Mitochondrial Diseases

AIm: This study evaluated the neuroprotective effect of intrathecally infused paclitaxel in the prevention of motoneuron death and mitochondrial dysfunction following brachial plexus avulsion injury. mATeRIAL and meTHods: Brachial root avulsion injury was induced in Sprague-Dawley rats. The Paclitaxel treatment group (n = 32) received a 5-d intrathecal infusion of paclitaxel (256 ng/d) via a micro infusion pump, whereas the Control group (n = 32) received normal saline. The cervical cord was harvested at survival times of 1, 2, 4, and 6 wk (n = 8 each). The number of surviving and nNOS-positive motoneurons at the injury level in the ventral horn was determined with NADPH-d histochemistry. Mitochondrial function at this location was measured with CcO histochemistry and densitometry. An independent t-test was applied to detect differences between the study groups at specific survival times. The Paclitaxel treatment group showed a significant relative reduction in nNOS expression at 2, 4, and 6 wk, and significantly improved mitochondrial function at 4 and 6 wk. Motoneuron survival was significantly increased at 2, 4, and 6 wk. CoNCLusIoN: Paclitaxel has a significant neuroprotective effect against spinal motoneuron degeneration following brachial plexus avulsion injury, which involves inhibition of nNOS expression and prevention of mitochondrial dysfunction.

The coexistence of neurogenic and myogenic features in
Scapuloperoneal syndrome is rarely ascribed to a single
gene. Defects in the nuclear envelope protein lamin A/C,
encoded by the LMNA gene, have been shown to be
associated with a variety of disorders affecting mainly the
muscular and adipose tissues and, more recently, with
autosomal recessive Charcot–Marie–Tooth type 2 neuropathy.
This report is about a patient presenting with features of
myopathy and neuropathy due to a dominant LMNA
mutation, suggesting that the peripheral nerve might be
affected in primary LMNA myopathy. Our observations
further support the marked intrafamilial and interfamilial
phenotypic heterogeneity associated with lamin A/C defects.

Mitochondrial myopathies are inborn metabolism defect diseases manifested by symptoms reflecting failure of the final step in the mitochondrial respiratory chain. Clinical expression of these conditions can vary widely, but typically includes organ systems with a high energy demand, such as striated muscle, myocardium, and nervous and liver tissues. In contrast, cutaneous manifestations are rare and are non-specific, most commonly presenting as pigmentation disorders. In this case report, we present a case of Alpers syndrome accompanied by hyperpigmentation and atrophy in skin folds.

Mitochondria display non-linear oscillation in NAD(P)H levels as a result of the delicate balance between NAD(P)H production during glycolysis and oxidation during the electron transport chain step. The purpose of this study was to examine the effects of selected elements on the mitochondrial oscillator in freshwater mussels Dreissena bugensis. Freshly isolated mitochondria were treated by increasing concentrations of zinc oxide nanoparticles (nZnO), erbium (Er) and lutetium (Lu) for 40 min, and the oscillations in NAD(P) H levels were measured using fluorescence spectroscopy. Under normal conditions, NAD(P)H levels oscillate with a period of 2 min (frequency 0.25) and an initial oxidation rate of NAD(P)H) during the first 20 min which stopped for the remainder of the exposure period. Exposure to the selected elements first showed that the NAD(P)H oxidation rate progressed well for over 20 min and the rate was significantly increased for nZnO (0.64 μg/L), Er (12 mg/L) and Lu (16 mg/...

TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a ...

Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history o...

Cardiac dysfunction occurs in several forms of limb girdle muscular dystrophy (LGMD). The aim of this study was to investigate cardiac involvement in calpainopathy (LGMD2A). Cardiovascular evaluation was performed in 10 patients with genetically verified LGMD2A by echocardiography, 3 Tesla - cardiovascular magnetic resonance, 24-h electrocardiography recordings with heart rate variability (HRV) analysis, and 24-h blood pressure recordings. No patient with calpainopathy showed impairment of left or right ventricular function. One patient had a small amount (2% of left ventricle mass) of late gadolinium enhancement. HRV analysis revealed no significant difference compared with external reference data. The main finding of this study is the lack of cardiac involvement in patients with calpainopathy. Cardiac involvement was not found, even in individuals with advanced age and greater disease severity. Furthermore, we did not observe an overall reduction of cardiac autonomic regulation in...

In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional, their DNA is damaged, and capillary cells undergo accelerated apoptosis. Matrix metalloproteinase-2 (MMP2) becomes activated and proapoptotic, and the therapies that inhibit the development of diabetic retinopathy alleviate MMP2 activation. The authors sought to elucidate the possible mechanism by which activated MMP2 contributes to mitochondrial dysfunction. METHODS. The effect of the regulation of MMP2 on mitochondrial dysfunction and the subcellular localization of the molecular chaperone important for mitochondrial integrity (Hsp60) and gap junction protein connexin 43 were investigated in retinal endothelial cells. The results were confirmed in retinal mitochondria isolated from diabetic mouse overexpressing Mn-SOD and in the retinas of normal rats that received intravitreal administration of MMP2. RESULTS. High glucose increased MMP2 and decreased connexin 43 in the mitochondria of retinal endothelial cells. Although the Hsp60 gene transcript was increased, its abundance in the mitochondria was decreased, and its interaction with MMP2 was increased. In mice, the overexpression of MnSOD protected retinal mitochondria from diabetes-induced increases in MMP2 and decreases in Hsp60 and connexin 43. MMP2 administration in normal rats damaged the retinal mitochondria, decreased Hsp60 and connexin 43, and accelerated the apoptosis of retinal capillary cells. CONCLUSIONS. Elevated MMP2 in the mitochondria degrades its membranes by modulating Hsp60 and damaging connexin 43, and this activates the apoptotic machinery. Better understanding of MMP2-mediated mitochondrial damage could help identify new strategies for the treatment of this blinding disease.

Mitochondrial complex I (NADH dehydrogenase) is a major contributor to neuronal energetics, and mutations in complex I lead to vision loss. Functional, neuroanatomical and transcriptional consequences of complex I deficiency were investigated in retinas of the Ndufs4 knockout mouse. Whole-eye ERGs and multielectrode arrays confirmed a major retinal ganglion cell functional loss at P32, and retinal ganglion cell loss at P42. RNAseq demonstrated a mild and then sharp increase in innate immune and inflammatory retinal transcripts at P22 and P33, respectively, which were confirmed with QRT-PCR. Intraperitoneal injection of the inflammogen lipopolysaccharide further reduced retinal ganglion cell function in Ndufs4 KO, supporting the connection between inflammatory activation and functional loss. Complex I deficiency in the retina clearly caused innate immune and inflammatory markers to increase coincident with loss of vision, and RGC functional loss. How complex I incites inflammation and functional loss is not clear, but could be the result of misfolded complex I generating a 'nonself' response, and induction of innate immune response transcripts was observed before functional loss at P22, including β-2 microglobulin and Cx3cr1, and during vision loss at P31 (B2m, Tlr 2, 3, 4, C1qa, Cx3cr1 and Fas). These data support the hypothesis that mitochondrial complex I dysfunction in the retina triggers an innate immune and inflammatory response that results in loss of retinal ganglion cell function and death, as in Leber's hereditary Optic Neuropathy and suggests novel therapeutic routes to counter mitochondrial defects that contribute to vision loss.

Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid ␤ on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that Ϸ40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with ␤-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or A␤-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid ␤ production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction. amyloid precursor protein ͉ DLP1 ͉ mitochondrial fragmentation ͉ OPA1 ͉ perinuclear accumulation

Indeed, some
LGMD1F patients had early-onset muscle weakness, but
Others had the adult form of the disease, with onset as
late as age 58, which supports the concept of age-dependent
penetrance in this disorder.
Other dominant disorders with late onset are characterized
by incomplete penetrance. It is therefore conceivable
that, if our clinical–genetic investigation had been
conducted when all individuals were at least age 58, the
Penetrance rate would likely have been complete.

Autism is etiologically heterogeneous; medical conditions are implicated in only a minority of cases, whereas metabolic disorders are even less common. Recently, there have been articles describing the association of autism with mitochondrial abnormalities. We critically review the current literature and conclude that mitochondrial disorders are probably a rare and insignificant cause of pure autism; however, evidence is accumulating that both autosomal recessive and maternally inherited mitochondrial disorders can present with autistic features. Most patients will present with multisystem abnormalities associated with autistic behavior. Finding biochemical or structural mitochondrial abnormalities in an autistic child does not necessarily imply a primary mitochondrial disorder but can also be secondary to technical inaccuracies or another genetic disorder. Clinicians should be careful in diagnosing a mitochondrial disorder in an autistic child because it has important implications ...

The aim of the present work was to investigate the mechanisms of oxidative damage of the liver mitochondria under diabetes and intoxication in rats as well as to evaluate the possibility of corrections of mitochondrial disorders by pharmacological doses of melatonin. The experimental (30 days) streptozotocin-induced diabetes mellitus caused a significant damage of the respiratory activity in rat liver mitochondria. In the case of succinate as a respiratory substrate, the ADP-stimulated respiration rate V3 considerably decreased (by 25%, p<0■ 05) as well as the acceptor control ratio (ACR) V3/V2 markedly diminished (by 25%, /?<0■ 01). We observed a decrease of the ADP-stimulated respiration rate V3 by 35% (p<0-05), with glutamate as substrate. In this case, ACR also decreased (by 20%, p<0-05). Surprisingly, the phosphorylation coefficient ADP/O did not change under diabetic liver damage. Acute rat carbon tetrachloride-induced intoxication resulted in considerable decrease of the phosphorylation coefficient because of uncoupling of the oxidation and phosphorylation processes in the liver mitochondria. The melatonin administration during diabetes (lOmg ■ kg-1 body weight, 30days, daily) showed a considerable protective effect on the liver mitochondrial function, reversing the decreased respiration rate V3 and the diminished ACR to the control values both for succinate-dependent respiration and for glutamate-dependent respiration. The melatonin administration to intoxicated animals (lOmg ■ kg"1 body weight, three times) partially increased the rate of succinate-dependent respiration coupled with phosphorylation. The impairment of mitochondrial respiratory plays a key role in the development of liver injury under diabetes and intoxication. Melatonin might be considered as an effector that regulates the mitochondrial function under diabetes.

The aim of the present work was to investigate the mechanisms of oxidative damage of the liver mitochondria under diabetes and intoxication in rats as well as to evaluate the possibility of corrections of mitochondrial disorders by pharmacological doses of melatonin. The experimental (30 days) streptozotocin‐induced diabetes mellitus caused a significant damage of the respiratory activity in rat liver mitochondria. In the case of succinate as a respiratory substrate, the ADP‐stimulated respiration rate V3 considerably decreased (by 25%, p &lt; 0·05) as well as the acceptor control ratio (ACR) V3/V2 markedly diminished (by 25%, p &lt; 0·01). We observed a decrease of the ADP‐stimulated respiration rate V3 by 35% (p &lt; 0·05), with glutamate as substrate. In this case, ACR also decreased (by 20%, p &lt; 0·05). Surprisingly, the phosphorylation coefficient ADP/O did not change under diabetic liver damage. Acute rat carbon tetrachloride‐induced intoxication resulted in considerable dec...

Biological systems exhibit quantum-coherent processes that persist and function at physiological temperatures, challenging the conventional view that coherence is too fragile for living conditions. This comprehensive review presents a unified framework for understanding quantum effects across four major domains of quantum biology: photosynthetic energy transfer, avian magnetic navigation, olfactory detection, and mitochondrial respiration. Rather than simply tolerating quantum effects despite the "noisy" cellular environment, biological systems have evolved sophisticated molecular architectures that actively preserve and exploit quantum coherence for enhanced function. We identify recurring design principles across these systems: structured protein scaffolds that create correlated environmental fluctuations, ordered water networks that reduce electromagnetic damping, and crystalline assemblies that prevent random motion while enabling controlled quantum dynamics. These coherence-preserving architectures enable quantum subsystems to feed directly into classical biochemical and bioelectrical networks, enhancing energy efficiency, sensing precision, and information transfer. The framework reveals life as a multi-layered, quantum-classical information system where femtosecond quantum dynamics couple to cellular and organismal processes through mathematical optimization principles. Particularly significant are implications for neuroscience and cognition, where mitochondrial quantum effects could influence synaptic plasticity and potentially consciousness itself through quantumenhanced energy metabolism and coherent bioelectric signaling. We provide testable experimental predictions and outline validation approaches using two-dimensional electronic spectroscopy, isotope substitution studies, and multi-modal bioelectric recordings. Applications span bio-inspired quantum computing, quantum sensors approaching biological sensitivity limits, and therapeutic interventions targeting quantum-coherent biological processes. This interdisciplinary synthesis establishes quantum biology as a mature field with profound implications for understanding life's fundamental operating principles.

Background: Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy. Case presentation: We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain. Conclusion: Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.

Fanconi syndrome; mitochondrial DNA deletion; pancreatitis Mitochondrial DNA (mtDNA) deletion is a rare occurrence that results in defects to oxidative phosphorylation. The common clinical presentations of mtDNA deletion vary but include mitochondrial myopathy, Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. Here, we report the case of a 10-year-old boy who presented with progressive deterioration of his clinical status (which included hypoglycemia, short stature, sensorineural hearing loss, retinitis pigmentosa, and chronic gastrointestinal dysmotility) that progressed to acute deterioration with pancreatitis, Fanconi syndrome, lactic acidosis, and acute encephalopathy. Following treatment, the patient was stabilized and his neurological condition improved. Through a combination of histological examinations and biochemical and molecular analyses, mitochondrial disease was confirmed. A novel 3670-base pair deletion (deletion of mtDNA nt 7,628-11,297) was identified in the muscle tissue. A direct repeat of CTACT at the breakpoints was also detected.

Quantitative MRI and phosphorus magnetic resonance spectroscopy ( 31 P-MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age T SD, 57 T 14 years) and ®ve with PM (42 T 12 years) and with age at disease onset 53 T 16 and 38 T 12 years, respectively, were included in the study together with 18 agematched controls. Post-exercise 31 P-MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half-times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton ef¯ux from muscle ®bres was signi®cantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of 31 P-MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton ef¯ux rate. There was no correlation between the MRS-detectable abnormalities and the degree of in¯ammation or fatty in®ltration of the muscle, as measured by MRI. The in vivo ®ndings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton ef¯ux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insuf®ciency in these patients.

Phospholipid-bound Omega-3s in krill oil represent an advanced nutritional delivery system that integrates EPA and DHA esterified to phosphatidylcholine (PC) with naturally co-existing Astaxanthin.
This triad provides superior bioavailability, membrane compatibility, and oxidative stability compared with triglyceride (TG) or ethyl ester (EE) fish oils.

Clinical studies confirm 1.3-3× higher absorption efficiency, direct incorporation into cell membranes, and more effective blood–brain barrier penetration, enabling lower doses to achieve equivalent or greater biological benefits.

Mechanistic Advantages
- Enhanced Absorption & Stability: PC-bound Omega-3s bypass bile and lipase dependence, improving uptake in elderly or those with digestive insufficiency, while Astaxanthin protects EPA/DHA from oxidation.
- Neurocognitive Health: DHA-PC efficiently elevates brain DHA, supporting synaptic plasticity, neurotransmission, mood stability, and memory.
- Cardiovascular & Lipid Regulation: Improves HDL/LDL ratio, reduces triglycerides, inhibits LDL oxidation, and supports endothelial nitric oxide production.
- Liver & Metabolism: PC-driven VLDL assembly promotes hepatic triglyceride export, alleviating fatty liver and improving insulin sensitivity.
- Anti-Inflammatory & Antioxidant Defense: EPA/DHA-derived resolvins and PC-bound lipids downregulate NF-κB, IL-6, and TNF-α; Astaxanthin provides mitochondrial protection against ROS.
- Synergistic Nutrient Delivery: The phospholipid matrix enhances co-absorption of lipid-soluble nutrients, further amplifying systemic resilience.

Target Populations
- Elderly individuals: Cognitive decline, memory loss, neurodegeneration risk.
- Professionals & students: High cognitive load, stress, attention and mood imbalance.
- Cardiovascular risk groups: Dyslipidemia, hypertension, atherosclerosis, metabolic syndrome.
- Hepatic/metabolic populations: NAFLD/MASLD, insulin resistance, obesity.
- Digestive-compromised individuals: Post-cholecystectomy, pancreatic insufficiency, poor fat absorption.
- Women’s health: Pregnancy (neurodevelopmental support for fetus), menopausal women (mood, cognition, cardiovascular protection).
- Athletes & active individuals: Inflammation control, muscle recovery, mitochondrial energy support.

By addressing the triple nutritional gap of modern diets - choline, omega-3 fatty acids, and phospholipids - phospholipid-bound Omega-3s offer a biomimetic, multi-system strategy for long-term health optimization across diverse populations.

Mitochondria play an important role in controlling the life and death of a cell. Consequently, mitochondrial dysfunction leads to a range of human diseases such as ischemia -reperfusion injury, sepsis, and diabetes. Although the molecular mechanisms responsible for mitochondriamediated disease processes are not fully elucidated yet, the oxidative stress appears to be critical. Accordingly, strategies are being developed for the targeted delivery of antioxidants to mitochondria. In this review, we shall briefly discuss cellular reactive oxygen species metabolism and its role in pathophysiology; the currently existing antioxidants and possible reasons why they are not effective in ameliorating oxidative stressmediated diseases; and recent developments in mitochondrially targeted antioxidants and their future promise for disease treatment.

Astaxanthin is a xanthophyll carotenoid with unique membrane-spanning anti-oxidative and anti-inflammatory activity.
It penetrates the blood-retinal barrier to protect ocular tissues, enhance microcirculation, alleviate visual fatigue, and delay age-related macular degeneration.

Cardiovascular benefits include reduction of lipid peroxidation, improvement of endothelial function, favorable modulation of blood lipids, and increased cerebral blood flow, supporting both heart and brain health.
In reproductive health, clinical trials demonstrate improved sperm motility, morphology, and pregnancy outcomes, alongside ovarian protection and folliculo-genesis support.
For skin, Astaxanthin reduces UV-induced oxidative stress and collagen degradation, improving hydration, elasticity, and pigmentation.
It further acts as an immune-nutrient, enhancing NK cell activity, secretory IgA, and reducing NF-κB-mediated inflammation.
Clinical evidence supports safe long-term use at 8-16 mg/day.

Collectively, Astaxanthin represents a broad-spectrum nutritional intervention across ocular, cardiovascular, reproductive, skin, and immune systems, particularly for populations under oxidative stress.

Mitochondria are intracellular organelles located in the cytoplasm, that are essential for life and health. It is also known as the powerhouse of the cells and use a process called oxidative phosphorylation to generate energy. In side mitochondria, the lipid monomer fatty acids act as energy sources, membrane constituents, molecules for post translational modifications of proteins and cellular signaling factors. Plant cells possess couple of distinct type 2 Fatty Acid Synthase (FAS) systems. The two systems take place in plastids (ptFAS) and mitochondria (mtFAS). Lots of mtFAS components have been identified but, the physiological functions of mtFAS are still poorly understood. In this review, we have characterized five Arabidopsis mtFAS components, namely Mitochondrial β-Ketoacyl-ACP Synthase (mtKAS), Mitochondrial 3-Hydroxyacyl-ACP Dehydratase (mtHD), Mitochondrial Enoyl-ACP reductase (mtER), Mitochondrial Phosphopantetheinyl Transferase (mtPPT), and Mitochondrial Malonyl-CoA Synthetase (mtMCS). MtKAS, mtHD, and mtER catalyze 3 reactions of the 4 reactions of the acyl chain elongation cycle; mtPPT is responsible for activating Mitochondrial Acyl Carrier Protein (mtACP) by the addition of a phosphopantetheine cofactor; and mtMCS generates malonyl-CoA, the donor of 2-carbon elongation unit for the mtFAS system. Mitochondrial octanoyl-ACP is the precursor for the synthesis of lipoic acid, which is the coenzyme of the H-subunit of Glycine Decarboxylase Complex (GDC), a key enzyme of photorespiration. Accordingly, mutations in the mtFAS system can lead to a typical deficiency in photorespiration due to the depletion of the lipoylation of the H-subunit of GDC. These mutants are altered as an inferior effect of the deficiency in photorespiration. In addition, mutant analyses demonstrate that mitochondrial 3-hydroxymyristyl-ACP contributes to the biosynthesis of lipid alike molecules, suggesting a novel synthetic destination of the mtFAS intermediates. RNA-seq transcriptomic analyses of the mutants establish a regulatory network that is associated with the mtFAS functions is crucial for plant metabolic homeostasis.

Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G&gt;A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C&gt;G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked ...

This conference series, funded by the ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provides an opportunity to gather experts from within and outside ophthalmology to develop strategies to improve research into the causes and new treatments of blinding eye diseases. This year's conference focused on glaucoma research. As originally put forward by Robert Ritch, a major goal was to define strategies essential for the improvement of the current understanding of the role of glia, mitochondria, and the immune system in glaucomatous neurodegeneration. The scientific discussion of different opinions was also intended to illuminate promising treatment strategies for neuroprotection. A working group of 39 scientists from the fields of glaucoma and ocular immunology and working outside the traditional bounds of vision research, discussed the involvement of glia, mitochondria, and the immune system in glaucomatous neurodegeneration. Many observers from ARVO, Pfizer Ophthalmics, and ophthalmic research also attended the conference. The conference was divided into sessions formatted to evoke discussions focused on four areas of research: Session I: Dysfunction of the Retina and Optic Nerve Head Glia during Glaucomatous Neurodegeneration Session II: Mitochondrial Dysfunction Leading to Neurodegenerative Injury in Glaucoma Session III: Immune System Involvement in Glaucoma Session IV: Immunomodulatory Treatment Possibilities for Neuroprotection Each of these sessions was moderated by two experts in the area of discussion and began with a 10-minute overview of the session topic followed by a 30-minute keynote presentation by an outside expert and 10 minutes of discussion. Invited outside experts covered several areas of research, including the role of microglial senescence in autoimmune neurodegeneration

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

Background Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A &gt; G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements. Methods We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A &gt; G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damag...

OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a ‘drug repurposing’ approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients’ fibroblasts, allowing to select the most effective molecules. Our current results...

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for...

Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS...

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum ...

We here report on the existence of Leber&#39;s hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband&#39;s fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits. Hence, the definition of the path...

ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individual...

The MAG gene encodes myelin-associated glycoprotein (MAG), an abundant protein involved in axon-glial interactions and myelination during nerve regeneration. Several members of a consanguineous family with a clinical syndrome reminiscent of Pelizaeus-Merzbacher disease and demyelinating leukodystrophy on brain MRI were recently found to harbor a homozygous missense p.Ser133Arg MAG mutation. Here, we report two brothers from a nonconsanguineous family afflicted with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder. Exome sequencing revealed the homozygous missense mutation p.Arg118His in MAG. This Arg118 residue in immunoglobulin domain 1 is critical for sialic acid binding, providing a compelling mechanistic basis for disease pathogenesis.

The genetic landscape of neurodevelopmental disorders is constantly expanding and children with early-onset neurological phenotypes increasingly receive a genetic diagnosis. Nonetheless, the awareness of the chronic course of these conditions, and consequently their recognition and management in the adult population, is still limited. Results: Herein, we describe four patients with rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1related diseases), who received a genetic assignment only in the adulthood. All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood, prompting the referral to a neurologist. This phenotypic combination led eventually to the genetic testing. We report previously unrecognized features and highlight the peculiarities of the adult presentation of four neurodevelopmental disorders. This report expands the current knowledge on four rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1), which was mainly based on reports from paediatric cases. This case series emphasize the importance of a tight neurological surveillance extending beyond the childhood.

Mitochondrial dysfunction is believed to participate in Huntington’s disease (HD) pathogenesis. Here we compare the bioenergetic behavior of forebrain mitochondria isolated from different transgenic HD mice (R6/2, YAC128 and Hdh150 knock‐in) and wild‐type littermates with the first determination of in situ respiratory parameters in intact HD striatal neurons. We assess the Ca2+‐loading capacity of isolated mitochondria by steady Ca2+‐infusion. Mitochondria from R6/2 mice (12–13 weeks) and 12 months YAC128, but not homozygous or heterozygous Hdh150 knock‐in mice (15–17 weeks), exhibit increased Ca2+‐loading capacity when compared with respective wild‐type littermates. In situ mitochondria in intact striatal neurons show high respiratory control. Moreover, moderate expression of full‐length mutant huntingtin (in Hdh150 knock‐in heterozygotes) does not significantly impair mitochondrial respiration in unstimulated neurons. However, when challenged with energy‐demanding stimuli (NMDA‐re...

Mitochondrial dysfunction is believed to participate in Huntington’s disease (HD) pathogenesis. Here we compare the bioenergetic behavior of forebrain mitochondria isolated from different transgenic HD mice (R6/2, YAC128 and Hdh150 knock‐in) and wild‐type littermates with the first determination of in situ respiratory parameters in intact HD striatal neurons. We assess the Ca2+‐loading capacity of isolated mitochondria by steady Ca2+‐infusion. Mitochondria from R6/2 mice (12–13 weeks) and 12 months YAC128, but not homozygous or heterozygous Hdh150 knock‐in mice (15–17 weeks), exhibit increased Ca2+‐loading capacity when compared with respective wild‐type littermates. In situ mitochondria in intact striatal neurons show high respiratory control. Moreover, moderate expression of full‐length mutant huntingtin (in Hdh150 knock‐in heterozygotes) does not significantly impair mitochondrial respiration in unstimulated neurons. However, when challenged with energy‐demanding stimuli (NMDA‐re...

Background: Diabetes mellitus (DM) is associated with microvascular complications, such as diabetic retinopathy (DR). DR is one of the main causes of visual loss in individuals aged 20-64 years old. This study aims to investigate the independent associations between the stage of DR and a variety of possible risk factors, including years since DM diagnosis, HbA 1c levels, the coexistence of hypertension, age and gender.

Becker muscular dystrophy (BMD) has onset usually in childhood, frequently by 11 years. BMD can present in several ways such as waddling gait, exercise related cramps with or without myoglobinuria. Rarely cardiomyopathy might be the presenting feature. The evolution is variable. BMD is caused by dystrophin deficiency due to inframe deletions, mutations or duplications in dystrophin gene (Xp21.2) We review here the evolution and current therapy presenting a personal series of cases followed for over two decades, with multifactorial treatment regimen. Early treatment includes steroid treatment that has been analized and personalized for each case. Early treatment of cardiomyopathy with ACE inhibitors is recommended and referral for cardiac transplantation is appropriate in severe cases. Management includes multidisciplinary care with physiotherapy to reduce joint contractures and prolong walking. BMD is slowly progressive with phenotypic variability. Despite childhood onset, independe...

Kearns–Sayre syndrome (KSS) is a rare, multisystem mitochondrial disorder defined by onset before 20 years of age, chronic progressive external ophthalmoplegia (CPEO), and pigmentary retinopathy, often accompanied by cardiac conduction defects, neurological impairment, and endocrine abnormalities. The disease is typically caused by large-scale mitochondrial DNA (mtDNA) deletions, most frequently the “common 4,977 bp deletion,” disrupting oxidative phosphorylation and impairing cellular energy production in high-demand tissues. Epidemiologically, KSS is rare, with a reported prevalence of 1.6 per 100,000 in certain populations, but its true prevalence is likely underestimated due to diagnostic challenges.
Pathophysiologically, skeletal muscle biopsy often reveals ragged red fibers, reflecting mitochondrial proliferation and dysfunction, while ocular pathology demonstrates retinal pigment epithelium degeneration with a characteristic “salt-and-pepper” fundus. Neuropathology may include severe cerebral white matter demyelination, although the exact mechanisms remain unclear. Clinically, patients may present with ptosis, progressive ophthalmoplegia, sensorineural hearing loss, cerebellar ataxia, growth hormone deficiency, diabetes mellitus, or life-threatening cardiac conduction blocks.
Diagnosis requires molecular confirmation of mtDNA deletions, with next-generation sequencing (NGS) of blood or muscle tissue as the gold standard. Ancillary investigations include cerebrospinal fluid analysis, neuroimaging, MR spectroscopy, and comprehensive cardiac evaluation. Management is supportive, focusing on early detection and treatment of complications, including pacemaker implantation, endocrine replacement, folate supplementation, and rehabilitation strategies. Emerging therapeutic approaches, such as heteroplasmy shifting via mitochondrial-targeted nucleases and antioxidant supplementation with Coenzyme Q10 or its synthetic analog EPI-743, hold promise but remain experimental.
Given its progressive course and systemic involvement, KSS requires an interprofessional approach to optimize quality of life, prevent sudden cardiac death, and address treatable metabolic and endocrine dysfunctions.

Diabetic retinopathy (DR) is a common complication of diabetes and a major cause of acquired blindness in adults. Mitochondria are cellular organelles involved in energy production which contain mitochondrial DNA (mtDNA). We previously showed that levels of circulating mtDNA were dysregulated in DR patients, and there was some evidence of mtDNA damage. In the current project, our aim was to confirm the presence of, and determine the location and prevalence of, mtDNA mutation in DR. DNA isolated from peripheral blood from diabetes patients (n = 59) with and without DR was used to amplify specific mtDNA regions which were digested with surveyor nuclease S1 to determine the presence and location of heteroplasmic mtDNA mutations were present. An initial screen of the entire mtDNA genome of 6 DR patients detected a higher prevalence of mutations in amplicon P, covering nucleotides 14,443 to 1066 and spanning the control region. Further analysis of 42 subjects showed the presence of putat...

Significance We generated transmitochondrial mito-mice-tRNA Lys7731 as models for precise examination of the pathogenesis and transmission profiles of mtDNA mutations in the tRNA Lys genes and have obtained important information regarding primary prevention of the diseases caused by the mtDNA mutations. Although nuclear transplantation from oocytes of affected mothers into enucleated oocytes of unrelated women has been suggested, the methodology carries the technical risk of inducing nuclear abnormalities and prompts ethical concerns regarding the production of three-parent babies with normal mtDNA from unrelated oocyte donors. The current study suggests that the selection of oocytes with high proportions of normal mtDNA from affected mothers can be used to avoid these issues and therefore provides insights into mitochondrial genetics and medicine.

It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma fo...

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers’ plasma levels were compared between grou...

Oxidative phosphorylation system (OXPHOS) deficiencies are rare diseases but constitute the most frequent inborn errors of metabolism. We analyzed the autophagy route in 11 skin fibroblast cultures derived from patients with well characterized and distinct OXPHOS defects. Mitochondrial membrane potential determination revealed a tendency to decrease in 5 patients' cells but reached statistical significance only in 2 of them. The remaining cells showed either no change or a slight increase in this parameter. Colocalization analysis of mitochondria and autophagosomes failed to show evidence of increased selective elimination of mitochondria but revealed more intense autophagosome staining in patients' fibroblasts compared with controls. Despite the absence of increased mitophagy, Parkin recruitment to mitochondria was detected in both control and patients' cells and was slightly higher in cells harboring complex I defects. Western blot analysis of the autophagosome marker LC3B, confirmed significantly higher levels of the protein bound to autophagosomes, LC3B-II, in patients' cells, suggesting an increased bulk autophagy in OXPHOS defective fibroblasts. Inhibition of lysosomal proteases caused significant accumulation of LC3B-II in control cells, whereas in patients' cells this phenomenon was less pronounced. Electron microscopy studies showed higher content of late autophagic vacuoles and lysosomes in OXPHOS defective cells, accompanied by higher levels of the lysosomal marker LAMP-1. Our findings suggest that in OXPHOS deficient fibroblasts autophagic flux could be partially hampered leading to accumulation of autophagic vacuoles and lysosomes.

Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear. Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.

The aim of this study was to determine the diagnostic utility of chromosomal microarray analysis (CMA) in daily pediatric neurology practice and to identify the guiding clinical parameters for patients requiring this test. The CMA results for 91 patients with global developmental delay/intellectual disability (GDD/ID) admitted to our pediatric neurology clinic for various reasons between 2018 and 2020 were examined. Demographical and clinical data for 34 patients (37.4%) in whom del/dup was determined at CMA and 57 patients (62.6%) with normal CMA were compared. Results: There was no statistically significant difference between two groups in terms of demographic characteristics such as age, gender, type of delivery, gestational age, etc. Dysmorphisms, hypotonia, myelination abnormalities were significantly more frequent in patients with del/dup than in patients with normal result. The frequency of macrocephaly and obesity was higher in the normal group, and that of generalized seizures was higher among epileptic patients in this group. Nineteen (55.9%) of the 34 cases who have del/dup detected at analysis were regarded as pathogenic, 15 (44.1%) as uncertain clinical significance (likely pathogenic, likely benign and no subclassification). Conclusion: Since CMA is an expensive, laborious, and time-consuming test, considering clinical parameters when requesting CMA will yield high diagnostic efficiency. A high possibility of copy number variants may be predicted in GDD/ID patients with dysmorphisms, hypotonia, and myelination delay. CMA should represent the genetic analysis of choice in pediatric neurology practice in case of no finding suggesting a different etiology in these patients.