Pyruvate dehydrogenase is a potential mitochondrial off-target for gentamicin based on in silico predictions and in vitro inhibition studies.

During the drug development process, organ toxicity leads to an estimated failure of one-third of novel chemical entities. Drug-induced toxicity is increasingly associated with mitochondrial dysfunction, but identifying the underlying molecular mechanisms remains a challenge. Computational modeling techniques have proven to be a good tool in searching for drug off-targets.

Metabolic impact of genetic and chemical ADP/ATP carrier inhibition in renal proximal tubule epithelial cells.

Mitochondrial dysfunction is pivotal in drug-induced acute kidney injury (AKI), but the underlying mechanisms remain largely unknown. Transport proteins embedded in the mitochondrial inner membrane form a significant class of potential drug off-targets. So far, most transporter-drug interactions have been reported for the mitochondrial ADP/ATP carrier (AAC).

Time to Change: A Systems Pharmacology Approach to Disentangle Mechanisms of Drug-Induced Mitochondrial Toxicity.

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all Food and Drug Administration black box warnings, a variety of drug withdrawals, and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches.

Identifying trajectories of fatigue in patients with primary mitochondrial disease due to the m.3243A > G variant.

Severe fatigue is a common complaint in patients with primary mitochondrial disease. However, less is known about the course of fatigue over time. This longitudinal observational cohort study of patients with the mitochondrial DNA 3243 A>G variant explored trajectories of fatigue over 2 years, and characteristics of patients within these fatigue trajectories.

The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.

Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP) cations is a widely applied strategy for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant Trolox increases the levels of active mitochondrial complex I (CI), the first complex of the electron transport chain (ETC), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency. Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C-TPP).

Restoring cellular NAD(P)H levels by PPARα and LXRα stimulation to improve mitochondrial complex I deficiency.

Unlabelled: Mitochondrial complex I (CI), the first multiprotein enzyme complex of the oxidative phosphorylation system, plays a crucial role in cellular energy production. CI deficiency is associated with a variety of clinical phenotypes, including Leigh syndrome. At the cellular level, an increased NAD(P)H concentration is one of the hallmarks in CI-deficiency.

Dissecting Drug-Induced Cytotoxicity and Metabolic Dysfunction in Conditionally Immortalized Human Proximal Tubule Cells.

Fourteen to 26 percent of all hospitalized cases of acute kidney injury are explained by drug-induced toxicity, emphasizing the importance of proper strategies to pre-clinically assess renal toxicity. The MTT assay is widely used as a measure of cell viability, but largely depends on cellular metabolic activity. Consequently, MTT as a single assay may not be the best way to assess cytotoxicity of compounds that reduce mitochondrial function and cellular metabolic activity without directly affecting cell viability.

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study.

Background: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing.

The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury.

Purpose: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m's potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia.

Cognitive functioning and mental health in mitochondrial disease: A systematic scoping review.

Mitochondrial diseases (MDs) are rare, heterogeneous, hereditary and progressive in nature. In addition to the serious somatic symptoms, patients with MD also experience problems regarding their cognitive functioning and mental health. We provide an overview of all published studies reporting on any aspect of cognitive functioning and/or mental health in patients with MD and their relatives.

One mutation, three phenotypes: novel metabolic insights on MELAS, MIDD and myopathy caused by the m.3243A > G mutation.

Introduction: The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell's energy production.

Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice.

The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders.

Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population.

Background: Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.

NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4 mice and Leigh syndrome patients: A stabilizing role for NDUFAF2.

Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4 mouse tissues.

Psychological functioning in children suspected for mitochondrial disease: the need for care.

Background: Mitochondrial diseases (MD) are generally serious and progressive, inherited metabolic diseases. There is a high comorbidity of anxiety and depression and limitations in daily functioning. The complexity and duration of the diagnostic process and lack of knowledge about prognosis leads to uncertainty.

Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice.

Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature.

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1.

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment.

Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT).

Five non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype adult patients with m.3243A>G mutation after kidney transplantation: follow-up and review of the literature.

Background: Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking.

To be or not to be pink(1): contradictory findings in an animal model for Parkinson's disease.

The PTEN-induced putative kinase 1 knockout rat (Pink1) is marketed as an established model for Parkinson's disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1 rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by microdialysis.

A Mitochondrial Complex I Deficiency Phenotype Array.

Mitochondrial diseases are a group of rare life-threatening diseases often caused by defects in the oxidative phosphorylation system. No effective treatment is available for these disorders. Therapeutic development is hampered by the high heterogeneity in genetic, biochemical, and clinical spectra of mitochondrial diseases and by limited preclinical resources to screen and identify effective treatment candidates.

Live-Imaging Readouts and Cell Models for Phenotypic Profiling of Mitochondrial Function.

Mitochondria are best known as the powerhouses of the cells but their cellular role goes far beyond energy production; among others, they have a pivotal function in cellular calcium and redox homeostasis. Mitochondrial dysfunction is often associated with severe and relatively rare disorders with an unmet therapeutic need. Given their central integrating role in multiple cellular pathways, mitochondrial dysfunction is also relevant in the pathogenesis of various other, more common, human pathologies.

Octa-arginine boosts the penetration of elastin-like polypeptide nanoparticles in 3D cancer models.

Elastin-like polypeptide (ELP) nanoparticles are a versatile platform for targeted drug delivery. As for any type of nanocarrier system, an important challenge remains the ability of deep (tumor) tissue penetration. In this study, ELP particles with controlled surface density of the cell-penetrating peptide (CPP) octa-arginine (R8) were created by temperature-induced co-assembly.