UNASSIGNED: Variants in the PARS2 gene have been previously associated with developmental and epileptic encephalopathy. PARS2 deficiency was characterized as a neurodevelopmental and neurodegenerative disorder with early-onset seizures and global developmental delay. Herein, we reported the first case with severe heart failure due to lethal mitochondrial cardiomyopathy with PARS2 compound heterozygous variants.
UNASSIGNED: This patient demonstrated fatigue, chest tightness, and shortness of breath. An acute major illness had been identified at the initial evaluation, which was characterized by severe diaphoresis, dizziness, and fatigue. Blood-urine tandem mass spectrometry found multiple disorders in acid metabolism, characterized as increased homovanillic acid (130.39 mmol/L) and 2-hydroxyisovaleric acid (1.70 mmol/L), which are associated with myocardial injuries. Therefore, an inherited metabolic disorder was suspected and whole-exome sequencing was performed, revealing a novel compound heterozygous variant of c.953C>T and c.283G>A on PARS2. Echocardiography confirmed the findings from the MRI, which presented an increased left ventricular diameter at the end of the diastolic stage. The molecular structure of SYPM was established as AF-Q7L3T8-F1, and the identified mutant sites were located in the proline-tRNA ligase domain. However, the patient died due to severe heart failure.
UNASSIGNED: This is the first case to reveal a novel compound heterozygous variant of PARS2-induced lethal cardiomyopathy with unreversed heart failure. Thus, this report enhances our understanding of mitochondrial tRNA function in maintaining heart function.

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder with diverse characteristics, which make early diagnosis difficult. We report a case of 32-year-old woman with diabetes who was admitted due to weight loss and poor glycemic control. She had a history of gestational diabetes at age 26. Pancreatic function was evaluated by oral glucose tolerance. An ophthalmologic examination detected conjunctivitis and refractive errors and hearing tests were normal. The patient had a family of diabetes. Then we tested the patient and her first-degree relatives with a confirmed genetic mutation at position 3243 in the tRNA. After two years of treatment with linagliptin, both glycated hemoglobin and pancreatic function have shown improvement to some extent. Although MIDD is a rare form of diabetes, due to distinctive management and associated comorbidities it is important to diagnose.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) belongs to the group of mitochondrial encephalomyopathies. Anaesthesia for patients with CPEO may be associated with an increased risk due to known drug effects on mitochondrial metabolism. Therefore, the aim of this analysis was to evaluate anaesthesiological concepts in patients with CPEO requiring ophthalmic surgery.
METHODS: This is a retrospective, monocentric cohort analysis of eleven patients with CPEO undergoing ophthalmic surgery either with general anaesthesia or local anaesthesia in a German university hospital from January 2012 to February 2022.
RESULTS: A total of twelve ophthalmic surgery procedures were performed in eleven adult patients with CPEO. Six patients underwent surgery after receiving local anaesthesia (LA cohort). Five patients underwent six surgical procedures under general anaesthesia (GA cohort). In five cases within the GA cohort, propofol and remifentanil were used for the maintenance of anaesthesia. In one case, balanced anaesthesia with desflurane and remifentanil was used. The median duration of general anaesthesia was 37.5 min (range, 25-65 min). Patients stayed in the recovery room for a median of 48.5 min (range, 35-70 min). All patients were discharged on the first postoperative day. No relevant complications occurred in either the LA or GA cohort.
CONCLUSIONS: Both local and general anaesthesia are feasible concepts for patients with CPEO undergoing ophthalmic surgery. Propofol, at least with a short duration (less than one hour) of use, appears to be a feasible hypnotic drug in CPEO patients.

Exposure to bisphenol A (BPA) during gestation and lactation is considered to be a potential risk factor for autism spectrum disorder (ASD) in both humans and animals. As a novel alternative to BPA, 4-hydroxy-4\'-isopropoxydiphenylsulfone (BPSIP) is frequently detected in breast milk and placental barrier systems, suggesting potential transmission from the mother to offspring and increased risk of exposure. Gestation and lactation are critical periods for central nervous system development, which are vulnerable to certain environmental pollutants. Herein, we investigated the behavioral impacts and neurobiological effects of early-life exposure to BPSIP (0.02, 0.1, and 0.5 mg/kg body weight/day) in mice offspring. Behavioral studies indicated that BPSIP exposure induced ASD-like behaviors, including elevated anxiety-related behavior and decreased spatial memory, in both male and female pups. A distinct pattern of reduced social novelty was observed only in female offspring, accompanied by significant alterations in antioxidant levels. Transcriptome analysis demonstrated that differentially expressed genes (DEGs) were mainly enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, a decrease in the protein levels of complex IV (COX IV) across all tested populations suggests a profound impact on mitochondrial function, potentially leading to abnormal energy metabolism in individuals with autism. Additionally, changes in synaptic proteins, evidenced by alterations in synapsin 1 (SYN1) and postsynaptic density protein-95 (PSD95) levels in the cerebellum and hippocampus, support the notion of synaptic involvement. These findings suggest that BPSIP may induce sex-specific neurotoxic effects that involve oxidative stress, energy generation, and synaptic plasticity.

Leigh syndrome (LS), a complex multisystemic disorder, poses significant challenges in genetic medicine due to its intricate pathogenesis and wide-ranging clinical manifestations. Notably, these arise from mutations in either nuclear genetic DNA or mitochondrial DNA, affecting ATP production and resulting in diverse clinical outcomes. The unpredictable trajectory of this disease, ranging from severe developmental delays to early mortality, underscores the need for improved therapeutic solutions. This research pivots toward the novel use of induced pluripotent stem cells (iPSCs) as a promising platform for understanding disease mechanisms and spearheading patient-specific drug discoveries. Given the past successes of iPSCs in delineating organ-specific disorders and the recent endorsement of human iPSC-derived cardiomyocytes (CMs) by the FDA for drug evaluation, our work seeks to bridge this innovation to Leigh syndrome research. We detail a methodological approach to generate iPSCs from LS patients and differentiate them into iPSCs-CMs. Using multi-electrode array (MEA) analyses, we evaluate the field potential of these cells, spotlighting the potential of hiPSC-CM in drug validation and disease modeling. This pioneering approach offers a glimpse into the future of patient-centric therapeutic interventions for Leigh/Leigh-like syndrome.

UNASSIGNED: Mitochondrial diseases are known inborn errors affecting energy metabolism and are as common as chronic diseases such as diabetes, affecting approximately 1 in 5,000 people. The role of mitochondrial diseases/dysfunction has been highlighted in neurodevelopmental disorders like ASD, ADHD, intellectual disability, and speech delay, as well as various psychiatric conditions. Neurodevelopmental disorders are increasingly recognized as having behavioral and psychiatric symptoms. Our study aimed to investigate reports of mitochondrial disorders, noting neurodevelopmental disorders and psychiatric/behavioral conditions.
UNASSIGNED: This was done through a systematic review of literature from PubMed/MEDLINE, Scopus, and Cochrane Library up to November 2022.
UNASSIGNED: We found 277 publications, of which 139 met the inclusion criteria. We mostly found review articles with mention of mitochondrial dysfunction/disorder in relation to ASD with brief mentions of psychiatric/behavioral comorbidities.
UNASSIGNED: This suggests a need for broader research efforts beyond ASD to understand the relationship between mitochondrial disorder or dysfunction and various neurodevelopmental and psychiatric/behavioral comorbidities.

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.

UNASSIGNED: Cytochrome C oxidase (COX) deficiency is an uncommon inherited metabolic disorder. It is identified by a lack of the COX, also known as Complex IV. This enzyme plays a crucial role in the rate-limiting and oxygen-accepting step of the respiratory chain within the subcellular structures called mitochondria. The deficiency of COX can either be restricted to skeletal muscle tissues or can impact multiple tissues throughout the body.
UNASSIGNED: A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor. Leukodystrophy was observed in the brain magnetic resonance imaging, and genome sequencing identified a homozygous mutation in exon 1 and 7 of chromosome 17. This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV.
UNASSIGNED: In the medical field, inherited metabolic disorders can be complex to diagnose due to overlapping symptoms with other conditions. Mitochondria\'s oxidative phosphorylation system, including the COX enzyme complex, plays a crucial role in energy production. Mitochondrial disorders, including COX deficiency, can present at various stages of life with diverse symptoms. Treatment options focus on supportive care and potential benefits from supplements like coenzyme-Q10 and small-molecule therapies targeting mitochondrial function. Identifying genetic mutations is key for advancing treatments in this area.
UNASSIGNED: This report presents a unique case of developmental regression and muscle weakness in a paediatric patient, which can be attributed to a rare occurrence of type 3 nuclear mitochondrial complex IV deficiency.

UNASSIGNED: Acute kidney injury (AKI) is a severe condition marked by rapid renal function deterioration and elevated mortality, with traditional biomarkers lacking sensitivity and specificity. Rare tubulointerstitial diseases encompass a spectrum of disorders, primarily including monogenic diseases, immune-related conditions, and drug-induced tubulointerstitial diseases. The clinical manifestations vary from electrolyte and acid-base imbalances to kidney function insufficiency, which is associated with AKI in up to 20% of cases. Evidence indicated that rare tubulointerstitial diseases might provide new conceptual insights and perspectives for novel biomarkers and potential therapeutic strategies for AKI.
UNASSIGNED: Autosomal dominant tubulointerstitial kidney disease (ADTKD) and Fanconi syndrome (FS) are rare tubulointerstitial diseases. In ADTKD, UMOD and REN are closely related to AKI by affecting oxidative stress and tubuloglomerular feedback, which provide potential new biomarkers for AKI. Both rare tubulointerstitial diseases and AKI share etiologies and treatment responses. From the mechanism standpoint, rare tubulointerstitial diseases and AKI involve tubular transporter injury, initially manifesting as tubular dysfunction in tubulointerstitial disorder and progressing to AKI because of the programmed cell death with apoptosis, pyroptosis, or necroptosis of proximal tubule cells. Additionally, mitochondrial dysfunction has been identified as a common mechanism in both tubulointerstitial diseases and AKI induced by drugs, pSS, or monoclonal diseases. In the end, both AKI and FS patients and animal models responded well to the therapy of the primary diseases.
UNASSIGNED: In this review, we describe an overview of ADTKD and FS to identify their associations with AKI. Mitochondrial dysfunction contributes to rare tubulointerstitial diseases and AKI, which might provide a potential therapeutic target.

Reactive oxygen species (ROS) are metabolic by-products of cells, and abnormal changes in their levels are often associated with tumor development. Our aim was to determine the role of collagen and calcium binding EGF domain 1 (CCBE1) in oxidative stress and tumorigenesis in non-small cell lung cancer cells (NSCLC). We investigated the tumorigenic potential of CCBE1 in NSCLC using in vitro and in vivo models of CCBE1 overexpression and knockdown. Immunohistochemical staining results showed that the expression of CCBE1 in cancer tissues was significantly higher than that in adjacent tissues. Cell counting Kit 8, clonal formation, wound healing, and transwell experiments showed that CCBE1 gene knockdown significantly inhibited the migration, invasion, and proliferation of NSCLC cell lines. In terms of mechanism, the silencing of CCBE1 can significantly promote the morphological abnormalities of mitochondria, significantly increase the intracellular ROS level, and promote cell apoptosis. This change of oxidative stress can affect cell proliferation, migration, and invasion by regulating the phosphorylation level of ERK/JNK/P38 MAPK. Specifically, the downregulation of CCBE1 inhibits the phosphorylation of ERK/P38 and promotes the phosphorylation of JNK in NSCLC, and this regulation can be reversed by the antioxidant NAC. In vivo experiments confirmed that downregulating CCBE1 gene could inhibit the growth of NSCLC in BALB/c nude mice. Taken together, our results confirm the tumorigenic role of CCBE1 in promoting tumor invasion and migration in NSCLC, and reveal the molecular mechanism by which CCBE1 regulates oxidative stress and the ERK/JNK/P38 MAPK pathway.