among 142 older (age ≥ 65 years) survivors of acute respiratory failure, we found that higher serum GDF-15 measured during the week prior to hospital discharge was cross-sectionally associated with weaker diaphragm, limb and hand-grip strength, and longitudinally associated with lower rates of functional recovery over 6 months, independent of age, sex, pre-existing disability, comorbidity, frailty, Acute Physiology and Chronic Health Evaluation II scores and concurrent interleukin-6 levels.

Metabolic studies of a patient harbouring a novel S487L mutation in the catalytic subunit of AMPK.

AMP-activated protein kinase (AMPK) regulates many different metabolic pathways in eukaryote cells including mitochondria biogenesis and energy homeostasis. Here we identify a patient with hypotonia, weakness, delayed milestones and neurological impairment since birth harbouring a novel homozygous mutation in the AMPK catalytic α-subunit 1, encoded by the PRKAA1 gene. The homozygous mutation p.S487L in isoform 1 present in the patient is in a cryptic residue for AMPK activity. In the present study, we performed the characterization of mitochondrial respiratory properties of the patient, in comparison to healthy controls, through the culture of skin fibroblasts in order to understand some of the cellular consequences of the PRKAA1 mutation. In these assays, mitochondrial respiratory complex I showed lower activity, which was followed by a decrement in the mtDNA copy number, which is a probable consequence of the lower expression of PGC-1α and PRKAA1 itself as measured in our quantitative PCRs experiments. Confirming the effect of the patient mutation in respiration, transfection of patient fibroblasts with wild type PRKAA1 partially restore complex I level. The preliminary clinic evaluations of the patient suggested a metabolic defect related to the mitochondrial respiratory function, therefore treatment with CoQ10 supplementation dose started four years ago and a clear improvement in motor skills and strength has been achieved with this treatment.

Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.

Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease caused by mutations in APTX, which encodes the DNA strand-break repair protein aprataxin (APTX). CoQ10 deficiency has been identified in fibroblasts and muscle of AOA1 patients carrying the common W279X mutation, and aprataxin has been localized to mitochondria in neuroblastoma cells, where it enhances preservation of mitochondrial function. In this study, we show that aprataxin deficiency impairs mitochondrial function, independent of its role in mitochondrial DNA repair. The bioenergetics defect in AOA1-mutant fibroblasts and APTX-depleted Hela cells is caused by decreased expression of SDHA and genes encoding CoQ biosynthetic enzymes, in association with reductions of APE1, NRF1 and NRF2. The biochemical and molecular abnormalities in APTX-depleted cells are recapitulated by knockdown of APE1 in Hela cells and are rescued by overexpression of NRF1/2. Importantly, pharmacological upregulation of NRF1 alone by 5-aminoimidazone-4-carboxamide ribonucleotide does not rescue the phenotype, which, in contrast, is reversed by the upregulation of NRF2 by rosiglitazone. Accordingly, we propose that the lack of aprataxin causes reduction of the pathway APE1/NRF1/NRF2 and their target genes. Our findings demonstrate a critical role of APTX in transcription regulation of mitochondrial function and the pathogenesis of AOA1 via a novel pathomechanistic pathway, which may be relevant to other neurodegenerative diseases.

Fhl1 W122S causes loss of protein function and late-onset mild myopathy.

A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice.

Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation.

Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild-type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild-type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation.

Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice.

Primary human CoQ(10) deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ(10) biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with <20% CoQ(10) of control cells, revealed reduced activity of CoQ(10)-dependent complex II+III and ATP synthesis, without amplification of reactive oxygen species (ROS), markers of oxidative damage, or antioxidant defenses. In contrast, COQ2 and ADCK3 mutant fibroblasts, with 30-50% CoQ(10) of controls, showed milder bioenergetic defects but significantly increased ROS and oxidation of lipids and proteins. We hypothesized that absence of oxidative stress markers and cell death in PDSS2 mutant fibroblasts were due to the extreme severity of CoQ(10) deficiency. Here, we have investigated in vivo effects of Pdss2 deficiency in affected and unaffected organs of CBA/Pdss2(kd/kd) mice at presymptomatic, phenotypic-onset, and end-stages of the disease. Although Pdss2 mutant mice manifest widespread CoQ(9) deficiency and mitochondrial respiratory chain abnormalities, only affected organs show increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced citrate synthase activity, an index of mitochondrial mass. Our data indicate that kidney-specific loss of mitochondria triggered by oxidative stress may be the cause of renal failure in Pdss2(kd/kd) mice.

4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.

Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.

CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.

BACKGROUND: Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). SCOPE OF REVIEW: Here, we describe clinical and molecular features of CoQ(10) deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ(10) deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ(10) biosynthesis, often improve with CoQ(10) supplementation. In vitro and in vivo studies of CoQ(10) deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ(10) deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. MAJOR CONCLUSIONS: CoQ(10) deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. GENERAL SIGNIFICANCE: Studies of CoQ(10) deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010.

Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency.

BACKGROUND: COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q(10) (CoQ(10)). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ(10) deficiency. METHODS: A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed. RESULTS: The study found reduced COQ4 expression (48% of controls), CoQ(10) content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ(10) to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ(10.) Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ(10) biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ(10) supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. CONCLUSION: Mutations of COQ4 should be searched for in patients with CoQ(10) deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ(10) deficiency, as they could benefit from supplementation.

Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency.

Background and Objectives: Coenzyme Q10 (CoQ10)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ10 levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ10 deficiency. Methods: WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ10 deficiency and/or cerebellar ataxia. CoQ10 levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts. Results: A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A (ADCK3) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found (COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ10 levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect. Discussion: This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ10 deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ10 deficiency.

A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease.

Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q(10) biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q(10) deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth.

Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies.

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.

X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1.

Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.