The molecular machinery for maturation of primary mtDNA transcripts.

Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer.

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.

The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.

Genetic and sporadic forms of tauopathies-TAU as a disease driver for the majority of patients but the minority of tauopathies.

Ageing-associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann-Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT-related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU-based therapies.

Mitochondrial dysfunction-associated microbiota establishes a transmissible refractory response to anti-TNF therapy during ulcerative colitis.

Anti-TNF therapy can induce and maintain a remission status during intestinal bowel disease. However, up to 30% of patients do not respond to this therapy by mechanisms that are unknown. Here, we show that the absence of MCJ, a natural inhibitor of the respiratory chain Complex I, induces gut microbiota changes that are critical determinants of the lack of response in a murine model of DSS-induced inflammation. First, we found that MCJ expression is restricted to macrophages in human colonic tissue. Therefore, we demonstrate by transcriptomic analysis of colon macrophages from DSS-induced mice that MCJ-deficiency is linked to the expression of genes belonging to the FcγR signaling pathway and contains an anti-TNF refractory gene signature identified in ulcerative colitis patients. The gut microbial composition changes observed upon DSS treatment in the MCJ-deficient mice revealed the increased presence of specific colitogenic members, including Ruminococcus gnavus and Oscillospira, which could be associated with the non-response to TNF inhibitors. Further, we show that the presence of a microbiota associated resistance to treatment is dominant and transmissible to responsive individuals. Collectively, our findings underscore the critical role played by macrophage mitochondrial function in the gut ecological niche that can substantially affect not only the severity of inflammation but also the ability to successfully respond to current therapies.

Endothelial Cell Dysfunction and Hypoxia as Potential Mediators of Pain in Fabry Disease: A Human-Murine Translational Approach.

Fabry disease (FD) is caused by α-galactosidase A (AGAL) enzyme deficiency, leading to globotriaosylceramide accumulation (Gb3) in several cell types. Pain is one of the pathophysiologically incompletely understood symptoms in FD patients. Previous data suggest an involvement of hypoxia and mitochondriopathy in FD pain development at dorsal root ganglion (DRG) level. Using immunofluorescence and quantitative real-time polymerase chain reaction (qRT PCR), we investigated patient-derived endothelial cells (EC) and DRG tissue of the GLA knockout (KO) mouse model of FD. We address the question of whether hypoxia and mitochondriopathy contribute to FD pain pathophysiology. In EC of FD patients (P1 with pain and, P2 without pain), we found dysregulated protein expression of hypoxia-inducible factors (HIF) 1a and HIF2 compared to the control EC (p < 0.01). The protein expression of the HIF downstream target vascular endothelial growth factor A (VEGFA, p < 0.01) was reduced and tube formation was hampered in the P1 EC compared to the healthy EC (p < 0.05). Tube formation ability was rescued by applying transforming growth factor beta (TGFß) inhibitor SB-431542. Additionally, we found dysregulated mitochondrial fusion/fission characteristics in the P1 and P2 EC (p < 0.01) and depolarized mitochondrial membrane potential in P2 compared to control EC (p < 0.05). Complementary to human data, we found upregulated hypoxia-associated genes in the DRG of old GLA KO mice compared to WT DRG (p < 0.01). At protein level, nuclear HIF1a was higher in the DRG neurons of old GLA KO mice compared to WT mice (p < 0.01). Further, the HIF1a downstream target CA9 was upregulated in the DRG of old GLA KO mice compared to WT DRG (p < 0.01). Similar to human EC, we found a reduction in the vascular characteristics in GLA KO DRG compared to WT (p < 0.05). We demonstrate increased hypoxia, impaired vascular properties, and mitochondrial dysfunction in human FD EC and complementarily at the GLA KO mouse DRG level. Our data support the hypothesis that hypoxia and mitochondriopathy in FD EC and GLA KO DRG may contribute to FD pain development.

Deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax: a case report.

BACKGROUND: Deoxyguanosine kinase deficiency is mainly manifested by hepatic and neurological damage, hence it belongs to the hepatocerebral form of mitochondrial deoxyribonucleic acid depletion syndrome. The association between deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax has not currently been reported. CASE PRESENTATION: A 12-year-old Russian boy with deoxyguanosine kinase deficiency, a recipient of a liver transplant with amyotrophy secondary to his mitochondriopathy, presented with recurrent spontaneous bilateral pneumothorax refractory to drainage and surgery. CONCLUSION: To our knowledge, this is the first documented case of deoxyguanosine kinase deficiency associated with recurrent spontaneous pneumothorax, which could be considered a late complication of deoxyguanosine kinase deficiency. At this point, this is only an association and further studies and research need to be performed to help confirm the pathogenesis of this association.

The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications.

RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. KEY MESSAGES: RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause.

Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene.

We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15 years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1-2 beers, 3 years after her sister´s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including PPA2) showed SCN5A and CACNA1D variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided.   Conclusion: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol. What is Known: • Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias. • Variants of unknown significance can lead to misinterpretation. PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy. What is New: • Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle.

Diet-induced obesity augments ischemic myopathy and functional decline in a murine model of peripheral artery disease.

Peripheral artery disease (PAD) causes an ischemic myopathy contributing to patient disability and mortality. Most preclinical models to date use young, healthy rodents with limited translatability to human disease. Although PAD incidence increases with age, and obesity is a common comorbidity, the pathophysiologic association between these risk factors and PAD myopathy is unknown. Using our murine model of PAD, we sought to elucidate the combined effect of age, diet-induced obesity and chronic hindlimb ischemia (HLI) on (1) mobility, (2) muscle contractility, and markers of muscle (3) mitochondrial content and function, (4) oxidative stress and inflammation, (5) proteolysis, and (6) cytoskeletal damage and fibrosis. Following 16-weeks of high-fat, high-sucrose, or low-fat, low-sucrose feeding, HLI was induced in 18-month-old C57BL/6J mice via the surgical ligation of the left femoral artery at 2 locations. Animals were euthanized 4-weeks post-ligation. Results indicate mice with and without obesity shared certain myopathic changes in response to chronic HLI, including impaired muscle contractility, altered mitochondrial electron transport chain complex content and function, and compromised antioxidant defense mechanisms. However, the extent of mitochondrial dysfunction and oxidative stress was significantly greater in obese ischemic muscle compared to non-obese ischemic muscle. Moreover, functional impediments, such as delayed post-surgical recovery of limb function and reduced 6-minute walking distance, as well as accelerated intramuscular protein breakdown, inflammation, cytoskeletal damage, and fibrosis were only evident in mice with obesity. As these features are consistent with human PAD myopathy, our model could be a valuable tool to test new therapeutics.

Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation - a case report.

BACKGROUND: Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome. CASE PRESENTATION: The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally. CONCLUSION: CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.

Is Long COVID Syndrome a Transient Mitochondriopathy Newly Discovered: Implications of CPET.

The new outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has an impact worldwide, primarily as a medical emergency. Even that the total constellation is considered as a pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19) gives rise to dysfunction in multiple organs (e.g., brain, lungs, heart, muscles) that impairs cardiopulmonary (CP) function. Parallel to the CP consequences of COVID-19 is a significant reduction in physical activity. Cardiopulmonary exercise testing (CPET) is daily used in clinical practice to define prognosis, provide risk stratification and treatment strategy. As such, the significance of CPET is crucial concerning clinical assessments of COVID-19 patients. Furthermore, new studies aim at understanding the effects of SARS-CoV-2 infection in long term. Multiple studies have investigated the cardiopulmonary function and impairment of exercise endurance in such patients, as well as a possible prolonged physical impairment. With this review, we summarize the COVID-19-associated pathophysiology for the Long COVID (LC) syndrome as well as the importance of performing CPET.

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis.

Desmin mutations cause familial and sporadic cardiomyopathies. In addition to perturbing the contractile apparatus, both desmin deficiency and mutated desmin negatively impact mitochondria. Impaired myocardial metabolism secondary to mitochondrial defects could conceivably exacerbate cardiac contractile dysfunction. We performed metabolic myocardial phenotyping in left ventricular cardiac muscle tissue in desmin knock-out mice. Our analyses revealed decreased mitochondrial number, ultrastructural mitochondrial defects, and impaired mitochondria-related metabolic pathways including fatty acid transport, activation, and catabolism. Glucose transporter 1 and hexokinase-1 expression and hexokinase activity were increased. While mitochondrial creatine kinase expression was reduced, fetal creatine kinase expression was increased. Proteomic analysis revealed reduced expression of proteins involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta-oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Thus, desmin deficiency elicits a secondary cardiac mitochondriopathy with severely impaired oxidative phosphorylation and fatty and amino acid metabolism. Increased glucose utilization and fetal creatine kinase upregulation likely portray attempts to maintain myocardial energy supply. It may be prudent to avoid medications worsening mitochondrial function and other metabolic stressors. Therapeutic interventions for mitochondriopathies might also improve the metabolic condition in desmin deficient hearts.

Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.

BACKGROUND: COQ4 codes for a mitochondrial protein required for coenzyme Q10 (CoQ10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ10 deficiency leads to an early-onset mitochondrial multi-organ disorder. METHODS: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines. RESULTS: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ways and Means of Cellular Reconditioning for Kidney Regeneration.

BACKGROUND: Mitochondrial, lysosomal, and peroxisomal dysfunction; defective autophagy; mitophagy; and pexophagy, as well as the loss of glycocalyx integrity are known contributors to initiation and progression of diverse kidney diseases. Those cellular organelles are tightly interactive in health, and during development of a disease, damage in one may propagate to others. By extension, it follows that restoring an individual defect may culminate in a broader restorative spectrum and improvement of cell and organ functions. SUMMARY: A novel strategy of reconditioning cellular organellar dysfunction, which we define as refurbishment of pathogenically pivotal intra- or extracellular elements, damaged in the course of disease and impeding restoration, is briefly outlined in this overview. Individual therapeutic reconditioning approaches targeting selected organelles are cataloged. We anticipate that the proposed reconditioning strategy in the future may enrich the arsenal of regenerative medicine and nephrology. KEY MESSAGE: The arsenal of regenerative medicine and nephrology consisting of organ transplantation, use of stem cells, cell-free approaches, cell reprogramming strategies, and organ engineering has been enriched by the reconditioning strategy. The latter is based on the recognition of two facts that (a) impairment of diverse cellular organelles contributes to pathogenesis of kidney disease and (b) individual organelles are functionally interactively coupled, which explains the "domino effect" leading to their dysfunction. Reconditioning takes advantage of these facts and, while initially directed to restore the function of individual cellular organelles, culminates in the propagation of a therapeutic intervention to account for improved cell and organ function. Examples of such interventions are briefly summarized along the presentation of defective cellular organelles contributing to pathogenesis of kidney disease.

A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.

Loss of neuronal polarity and missorting of the axonal microtubule-associated-protein TAU are hallmarks of Alzheimer's disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and-here important-TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-missorting, indicating involvement of mitochondria in TAU-polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.

Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.

OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.

Systemic Effects Reflected in Specific Biomarker Patterns Are Instrumental for the Paradigm Change in Prostate Cancer Management: A Strategic Paper.

Prostate cancer (PCa) is reported as the most common malignancy and second leading cause of death in America. In Europe, PCa is considered the leading type of tumour in 28 European countries. The costs of treating PCa are currently increasing more rapidly than those of any other cancer. Corresponding economic burden is enormous, due to an overtreatment of slowly developing disease on one hand and underestimation/therapy resistance of particularly aggressive PCa subtypes on the other hand. The incidence of metastatic PCa is rapidly increasing that is particularly characteristic for young adults. PCa is a systemic multi-factorial disease resulting from an imbalanced interplay between risks and protective factors. Sub-optimal behavioural patterns, abnormal stress reactions, imbalanced antioxidant defence, systemic ischemia and inflammation, mitochondriopathies, aberrant metabolic pathways, gene methylation and damage to DNA, amongst others, are synergistically involved in pathomechanisms of PCa development and progression. To this end, PCa-relevant systemic effects are reflected in liquid biopsies such as blood patterns which are instrumental for predictive diagnostics, targeted prevention and personalisation of medical services (PPPM/3P medicine) as a new paradigm in the overall PCa management. This strategic review article highlights systemic effects in prostate cancer development and progression, demonstrates evident challenges in PCa management and provides expert recommendations in the framework of 3P medicine.

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention.

Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.

Chromium and cobalt intoxication mimicking mitochondriopathy.

A 53-year old male with a history of progressive visual impairment, hearing loss, peripheral neuropathy, poorly controlled diabetes mellitus, cardiomyopathy, and weight loss was referred to the rare disease center due to the suspicion of mitochondrial cytopathy. In line with mitochondrial dysfunction, lactate in CSF was increased. Genetic testing by whole-exome sequencing and mitochondrial DNA did not reveal a likely cause. The case remained unsolved until he developed pain in his right hip, where he had received total hip arthroplasty 12 years earlier. An orthopedic evaluation revealed substantial shrinkage of the head of the hip prosthesis. Due to metal-on-metal wear, debris chromium and cobalt levels in serum were massively increased and significantly improved with multisystemic impairment after exchanging the defective implant.