Leber\'s hereditary optic neuropathy (LHON) is a fairly prevalent mitochondrial disorder (1:50,000) arising from the dysfunction of the mitochondrial respiratory chain, which eventually leads to apoptosis of retinal ganglion cells. The usual presentation is that of a young male with a sequential reduction in visual acuity. OCT has been used to study the pattern of optic nerve involvement in LHON, showing early thickening of the inferior and superior retinal nerve fibre layer and ganglion cell layer thinning corresponding with the onset of symptoms. Of the three primary mutations for LHON, the m.14484T>C mutation has the best visual prognosis. Recent emerging therapeutic options for LHON include idebenone and the introduction of genetic vector therapy, which is currently in phase III clinical trials. Screening of family members and adequate advice to avoid environmental triggers, such as smoking and alcohol consumption, are also cornerstones in the management of LHON.

OBJECTIVE: To objectively assess visual function in Leber\'s Hereditary Optic Neuropathy (LHON) patients; this study evaluated pre- and post-idebenone treatment changes in primary visual cortical (V1) responses using functional magnetic resonance imaging (fMRI), given the challenges in subjective testing due to central retinal ganglion cell damage.
METHODS: A descriptive study involving four confirmed LHON patients.
METHODS: Four patients received 900 mg/day of oral idebenone for 24 weeks. Baseline and post-treatment visual acuity, visual fields, and BOLD fMRI responses while passively viewed drifting contrast pattern visual stimuli were compared with self-reported symptoms.
RESULTS: Post-idebenone, one patient showed positive trends across subjective tests, reported symptoms, and fMRI. Two patients had stable symptoms and fMRI responses; one improved on subjective tests, and another worsened slightly. Another patient improved in visual field tests despite worsening symptoms and fMRI trends.
CONCLUSIONS: fMRI may offer a valuable objective measure of visual functions in LHON and appears to be more relevant in assessing symptoms. Further research with more participants is needed to ascertain fMRI\'s role in developing objective visual assessments and treatment evaluation.

Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.

Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular antioxidant, but a very hydrophobic one. Because of that, other molecules have been envisaged, such as idebenone (IDE) and mitoquinone (MTQ), molecules having the same redox active benzoquinone moiety but higher solubility. We have used molecular dynamics to determine the location and interaction of these molecules, both in their oxidized and reduced forms, with membrane lipids in a membrane similar to that of the mitochondria. Both IDE and reduced IDE (IDOL) are situated near the membrane interface, whereas both MTQ and reduced MTQ (MTQOL) locate in a position adjacent to the phospholipid hydrocarbon chains. The quinone moieties of both ubiquinone 10 (UQ10) and reduced UQ10 (UQOL10) in contraposition to the same moieties of IDE, IDOL, MTQ and MTQOL, located near the membrane interphase, whereas the isoprenoid chains remained at the middle of the hydrocarbon chains. These molecules do not aggregate and their functional quinone moieties are located in the membrane at different depths but near the hydrophobic phospholipid chains whereby protecting them from ROS harmful effects.

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3\'s ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3\'s importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson\'s disease, and Alzheimer\'s disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone\'s anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

Chronic and excessive alcohol consumption leads to liver toxicity. There is a need to investigate effective therapeutic strategies to alleviate alcohol-induced liver injury, which remains the leading cause of liver-related morbidity and mortality worldwide. Therefore here, we looked into and evaluated how ethanol-induced hepatotoxicity was affected by coenzyme Q10 (CoQ10) and its analog, idebenone (IDE), on the NLRP3/caspase-1/IL-1 pathway. Hepatotoxicity induced in rats through the oral administration of gradually increasing dosages of ethanol (from 2 to 6 g/kg/day) over 30 days and the effect of CoQ10 (10 or 20 mg/kg) and IDE (50 or 100 mg/kg) were evaluated. Serum hepatotoxicity markers (ALT, AST, GGT, ALP, and TBIL), tissue oxidative stress markers and the mRNA expressions of IL-1β, IL-18, TGF-β, NF-κB, NLRP3, and caspase-1 were evaluated. Masson\'s trichrome staining was also used to visualize fibrosis in the liver tissue. The results indicated that ethanol exposure led to hepatotoxicity as well as considerable NLRP3/caspase-1/IL-1β pathway activation. Moreover, CoQ10 or IDE treatment reduced measured parameters in a dosage-dependent manner. Thus, by inhibiting the NLRP3/caspase-1/IL-1 pathway, CoQ10 and IDE can prevent the hepatotoxicity caused by ethanol, although CoQ10 is more effective than IDE. This study will provide insight into new therapeutic avenues that take advantage of the anti-inflammatory and antioxidant properties of CoQ10 and IDE in ethanol-induced liver diseases.

OBJECTIVE: Schwann cells are the main cells for myelination and regeneration of peripheral nerves. Idebenone is a synthetic antioxidant used to treat central nervous system diseases. The aim of the study is to determine whether idebenone can protect Schwann cells and increase cell activity under conditions of oxidative stress caused by hydrogen peroxide (H2O2) in vitro.
METHODS: In this experimental study, Schwann cells were pre-treated with various concentrations of idebenone and H2O2; after determining the appropriate doses, the cells were treated with 10 μM idebenone for 48 hours and 1000 μM H2O2 for the last two hours. The malondialdehyde (MDA) level, and activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were assessed by ELISA. Cell viability was assessed by the MTT assay. Western blot analysis was conducted to determine the expressions of myelin protein zero (MPZ) and peripheral myelin protein 22 (PMP22), and expression ratio of the Bax/Bcl-2 proteins. The percentage of cell apoptosis was evaluated by annexin V staining using flow cytometry.
RESULTS: Schwann cells under oxidative stress conditions caused by H2O2 and treated with idebenone had increased cell viability; increased SOD, CAT, and GPx activity; and increased expressions of the MPZ and PMP22 proteins. There was a decreased level of MDA, decreased expression ratio of Bax/Bcl-2 proteins, and a decrease in the percentage of apoptotic cells stained with Annexin V.
CONCLUSIONS: The appropriate dose of idebenone may improve both survival and function of Schwann cells exposed to H2O2 by reducing oxidative stress and apoptosis.

Leber\'s hereditary optic neuropathy (LHON) is the most common maternally inherited disease linked to mitochondrial DNA (mtDNA). The patients present with subacute asymmetric bilateral vision loss. Approximately 95% of the LHON cases are caused by m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6) mutations. The hallmark of hereditary optic neuropathies determined by mitochondrial dysfunction is the vulnerability and degeneration of retinal ganglion cells (RGC). We present the case of a 28-year-old man who came to our clinic complaining of a subacute decrease in visual acuity of his left eye. From his medical history, we found out that one month before he had the same symptoms in the right eye. From the family history, we noted that an uncle has had vision problems since childhood. We carried out complete blood tests, including specific antibodies for autoimmune and infectious diseases. Laboratory tests and MRI were within normal limits. A blood test of the mtDNA showed the presence of 11778 G>A mutation on the mtND6 gene. The medical history, the fundus appearance, the OCT, and the paraclinical investigations, made us diagnose our patient with Leber\'s hereditary optic neuropathy. As soon as possible, we began the treatment with systemic idebenone, 900 mg/day. We examined the patient 2, 6, and 10 weeks after initiating the treatment. Abbreviations: LHON = Leber\'s Hereditary Optic Neuropathy, mtDNA = mitochondrial DNA, VA = visual acuity, RE = right eye, LE = left eye, OCT = Optical coherence tomography, pRNFL = peripapillary retinal nerve fiber layer, GCL = retinal ganglion cells layer, MRI = magnetic resonance imaging, VEP = visual evoked potentials, VEP IT = VEP implicit time, VEP A = VEP amplitude.

Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone\'s capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.