Can chatbots enhance the management of pediatric sialadenitis in clinical practice?

OBJECTIVE: The purpose of this study was to assess how well ChatGPT, an AI-powered chatbot, performed in helping to manage pediatric sialadenitis and identify when sialendoscopy was necessary. METHODS: 49 clinical cases of pediatric sialadenitis were retrospectively reviewed. ChatGPT was given patient data, and it offered differential diagnoses, proposed further tests, and suggested treatments. The decisions made by the treating otolaryngologists were contrasted with the answers provided by ChatGPT. Analysis was done on ChatGPT response consistency and interrater reliability. RESULTS: ChatGPT showed 78.57% accuracy in primary diagnosis, and 17.35% of cases were considered likely. On the other hand, otolaryngologists recommended fewer further examinations than ChatGPT (111 vs. 60, p < 0.001). For additional exams, poor agreement was found between ChatGPT and otolaryngologists. Only 28.57% of cases received a pertinent and essential treatment plan via ChatGPT, indicating that the platform's treatment recommendations were frequently lacking. For treatment ratings, judges' interrater reliability was greatest (Kendall's tau = 0.824, p < 0.001). For the most part, ChatGPT's response constancy was high. CONCLUSIONS: Although ChatGPT has the potential to correctly diagnose pediatric sialadenitis, there are a number of noteworthy limitations with regard to its ability to suggest further testing and treatment regimens. Before widespread clinical use, more research and confirmation are required. To guarantee that chatbots are utilized properly and effectively to supplement human expertise rather than to replace it, a critical viewpoint is required.

Mitochondrial iron deficiency triggers cytosolic iron overload in PKAN hiPS-derived astrocytes.

Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.

Iron imbalance in neurodegeneration.

Iron is an essential element for the development and functionality of the brain, and anomalies in its distribution and concentration in brain tissue have been found to be associated with the most frequent neurodegenerative diseases. When magnetic resonance techniques allowed iron quantification in vivo, it was confirmed that the alteration of brain iron homeostasis is a common feature of many neurodegenerative diseases. However, whether iron is the main actor in the neurodegenerative process, or its alteration is a consequence of the degenerative process is still an open question. Because the different iron-related pathogenic mechanisms are specific for distinctive diseases, identifying the molecular mechanisms common to the various pathologies could represent a way to clarify this complex topic. Indeed, both iron overload and iron deficiency have profound consequences on cellular functioning, and both contribute to neuronal death processes in different manners, such as promoting oxidative damage, a loss of membrane integrity, a loss of proteostasis, and mitochondrial dysfunction. In this review, with the attempt to elucidate the consequences of iron dyshomeostasis for brain health, we summarize the main pathological molecular mechanisms that couple iron and neuronal death.

Intraoperative Neuromonitoring Does Not Reduce the Risk of Temporary and Definitive Recurrent Laryngeal Nerve Damage during Thyroid Surgery: A Systematic Review and Meta-Analysis of Endoscopic Findings from 73,325 Nerves at Risk.

BACKGROUND: While intraoperative neuromonitoring (IONM) helps the early identification of recurrent laryngeal nerve (RLN) damage, IONM's role in RLN damage prevention is not defined, given the lack of large studies on the subject. METHODS: In a PRISMA-compliant framework, all original thyroid surgery prospective studies providing early postoperative endoscopic data for all patients were pooled in a random-effects meta-analysis. We compared the temporary (and definitive where available) RLN damage rates according to IONM use and IONM type (intermittent, I-IONM, or continuous, C-IONM). RESULTS: We identified 2358 temporary and 257 definitive RLN injuries in, respectively, 73,325 and 66,476 nerves at risk. The pooled temporary and definitive RLN injury rates were, respectively, 3.15% and 0.422% considering all procedures, 3.29% and 0.409% in cases using IONM, and 3.16% and 0.463 in cases not using IONM. I-IONM and C-IONM, respectively, showed a pooled temporary RLN injury rate of 2.48% and 2.913% and a pooled definitive injury rate of 0.395% and 0.4%. All pooled rates had largely overlapping 95% confidence intervals. CONCLUSIONS: Our data suggest that IONM does not affect the temporary or definitive RLN injury rate following thyroidectomy, though its use can be advised in selected cases and for bilateral palsy prevention.

PPAR Gamma Agonist Leriglitazone Recovers Alterations Due to Pank2-Deficiency in hiPS-Derived Astrocytes.

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN.

Association of pancreatitis with risk of diabetes: analysis of real-world data.

Introduction: Diabetes is a major cause of disease burden with considerable public health significance. While the pancreas plays a significant role in glucose homeostasis, the association between pancreatitis and new onset diabetes is not well understood. The purpose of this study was to examine that association using large real-world data. Materials and methods: Utilizing the IBM® MarketScan® commercial claims database from 2016 to 2019, pancreatitis and diabetes regardless of diagnostic category, were identified using International Classification of Diseases, Tenth Revision [ICD-10] codes. We then performed descriptive analyses characterizing non-pancreatitis (NP), acute pancreatitis (AP), and chronic pancreatitis (CP) cohort subjects. Stratified Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of diabetes across the three clinical categories. Results: In total, 310,962 individuals were included in the analysis. During 503,274 person-years of follow-up, we identified 15,951 incident diabetes cases. While men and women had higher incidence rates of CP and AP-related diabetes, the rates were significantly greater in men and highest among individuals with CP (91.6 per 1000 persons-years (PY)) followed by AP (75.9 per 1000-PY) as compared to those with NP (27.8 per 1000-PY). After adjustment for diabetes risk factors, relative to the NP group, the HR for future diabetes was 2.59 (95% CI: 2.45-2.74) (P<0.001) for the CP group, and 2.39 (95% CI: 2.30-2.48) (P<0.001) for the AP group. Conclusion: Pancreatitis was associated with a high risk of diabetes independent of demographic, lifestyle, and comorbid conditions.

PKAN hiPS-Derived Astrocytes Show Impairment of Endosomal Trafficking: A Potential Mechanism Underlying Iron Accumulation.

PKAN disease is caused by mutations in the PANK2 gene, encoding the mitochondrial enzyme pantothenate kinase 2, catalyzing the first and key reaction in Coenzyme A (CoA) biosynthetic process. This disorder is characterized by progressive neurodegeneration and excessive iron deposition in the brain. The pathogenic mechanisms of PKAN are still unclear, and the available therapies are only symptomatic. Although iron accumulation is a hallmark of PKAN, its relationship with CoA dysfunction is not clear. We have previously developed hiPS-derived astrocytes from PKAN patients showing iron overload, thus recapitulating the human phenotype. In this work, we demonstrated that PKAN astrocytes presented an increase in transferrin uptake, a key route for cellular iron intake via transferrin receptor-mediated endocytosis of transferrin-bound iron. Investigation of constitutive exo-endocytosis and vesicular dynamics, exploiting the activity-enriching biosensor SynaptoZip, led to the finding of a general impairment in the constitutive endosomal trafficking in PKAN astrocytes. CoA and 4-phenylbutyric acid treatments were found to be effective in partially rescuing the aberrant vesicular behavior and iron intake. Our results demonstrate that the impairment of CoA biosynthesis could interfere with pivotal intracellular mechanisms involved in membrane fusions and vesicular trafficking, leading to an aberrant transferrin receptor-mediated iron uptake.

Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype.

Neurodegeneration associated with defective pantothenate kinase-2 (PKAN) is an early-onset monogenic autosomal-recessive disorder. The hallmark of the disease is the massive accumulation of iron in the globus pallidus brain region of patients. PKAN is caused by mutations in the PANK2 gene encoding the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway. To date, the way in which this alteration leads to brain iron accumulation has not been elucidated. Starting from previously obtained hiPS clones, we set up a differentiation protocol able to generate inhibitory neurons. We obtained striatal-like medium spiny neurons composed of approximately 70-80% GABAergic neurons and 10-20% glial cells. Within this mixed population, we detected iron deposition in both PKAN cell types, however, the viability of PKAN GABAergic neurons was strongly affected. CoA treatment was able to reduce cell death and, notably, iron overload. Further differentiation of hiPS clones in a pure population of astrocytes showed particularly evident iron accumulation, with approximately 50% of cells positive for Perls staining. The analysis of these PKAN astrocytes indicated alterations in iron metabolism, mitochondrial morphology, respiratory activity, and oxidative status. Moreover, PKAN astrocytes showed signs of ferroptosis and were prone to developing a stellate phenotype, thus gaining neurotoxic features. This characteristic was confirmed in iPS-derived astrocyte and glutamatergic neuron cocultures, in which PKAN glutamatergic neurons were less viable in the presence of PKAN astrocytes. This newly generated astrocyte model is the first in vitro disease model recapitulating the human phenotype and can be exploited to deeply clarify the pathogenetic mechanisms underlying the disease.

Erythema Multiforme Major following SARS-CoV-2 vaccine.

Erythema multiforme major, an immune-mediated skin reaction to infections or medications with oral involvement, should be taken into account as a potential side effect of several vaccines, including SARS-CoV-2. Correct patient history collection allows prompt recognition and subsequent successful medical management with oral corticosteroids.

Mitochondrial Ferritin: Its Role in Physiological and Pathological Conditions.

In 2001, a new type of human ferritin was identified by searching for homologous sequences to H-ferritin in the human genome. After the demonstration that this ferritin is located specifically in the mitochondrion, it was called mitochondrial ferritin. Studies on the properties of this new type of ferritin have been limited by its very high homology with the cytosolic H-ferritin, which is expressed at higher levels in cells. This great similarity made it difficult to obtain specific antibodies against the mitochondrial ferritin devoid of cross-reactivity with cytosolic ferritin. Thus, the knowledge of the physiological role of mitochondrial ferritin is still incomplete despite 20 years of research. In this review, we summarize the literature on mitochondrial ferritin expression regulation and its physical and biochemical properties, with particular attention paid to the differences with cytosolic ferritin and its role in physiological condition. Until now, there has been no evidence that the alteration of the mitochondrial ferritin gene is causative of any disorder; however, the identified association of the mitochondrial ferritin with some disorders is discussed.

Pathogenic mechanism and modeling of neuroferritinopathy.

Neuroferritinopathy is a rare autosomal dominant inherited movement disorder caused by alteration of the L-ferritin gene that results in the production of a ferritin molecule that is unable to properly manage iron, leading to the presence of free redox-active iron in the cytosol. This form of iron has detrimental effects on cells, particularly severe for neuronal cells, which are highly sensitive to oxidative stress. Although very rare, the disorder is notable for two reasons. First, neuroferritinopathy displays features also found in a larger group of disorders named Neurodegeneration with Brain Iron Accumulation (NBIA), such as iron deposition in the basal ganglia and extrapyramidal symptoms; thus, the elucidation of its pathogenic mechanism may contribute to clarifying the incompletely understood aspects of NBIA. Second, neuroferritinopathy shows the characteristic signs of an accelerated process of aging; thus, it can be considered an interesting model to study the progress of aging. Here, we will review the clinical and neurological features of neuroferritinopathy and summarize biochemical studies and data from cellular and animal models to propose a pathogenic mechanism of the disorder.

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration.

Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease.

Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging.

Neuroferritinopathy (NF) is a movement disorder caused by alterations in the L-ferritin gene that generate cytosolic free iron. NF is a unique pathophysiological model for determining the direct consequences of cell iron dysregulation. We established lines of induced pluripotent stem cells from fibroblasts from two NF patients and one isogenic control obtained by CRISPR/Cas9 technology. NF fibroblasts, neural progenitors, and neurons exhibited the presence of increased cytosolic iron, which was also detectable as: ferritin aggregates, alterations in the iron parameters, oxidative damage, and the onset of a senescence phenotype, particularly severe in the neurons. In this spontaneous senescence model, NF cells had impaired survival and died by ferroptosis. Thus, non-ferritin-bound iron is sufficient per se to cause both cell senescence and ferroptotic cell death in human fibroblasts and neurons. These results provide strong evidence supporting the primary role of iron in neuronal aging and degeneration.

Iron Pathophysiology in Neurodegeneration with Brain Iron Accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of seriously devastating and life-threatening rare monogenic diseases characterized by focal iron accumulation in the brain. The main symptoms of NBIA comprise progressive movement disorder, often including painful dystonia, parkinsonism, mental disability, and early death. Currently, a single established therapy is not available to reverse the progression of these debilitating disorders. The complexity of NBIA emerged from the identification of various causative genes, and up to 15 genes have been identified to date. Although the NBIA genes are involved in different cellular biochemical pathways, they show the common characteristic of generating severe iron accumulation in the basal ganglia of the patients' brains. Thus, the molecular events that lead to brain iron overload and their important roles in the pathophysiology of the diseases are not easy to identify and are poorly understood. This review summarizes the current knowledge on NBIA disorders, with a particular focus on the data describing the role of iron in the pathogenic mechanisms.

Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis.

AIMS: Iron overload (IO) is a life-threatening complication of chronic hemolytic disorders such as ß-thalassemia. IO results in severe cellular oxidative damage, leading to organ failure. Peroxiredoxin-2 (Prx2), a typical 2-cysteine-(Cys)-peroxiredoxin, is an important component of the cytoprotective system, but its response to IO is still to be fully defined. RESULTS: We studied the effects of IO on Prx2-knockout mice (Prx2-/-). The absence of Prx2 enhanced toxicity due to IO on erythropoiesis. We found that IO failed to induce the typical hepcidin (Hamp) upregulation in Prx2-/- mice due to its failure to activate the signal transducer and activator of transcription-3 (STAT3) with intact Jak2 signaling. In Prx2-/- mice, the loss of Hamp response was also observed after administration of a single dose of oral iron. When lipopolysaccharide (LPS) was used to explore IL6-STAT3 activation in Prx2-/- mice, STAT3 activation and Hamp upregulation were once again defective. Treatment with PEP-fusion-recombinant-Prx2 (PEP Prx2) significantly increased STAT3 activation with upregulation of Hamp expression in both IO- and LPS-exposed Prx2-/- mice. We also confirmed the beneficial effects of PEP Prx2 on Hamp expression through STAT3 activation in ß-thalassemic mice. INNOVATION: We propose that Prx2 plays a key role in responding to cytotoxicity of IO, directly targeting STAT3-transcriptional factor in a Jak2-independent fashion and regulating Hamp in response to canonical stimuli. CONCLUSION: Collectively, our data highlight a novel role of Prx2 in iron homeostasis. Prx2 is a key cytoprotector against IO that is induced either by iron supplementation or due to chronic hemolysis as in ß-thalassemia. Prx2 is required to support STAT3 transcriptional activity and regulation of Hamp expression. Antioxid. Redox Signal. 28, 1-14.

Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an early onset and severely disabling neurodegenerative disease for which no therapy is available. PKAN is caused by mutations in PANK2, which encodes for the mitochondrial enzyme pantothenate kinase 2. Its function is to catalyze the first limiting step of Coenzyme A (CoA) biosynthesis. We generated induced pluripotent stem cells from PKAN patients and showed that their derived neurons exhibited premature death, increased ROS production, mitochondrial dysfunctions-including impairment of mitochondrial iron-dependent biosynthesis-and major membrane excitability defects. CoA supplementation prevented neuronal death and ROS formation by restoring mitochondrial and neuronal functionality. Our findings provide direct evidence that PANK2 malfunctioning is responsible for abnormal phenotypes in human neuronal cells and indicate CoA treatment as a possible therapeutic intervention.

H ferritin silencing induces protein misfolding in K562 cells: A Raman analysis.

The redox state of the cell is involved in the regulation of many physiological functions as well as in the pathogenesis of several diseases, and is strictly dependent on the amount of iron in its catalytically active state. Alterations of iron homeostasis determine increased steady-state concentrations of Reactive Oxygen Species (ROS) that cause lipid peroxidation, DNA damage and altered protein folding. Ferritin keeps the intracellular iron in a non-toxic and readily available form and consequently plays a central role in iron and redox homeostasis. The protein is composed by 24 subunits of the H- and L-type, coded by two different genes, with structural and functional differences. The aim of this study was to shed light on the role of the single H ferritin subunit (FHC) in keeping the native correct protein three-dimensional structure. To this, we performed Raman spectroscopy on protein extracts from K562 cells subjected to FHC silencing. The results show a significant increase in the percentage of disordered structures content at a level comparable to that induced by H2O2 treatment in control cells. ROS inhibitor and iron chelator were able to revert protein misfolding. This integrated approach, involving Raman spectroscopy and targeted-gene silencing, indicates that an imbalance of the heavy-to-light chain ratio in the ferritin composition is able to induce severe but still reversible modifications in protein folding and uncovers new potential pathogenetic mechanisms associated to intracellular iron perturbation.

A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits.

Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498-499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains. Transgenic mice in the FVB background showed high accumulation of the mutated ferritin in brain where it correlated with increased iron deposition with age, as scored by magnetic resonance imaging. Notably, the accumulation of iron-ferritin bodies was accompanied by signs of oxidative damage. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Nevertheless, also these mice showed oxidative alterations in the brain. Furthermore, post-natal hippocampal neurons obtained from these mice experienced a marked increased cell death in response to chronic iron overload and/or acute oxidative stress, in comparison to wild-type neurons. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Rotarod test revealed a progressive impaired motor coordination building up with age, FTL mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum. Our data show that our 498-499InsTC mouse models recapitulate early pathological and clinical traits of the human neuroferritinopathy, thus providing a valuable model for the study of the disease. Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy.

Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome.

The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient's fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.

Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.