Defects In Mitochondrial Function Research Articles

Factors Influencing Effects of Low-dose Radiation Exposure.

It is now well accepted that the mechanisms induced by low-dose exposures to ionizing radiation (LDR) are different from those occurring after high-dose exposures. However, the downstream effects of these mechanisms are unclear as are the quantitative relationships between exposure, effect, harm, and risk. In this paper, we will discuss the mechanisms known to be important with an overall emphasis on how so-called "non-targeted effects" (NTE) communicate and coordinate responses to LDR. Targeted deposition of ionizing radiation energy in cells causing DNA damage is still regarded as the dominant trigger leading to all downstream events whether targeted or non-targeted. We regard this as an over-simplification dating back to formal target theory. It ignores that last 100 y of biological research into stress responses and signaling mechanisms in organisms exposed to toxic substances, including ionizing radiation. We will provide evidence for situations where energy deposition in cellular targets alone cannot be plausible as a mechanism for LDR effects. An example is where the energy deposition takes place in an organism not receiving the radiation dose. We will also discuss how effects after LDR depend more on dose rate and radiation quality rather than actual dose, which appears rather irrelevant. Finally, we will use recent evidence from studies of cataract and melanoma induction to suggest that after LDR, post-translational effects, such as protein misfolding or defects in energy metabolism or mitochondrial function, may dominate the etiology and progression of the disease. A focus on such novel pathways may open the way to successful prophylaxis and development of new biomarkers for better risk assessment after low dose exposures.

Disrupted mitochondrial transcription factor A expression promotes mitochondrial dysfunction and enhances ocular surface inflammation by activating the absent in melanoma 2 inflammasome

PurposeSevere dry eye disease causes ocular surface damage, which is highly associated with mitochondrial dysfunction. Mitochondrial transcription factor A (TFAM) is essential for packaging mitochondrial DNA (mtDNA) and is crucial for maintaining mitochondrial function. Herein, we aimed to explore the effect of a decreased TFAM expression on ocular surface damage. MethodsFemale C57BL/6 mice were induced ocular surface injury by topical administrating benzalkonium chloride (BAC). Immortalized human corneal epithelial cells (HCECs) were stimulated by tert-butyl hydroperoxide (t-BHP) to create oxidative stress damage. HCECs with TFAM knockdown were established. RNA sequencing was employed to analyze the whole-genome expression. Mitochondrial changes were measured by transmission electron microscopy, Seahorse metabolic flux analysis, mitochondrial membrane potential, and mtDNA copy number. TFAM expression and inflammatory cytokines were determined using RT-qPCR, immunohistochemistry, immunofluorescence, and immunoblotting. ResultsIn both the corneas of BAC-treated mice and t-BHP-induced HCECs, we observed impaired TFAM expression, accompanied by mitochondrial structure and function defects. TFAM downregulation in HCECs suppressed mitochondrial respiratory capacity, reduced mtDNA content, induced mtDNA leakage into the cytoplasm, and led to inflammation. RNA sequencing revealed the absent in melanoma 2 (AIM2) inflammasome was activated in the corneas of BAC-treated mice. The AIM2 inflammasome activation was confirmed in TFAM knockdown HCECs. TFAM knockdown in t-BHP-stimulated HCECs aggravated mitochondrial dysfunction and the AIM2 inflammasome activation, thereby further triggering the secretion of inflammatory factors such as interleukin (IL) -1β and IL-18. ConclusionsTFAM reduction impaired mitochondrial function, activated AIM2 inflammasome and promoted ocular surface inflammation, revealing an underlying molecular mechanism for ocular surface disorders.

Hansenula polymorpha cells lacking the ER-localized peroxins Pex23 or Pex29 show defects in mitochondrial function and morphology.

Pex23 family proteins localize to the endoplasmic reticulum and play a role in peroxisome and lipid body formation. The yeast Hansenula polymorpha contains four members: Pex23, Pex24, Pex29 and Pex32. We previously showed that loss of Pex24 or Pex32 results in severe peroxisomal defects, caused by reduced peroxisome-endoplasmic reticulum contact sites. We now analyzed the effect of the absence of all four Pex23 family proteins on other cell organelles. Vacuoles were normal in all four deletion strains. The number of lipid droplets was reduced in pex23 and pex29, but not in pex24 and pex32 cells, indicating that peroxisome and lipid droplet formation require different Pex23 family proteins in H. polymorpha. In pex23 and pex29 cells mitochondria were fragmented and clustered accompanied by reduced levels of the fusion protein Fzo1. Deletion of DNM1 suppressed the morphological phenotype of pex23 and pex29 cells, suggesting that mitochondrial fusion is affected. pex23 and pex29 cells showed retarded growth and reduced mitochondrial activities. The growth defect was partially suppressed by DNM1 deletion as well as by an artificial mitochondrion-endoplasmic reticulum tether. Hence, the absence of Pex23 family proteins may influence mitochondrion-endoplasmic reticulum contact sites.

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.

Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.

The mitochondria‒paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions.

Rationale: Stem cell-based therapies have emerged as promising tools for tissue engineering and regenerative medicine, but their therapeutic efficacy is largely limited by the oxidative stress-induced loss of transplanted cells at injured tissue sites. To address this issue, we aimed to explore the underlying mechanism and protective strategy of ROS-induced MSC loss. Methods: Changes in TFAM (mitochondrial transcription factor A) signaling, mitochondrial function, DNA damage, apoptosis and senescence in MSCs under oxidative stress conditions were assessed using real-time PCR, western blotting and RNA sequencing, etc. The impact of TFAM or lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) knockdown or overexpression on mitochondrial function, DNA damage repair, apoptosis and senescence in MSCs was also analyzed. The effect of mitochondrion-targeted antioxidant (Mito-TEMPO) on the survival of transplanted MSCs was evaluated in a mouse model of renal ischemia/reperfusion (I/R) injury. Results: Mitochondrial ROS (mtROS) bursts caused defects in TFAM signaling and overall mitochondrial function, which further impaired NEAT1 expression and its mediated paraspeckle formation and DNA repair pathways in MSCs, thereby jointly promoting MSC senescence and death under oxidative stress. In contrast, targeted inhibition of the mtROS bursts is a sufficient strategy for attenuating early transplanted MSC loss at injured tissue sites, and coadministration of Mito-TEMPO improved the local retention of transplanted MSCs and reduced oxidative injury in ischemic kidneys. Conclusions: This study identified the critical role of the mitochondria‒paraspeckle axis in regulating cell survival and may provide insights into developing advanced stem cell therapies for tissue engineering and regenerative medicine.

The role of FNDC5/Irisin in brain energy metabolism in models of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) brains present defective metabolic profiles that are associated with amyloid‐β (Aβ) accumulation. We have previously shown that physical exercise promotes the expression of FNDC5/irisin, which in turn acts in the brain to trigger neuroprotection in AD models. Here, we investigated whether irisin rescues defective mitochondrial function induced by Aβ oligomers (AβOs).MethodHippocampal slices from 4‐month‐old wild‐type C57BL/6J mice were prepared and exposed to AβOs (1 µM) in the presence or absence of recombinant irisin (25 nM) for 3 h. We assessed levels of proteins related to mitochondrial fusion (MFN1, OPA1) and fission (DRP1) by Western blotting and mitochondrial function, by high‐resolution respirometry. Biochemical assays were used to determine glucose uptake, lactate content and NAD levels.ResultsAcute exposure to AβOs or irisin did not trigger any significant changes in proteins associated with mitochondrial dynamics or the amount of lactate released after AβOs exposure. Initial results indicate that irisin prevents the variations caused by AβOs in NAD+ levels and glucose uptake in hippocampal slices. Slices exposed to AβOs show a trend of reduction in ATP synthesis‐, complexes II/III‐coupled O2 and in residual O2 consumption. Treatment with irisin seems to prevent these events.ConclusionIrisin seems to preserve against the impact of AβOs on selective mitochondrial properties in the hippocampus. Future studies will further elucidate the mechanisms by which irisin is neuroprotective in AD mice.

Mitochondria as a target for exercise-mitigated type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is one of most common metabolic diseases and continues to be a leading cause of death worldwide. Although great efforts have been made to elucidate the pathogenesis of diabetes, the underlying mechanism still remains unclear. Notably, overwhelming evidence has demonstrated that mitochondria are tightly correlated with the development of T2DM, and the defects of mitochondrial function in peripheral insulin-responsive tissues, such as skeletal muscle, liver and adipose tissue, are crucial drivers of T2DM. Furthermore, exercise training is considered as an effective stimulus for improving insulin sensitivity and hence is regarded as the best strategy to prevent and treat T2DM. Although the precise mechanisms by which exercise alleviates T2DM are not fully understood, mitochondria may be critical for the beneficial effects of exercise.

Mitochondrial protein and organelle quality control-Lessons from budding yeast.

Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.

Pharmacological rescue of mitochondrial and neuronal defects in SPG7 hereditary spastic paraplegia patient neurons using high throughput assays.

SPG7 is the most common form of autosomal recessive hereditary spastic paraplegia (HSP). There is a lack of HSP-SPG7 human neuronal models to understand the disease mechanism and identify new drug treatments. We generated a human neuronal model of HSP-SPG7 using induced pluripotent stem (iPS) cell technology. We first generated iPS cells from three HSP-SPG7 patients carrying different disease-causing variants and three healthy controls. The iPS cells were differentiated to form neural progenitor cells (NPCs) and then from NPCs to mature cortical neurons. Mitochondrial and neuronal defects were measured using a high throughout imaging and analysis-based assay in live cells. Our results show that compared to control NPCs, patient NPCs had aberrant mitochondrial morphology with increased mitochondrial size and reduced membrane potential. Patient NPCs develop to form mature cortical neurons with amplified mitochondrial morphology and functional defects along with defects in neuron morphology - reduced neurite complexity and length, reduced synaptic gene, protein expression and activity, reduced viability and increased axonal degeneration. Treatment of patient neurons with Bz-423, a mitochondria permeability pore regulator, restored the mitochondrial and neurite morphological defects and mitochondrial membrane potential back to control neuron levels and rescued the low viability and increased degeneration in patient neurons. This study establishes a direct link between mitochondrial and neuronal defects in HSP-SPG7 patient neurons. We present a strategy for testing mitochondrial targeting drugs to rescue neuronal defects in HSP-SPG7 patient neurons.

Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease.

In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeuUUR and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development.

Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation

Microdeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes, mrpl40 and prodha, encode for mitochondrial proteins and, similar to what we observed in mrpl40 and prodha mutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Single mutant analysis shows that both mrpl40 and prodha mutants display aberrant neural stem and progenitor cell proliferation, with each gene regulating distinct cell populations. Finally, double mutants for both mrpl40 and prodha display aggravated behavioral phenotypes and neural stem and progenitor cell analysis reveals a previously unrecognized partially redundant role for mrpl40 and prodha in regulating radial glia-like cell proliferation. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.

Abstract IA017: Metabolic reprogramming and kidney cancer progression

Abstract Many human diseases, including cancer, involve alterations of cellular metabolism caused either directly or indirectly by mutations in genes that regulate the metabolic network. In cancer, reprogrammed metabolic activities arising from mutations in tumor suppressors and oncogenes are thought to contribute both to cancer initiation and progression, particularly metastasis. In clear cell renal cell carcinoma, as with many other kinds of cancer, mortality is largely dictated by metastatic dissemination. It is therefore of interest to identify aspects of metabolic reprogramming that promote metastasis in ccRCC patients. We used a multidisciplinary clinical approach to infuse 13C-labeled nutrients during surgical tumor resection in ccRCC patients. Compared to the adjacent kidney, ccRCCs displayed suppressed labelling of tricarboxylic acid (TCA) cycle intermediates, both in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is a tissue intrinsic property of these tumors. Infusions of 13C-acetate and 13C-glutamine in patients, coupled with metabolic analysis of mitochondria isolated from kidney and tumor tissue, revealed primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly had enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. Using a syngeneic RCC mouse model capable of spontaneous metastasis from the kidney, we found that inhibiting oxidative phosphorylation reduced metastasis to the lung without impacting tumor growth in the kidney. In human ccRCC cells, stimulating respiration was sufficient to promote metastatic colonization in the lung. Altogether, these findings indicate that metabolic properties evolve during human ccRCC progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin. Citation Format: Ralph J. DeBerardinis. Metabolic reprogramming and kidney cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA017.

Abstract P3188: Establishing The Mitochondrial Citrate Transporter As A Regulator Of Cardiac Morphogenesis

Congenital heart disease (CHD) results from structural and functional defects of the heart that arise during embryonic development. CHD represents the most common type of birth defect and in the United States alone, affects ~1% of births per year. One common genetic cause of CHD is 22q11.2 deletion syndrome (22q11.2DS), where ~75% of 22q11.2DS patients present with CHD. SLC25A1 , which is found within the 22q11.2DS critical deletion region, encodes for the mitochondrial citrate carrier, a solute transporter localized to the inner mitochondrial membrane. In developing a knockout mouse model to study the in vivo functions of SLC25A1, we uncovered an unexpected perinatal-lethal phenotype that suggests roles for SLC25A1 in heart development. Hearts from Slc25a1 knockout embryos display a striking array of cardiac malformations including persistence of an expanded zone of trabeculated myocardium, reduced compact myocardium, and ventricular septal defects. Analysis of mitochondrial structure and function reveal that loss of Slc25a1 causes mitochondrial ultrastructural and functional defects. Lastly, transcriptomics analyses of metabolism-related genes revealed that Slc25a1 deletion causes widespread alterations in metabolic gene expression in a dosage-dependent manner. Our results highlight a novel role for SLC25A1 in cardiac morphogenesis and the transcriptional control of metabolic networks in the developing heart and point to a new role for SLC25A1 in the metabolic maturation of the developing myocardium.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a “metabolic support therapy” (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality of life (QoL), communication, and comorbidities. Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae.

Mitochondrial diseases (MDs) refer to a group of clinically and genetically heterogeneous pathologies characterized by defective mitochondrial function and energy production. Unfortunately, there is no effective treatment for most MDs, and current therapeutic management is limited to relieving symptoms. The yeast Saccharomyces cerevisiae has been efficiently used as a model organism to study mitochondria-related disorders thanks to its easy manipulation and well-known mitochondrial biogenesis and metabolism. It has been successfully exploited both to validate alleged pathogenic variants identified in patients and to discover potential beneficial molecules for their treatment. The so-called "drug drop test", a phenotype-based high-throughput screening, especially if coupled with a drug repurposing approach, allows the identification of molecules with high translational potential in a cost-effective and time-saving manner. In addition to drug identification, S. cerevisiae can be used to point out the drug's target or pathway. To date, drug drop tests have been successfully carried out for a variety of disease models, leading to very promising results. The most relevant aspect is that studies on more complex model organisms confirmed the effectiveness of the drugs, strengthening the results obtained in yeast and demonstrating the usefulness of this screening as a novel approach to revealing new therapeutic molecules for MDs.

Pooled analysis of frontal lobe transcriptomic data identifies key mitophagy gene changes in Alzheimer's disease brain.

The growing prevalence of Alzheimer's disease (AD) is becoming a global health challenge without effective treatments. Defective mitochondrial function and mitophagy have recently been suggested as etiological factors in AD, in association with abnormalities in components of the autophagic machinery like lysosomes and phagosomes. Several large transcriptomic studies have been performed on different brain regions from AD and healthy patients, and their data represent a vast source of important information that can be utilized to understand this condition. However, large integration analyses of these publicly available data, such as AD RNA-Seq data, are still missing. In addition, large-scale focused analysis on mitophagy, which seems to be relevant for the aetiology of the disease, has not yet been performed. In this study, publicly available raw RNA-Seq data generated from healthy control and sporadic AD post-mortem human samples of the brain frontal lobe were collected and integrated. Sex-specific differential expression analysis was performed on the combined data set after batch effect correction. From the resulting set of differentially expressed genes, candidate mitophagy-related genes were identified based on their known functional roles in mitophagy, the lysosome, or the phagosome, followed by Protein-Protein Interaction (PPI) and microRNA-mRNA network analysis. The expression changes of candidate genes were further validated in human skin fibroblast and induced pluripotent stem cells (iPSCs)-derived cortical neurons from AD patients and matching healthy controls. From a large dataset (AD: 589; control: 246) based on three different datasets (i.e., ROSMAP, MSBB, & GSE110731), we identified 299 candidate mitophagy-related differentially expressed genes (DEG) in sporadic AD patients (male: 195, female: 188). Among these, the AAA ATPase VCP, the GTPase ARF1, the autophagic vesicle forming protein GABARAPL1 and the cytoskeleton protein actin beta ACTB were selected based on network degrees and existing literature. Changes in their expression were further validated in AD-relevant human in vitro models, which confirmed their down-regulation in AD conditions. Through the joint analysis of multiple publicly available data sets, we identify four differentially expressed key mitophagy-related genes potentially relevant for the pathogenesis of sporadic AD. Changes in expression of these four genes were validated using two AD-relevant human in vitro models, primary human fibroblasts and iPSC-derived neurons. Our results provide foundation for further investigation of these genes as potential biomarkers or disease-modifying pharmacological targets.

Synchronous Interventions of Glucose and Mitochondrial Metabolisms for Antitumor Bioenergetic Therapy.

Hydrogen sulfide (H2 S)-based mitochondrial bioenergetic intervention is an attractive therapeutic modality. However, its therapeutic efficacy is limited owning to metabolic plasticity, which allows tumors to shift their metabolic phenotype between oxidative phosphorylation and glycolysis for energy compensation. To overcome this flexibility, a glycopolymer containing a caged H2 S and hydrogen peroxide (H2 O2 ) dual-donor (1-thio-β-D-glucose [thioglucose]) was synthesized to wrap glucose oxidase (GOx) for complete depletion of tumorigenic energy sources. The loaded GOx catalyzed the glutathione-activated thioglucose to generate cytotoxic H2 S/H2 O2 , which further induced synergistic defects in mitochondrial function by suppressing cytochrome c oxidase (COX IV) expression and damaging the mitochondrial membrane potential. GOx also blocked glycolysis by depleting endogenous glucose. This synchronous intervention strategy exhibited good anticancer performance, broadening the horizon of antitumor bioenergetic therapy. This article is protected by copyright. All rights reserved.

Targeting Sigma-1 Receptor: A Promising Strategy in the Treatment of Parkinson's Disease.

Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson's disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Sigma-1 receptors are molecular chaperones located at mitochondria-associated ER membrane. Their activation (by endogenous ligands or agonists) has shown neuroprotective and neurorestorative effects in various diseases. This review discusses the roles of activated Sig-1 receptors in modulating various pathophysiological features of Parkinson's disease like alpha-synuclein aggregates, neuroinflammation, excitotoxicity, and oxidative stress.

Defects in Mitochondrial Functions Affect the Survival of Yeast Cells Treated with Non-Thermal Plasma.

Exposure of living cells to non-thermal plasma produced in various electrical discharges affects cell physiology and often results in cell death. Even though plasma-based techniques have started finding practical applications in biotechnology and medicine, the molecular mechanisms of interaction of cells with plasma remain poorly understood. In this study, the involvement of selected cellular components or pathways in plasma-induced cell killing was studied employing yeast deletion mutants. The changes in yeast sensitivity to plasma-activated water were observed in mutants with the defect in mitochondrial functions, including transport across the outer mitochondrial membrane (∆por1), cardiolipin biosynthesis (∆crd1, ∆pgs1), respiration (ρ0) and assumed signaling to the nucleus (∆mdl1, ∆yme1). Together these results indicate that mitochondria play an important role in plasma-activated water cell killing, both as the target of the damage and the participant in the damage signaling, which may lead to the induction of cell protection. On the other hand, our results show that neither mitochondria-ER contact sites, UPR, autophagy, nor proteasome play a major role in the protection of yeast cells from plasma-induced damage.