Abnormal Mitochondrial Dynamics Research Articles

Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.

The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN+ and PGC-1α/β-tubulin+ neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/β-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN+ co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.

Drp1 Regulated Mitochondrial Hypofission Promotes the Invasion and Proliferation of Growth Hormone-Secreting Pituitary Adenomas via Activating STAT3.

The invasiveness and high proliferation rate of growth hormone-secreting pituitary adenomas (GHPAs) are closely related to poor prognosis in patients. We previously reported that abnormal glycolysis participates in this process; however, the role of mitochondria in the invasion and proliferation of GHPAs remains unknown. In the current study, stereological methods were first used to quantitatively calculate the number and morphology of mitochondria. The results revealed that the numbers, volumes and membrane areas of mitochondria were decreased in invasive GHPAs (IGHPAs) samples compared to noninvasive GHPAs (NIGHPAs) samples. Furthermore, significantly downregulated mRNA and protein levels of dynamin-related protein 1 (Drp1) were detected in IGHPAs, but no notable changes in fusion related molecules (Mfn1, Mfn2 and OPA1) were detected, suggesting that the abnormal mitochondrial dynamics in IGHPAs are characterized by hypofission. Mitochondrial hypofission caused by Mdivi-1, a specific Drp1 inhibitor, enhanced the invasion and proliferation of GH3 cell lines and primary cells from patients with GHPAs in vitro and in vivo, while overexpression of Drp1 reversed these processes. Mechanistically, mitochondrial hypofission might activate signal transducer and activator of transcription 3 (STAT3). Specifically, elevated nuclear pSTAT3Y705 may promote GH3 cell invasion by upregulating the activity of matrix metalloproteinase 2/9, and elevated mitochondrial pSTAT3S727 may promote GH3 cell proliferation by inhibiting the mitochondria-dependent apoptotic pathway. Taken together, our findings suggest that mitochondrial hypofission induced by Drp1 might strengthen the invasion and proliferation of GHPA tumor cells by activating STAT3, providing us with a new perspective on how mitochondria regulate the development of IGHPAs.

Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.

In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.

Calpain-mediated cleavage of mitochondrial fusion/fission proteins in acetaminophen-induced mice liver injury

Mitochondrial dysfunction was considered to be a critical event in acetaminophen (APAP) -induced hepatotoxicity. Recent studies suggest that abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in APAP-induced liver injury, yet the underlying mechanisms responsible for deregulated mitochondrial dynamics remains elusive. In this study, C57BL/6 mice were used to establish a model of acute liver injury via intraperitoneal (i.p.) injection with overdose of APAP. Furthermore, calpain intervention experiments were achieved by the inhibitors ALLN or calpeptin. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in mitochondrial dynamics and calpain degradative pathway were determined by electron microscopy, immunoblot and calpain activity kit. The results demonstrated that APAP overdose resulted in a severe liver injury, mitochondrial damage and an obvious cleavage of fusion/fission proteins. Meanwhile, the activation of calpain degradative machinery in liver were observed following APAP. By contrast, pretreatment of calpain inhibitors significantly inhibited the activation of calpains. Our further investigation found that ALLN or calpeptin administration significantly suppresses the changes of mitochondrial dynamics in APAP-treated mice and finally protected against APAP-induced hepatoxicity. Overall, these results suggest that calpain-mediated cleavage of mitochondrial dynamics proteins was involved in the pathogenic process of mitochondrial dysfunction and thus present a potential molecular coupling APAP-induced hepatotoxicity.

Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer's Disease Model Mice.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

Biomass-related PM2.5 induces mitochondrial fragmentation and dysfunction in human airway epithelial cells

The use of biomass for cooking and heating is considered an important factor associated with chronic obstructive pulmonary disease (COPD), but few studies have previously addressed its underlying mechanisms. Therefore, this research aimed to evaluate the effects of biomass-related PM2.5 (BRPM2.5) exposure on 16HBE human airway epithelial cells and in mice with regard to mitochondrial dysfunction. Our study indicated that BRPM2.5 exposure of 16HBE cells resulted in mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased expression of fission proteins-phospho-DRP1, increased mitochondrial ROS (mtROS), and decreased levels of ATP. BRPM2.5 altered the mitochondrial metabolism of 16HBE cells by decreasing mitochondrial oxygen consumption and glycolysis. However, Mitochondria targeted peptide SS-31 eliminated mitochondrial ROS and alleviated the ATP deficiency and proinflammatory cytokines release. BRPM2.5 exposure resulted in abnormal mitochondrial morphological alterations both in 16HBE and in lung tissue. Taken together, these results suggest that BRPM2.5 has detrimental effects on human airway epithelial cells, leading to mitochondrial dysfunction, abnormal mitochondrial metabolism and altered mitochondrial dynamics. The present study provides the first evidence that disruption of mitochondrial structure and mitochondrial metabolism may be one of the mechanisms of BRPM2.5-induced respiratory dysfunction.

Fasudil protects neurons through inhibiting oxidative stress response and restoring mitochondrial fission-fusion imbalance

The pathogenesis of Alzheimer's disease (AD) is closely related to oxidative stress response and abnormal mitochondrial dynamics. Our previous research demonstrated that Fasudil has neuroprotective effect. Our aim was to explore whether Fasudil has beneficial effect on alleviating oxidative stress and regulating mitochondiral dynamics in APP/PS1 transgenic AD mice.

Exercise-Induced Benefits for Alzheimer's Disease by Stimulating Mitophagy and Improving Mitochondrial Function.

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria due to their higher bioenergetic demand. Mitochondrial dysfunction is closely associated with a variety of aging-related neurological disorders, such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and superfluous mitochondria has been reported as an early stage that significantly facilitates the progression of AD. Mitochondrial damage causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating β-amyloid (Aβ) accumulation and Tau hyperphosphorylation, and further leading to cognitive decline and memory loss. Although there is an intricate parallel relationship between mitochondrial dysfunction and AD, their triggering factors, such as Aβ aggregation and hyperphosphorylated Tau protein and action time, are still unclear. Moreover, many studies have confirmed abnormal mitochondrial biosynthesis, dynamics and functions will present once the mitochondrial quality control is impaired, thus leading to aggravated AD pathological changes. Accumulating evidence shows beneficial effects of appropriate exercise on improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, enhance cognitive capacity and reduce the risks of cognitive impairment and dementia in later life. Therefore, stimulating mitophagy and optimizing mitochondrial function through exercise may forestall the neurodegenerative process of AD.

NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis.

Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.

NAD+ deficiency and mitochondrial dysfunction in granulosa cells of women with polycystic ovary syndrome‡.

Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine disorder characterized by ovulation dysfunction, androgen excess, ovarian polycystic changes, insulin resistance, and infertility. Although underlying mechanisms for PCOS are still unknown, inflammation and mitochondrial dysfunction in granulosa cells (GCs) of PCOS patients have been reported. Here, we found that Nicotinamide Adenine Dinucleotide (NAD+) levels in GCs of PCOS patients was significantly decreased when compared with controls. Also, we found that higher expression of inflammation factors, increased reactive oxygen species (ROS) accumulation, lower adenosine triphosphate (ATP) generation, and decreased mitochondrial membrane potential, as well as abnormal mitochondrial dynamics in GCs of PCOS patients. In addition, the NAD+ levels were decreased after activation of inflammation in human granulosa-like tumor cell line (KGN) treated by Lipopolysaccharide (LPS). However, supplementation of nicotinamide riboside (NR), a NAD+ precursor, could largely restore the NAD+ content, reduce ROS levels and improve mitochondrial function demonstrated by increased mitochondrial membrane potential and ATP generation in LPS-treated KGN cells. Our data suggested that inflammation decreased NAD+ levels in GCs of PCOS patients, while supplementation of NR could restore NAD+ levels and alleviated mitochondrial dysfunction in GCs of PCOS patients.

Aconitine induces mitochondrial energy metabolism dysfunction through inhibition of AMPK signaling and interference with mitochondrial dynamics in SH-SY5Y cells

Aconitine, a highly toxic alkaloid derived from Aconitum L., affects the central nervous system and peripheral nervous system. However, the underlying mechanism of aconitine-induced neurotoxicity remains unclear. This study investigates the effects and mechanism of aconitine on mitochondrial energy metabolism in SH-SY5Y cells. Results demonstrated that aconitine exposure suppressed cell proliferation and led to an increase in reactive oxygen species (ROS) and excessive lactate dehydrogenase (LDH) release. Aconitine (400 μmol/L) induced abnormal mitochondrial energy metabolism that quantified by the significant decrease in ATP production, basal respiration, proton leak, maximal respiration, and succinate dehydrogenase (SDH) activity. Phosphorylation of AMPK was significantly reduced in aconitine-treated SH-SY5Y cells. The AMPK activator AIACR pretreatment effectively promoted ATP production to ameliorate mitochondrial energy metabolism disorder caused by aconitine. Mitochondrial biosynthesis was inhibited after treatment with 400 μmol/L aconitine, which was characterized by mitochondria number, TFAM expression, and mtDNA copy number. Moreover, aconitine prompted the down-regulation of mitochondrial fusion proteins OPA1, Mfn1 and Mfn2, and the up-regulation of mitochondrial fission proteins p-Drp1 and p-Mff. These results suggest that aconitine induces mitochondrial energy metabolism dysfunction in SH-SY5Y cells, which may involve the inhibition of AMPK signaling and abnormal mitochondrial dynamics.

A Single Dose of Exercise Initiates Corrective Mitochondrial Plasticity in Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is the most common life-limiting muscular dystrophy in adults. Abnormal mitochondrial function and dynamics have been observed in DM1 patient derived cells, which likely exacerbates the muscle pathology in DM1. Exercise is safe, low-cost, and accessible medicine that reaps robust benefits to mitochondrial biology. However, in DM1 muscle, in vivo assessments of mitochondrial dynamics and mitophagy, as well as the effects of exercise therein, remain unexamined. Therefore, this study aims to further elucidate mitochondrial properties in a mouse model of DM1 (HSALR) and examine the mitochondrial response following an acute bout of exercise. Both wild-type (WT) and HSALR mice performed a progressive, vigorous bout of exercise on a treadmill until the inability to continue running was objectively determined. Muscle samples were collected at rest and at various timepoints following exercise. At rest, phosphorylated dynamin-related protein 1 (p-DRP1Ser616), total DRP1 and Parkin levels were elevated (p < 0.05) in HSALR mice compared to WT. Furthermore, the mitofusin-2 (MFN2)-to-DRP ratio was significantly lower in HSALR animals relative to their WT counterparts. Exercise capacity was lower (p < 0.05) in HSALR mice compared to WT. Immediately following exercise, p-DRP1Ser616 levels were significantly increased in WT animals but returned to the resting state at 3 hours post-exercise. In contrast, HSALR showed elevated (p < 0.05) p-DRP1Ser616 until 3 hours post-exercise before returning to basal levels at 12 hours. Mitochondrial fission 1 (Fis1) protein content significantly increased 3 hours post-exercise in WT animals and 12 hours post-exercise in the HSALR group. MFN2 content was augmented (p < 0.05) immediately following exercise and remained elevated up to 24 hours in HSALR mice only, thus, restoring the MFN2-to-DRP1 ratio. Lastly, fission and mitophagy related mRNA transcripts were blunted immediately and 3 hours (p < 0.05) following exercise while the transcription of fusion related genes was augmented (p < 0.05). In contrast, the expression of mitophagy related genes was significantly increased 12 and 24 hours following the exercise bout. Collectively, these data provide further evidence for mitochondrial dysfunction within DM1 biology. An imbalance in fusion and fission processes could greatly diminish mitochondrial function, which could in turn accelerate skeletal muscle atrophy. Exercise may be a promising intervention to correct the imbalance in mitochondrial dynamics and augment overall mitochondrial function within DM1 muscle.

CB1 receptor antagonist rimonabant protects against chronic intermittent hypoxia-induced renal injury in rats

BackgroundObstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.MethodsMale Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.ResultsCB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.ConclusionCIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.

Iptakalim alleviates synaptic damages via targeting mitochondrial ATP-sensitive potassium channel in depression.

Synaptic plasticity damages play a crucial role in the onset and development of depression, especially in the hippocampus, which is more susceptible to stress and the most frequently studied brain region in depression. And, mitochondria have a major function in executing the complex processes of neurotransmission and plasticity. We have previously demonstrated that Iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could improve the depressive-like behavior in mice. But the underlying mechanisms are not well understood. The present study demonstrated that Ipt reversed depressive-like phenotype in vivo (chronic mild stress-induced mice model of depression) and in vitro (corticosterone-induced cellular model). Further study showed that Ipt could upregulate the synaptic-related proteins postsynaptic density 95 (PSD 95) and synaptophysin (SYN), and alleviated the synaptic structure damage. Moreover, Ipt could reverse the abnormal mitochondrial fission and fusion, as well as the reduced mitochondrial ATP production and collapse of mitochondrial membrane potential in depressive models. Knocking down the mitochondrial ATP-sensitive potassium (Mito-KATP) channel subunit MitoK partly blocked the above effects of Ipt. Therefore, our results reveal that Ipt can alleviate the abnormal mitochondrial dynamics and function depending on MitoK, contributing to improve synaptic plasticity and exert antidepressive effects. These findings provide a candidate compound and a novel target for antidepressive therapy.

S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy

AimsSepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE. Main methodsFPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells. Key findingsWestern blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects both in vivo and in vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosis in vitro. SignificanceThis study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.

Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.

The purpose of this study is to study the neuroprotective role of selective serotonin reuptake inhibitor (SSRI), citalopram, against Alzheimer's disease (AD). Multiple SSRIs, including citalopram, are reported to treat patients with depression, anxiety and AD. However, their protective cellular mechanisms have not been studied completely. In the current study, we investigated the protective role of citalopram against impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective mitophagy and synaptic dysfunction in immortalized mouse primary hippocampal cells (HT22) expressing mutant APP (SWI/IND) mutations. Using quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed mutant full-length APP/C-terminal fragments and Aβ levels and mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes in mAPP-HT22 cells and mAPP-HT22 cells treated with citalopram. Increased levels of mRNA levels of mitochondrial fission genes, decreased levels of fusion biogenesis, autophagy, mitophagy and synaptic genes were found in mAPP-HT22 cells relative to WT-HT22 cells. However, mAPP-HT22 cells treated with citalopram compared to mAPP-HT22 cells revealed reduced levels of the mitochondrial fission genes, increased fusion, biogenesis, autophagy, mitophagy and synaptic genes. Our protein data agree with mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells; these were reversed in citalopram-treated mAPP-HT22 cells. Cell survival rates were increased in citalopram-treated mAPP-HT22 relative to citalopram-untreated mAPP-HT22. Further, mAPP and C-terminal fragments werealso reduced in citalopram-treated cells. These findings suggest that citalopram reduces mutant APP and Aβ and mitochondrial toxicities and may have a protective role of mutant APP and Aβ-induced injuries in patients with depression, anxiety and AD.

Роль дисфункції мітохондрій у розвитку хвороби Альцгеймера

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intensive research have shown that multicellular changes are involved in AD’s development and progression, including mitochondrial damage, synaptic dysfunction, formation and accumulation of beta-amyloid (Aβ), formation and accumulation of hyperphosphorylated tau protein, and loss of neurons in patients with this disease. Among them, mitochondrial dysfunction and synaptic damage are the primary manifestations in the disease process. Recent studies have also shown that defective mitophagy caused by Aβ and tau protein are the main indicators in AD’s pathogenesis. This review includes an overview of recent researches on the role of mitochondria in AD development. The review summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics, changes in mitochondrial DNA, and calcium dyshomeostasis in AD pathogenesis

MicroRNA-125b alleviates hydrogen-peroxide-induced abnormal mitochondrial dynamics in HT22 cells by inhibiting p53.

Micro-RNA125b (miR-125b) and tumor protein p53 (p53) are involved in the regulation of mitochondrial dynamics; however, the mechanism of their possible interaction during oxidative stress remains unclear. In this study, we investigated the role and mechanism of miR-125b and p53 in oxidative stress-induced mitochondrial damage in immortalized mouse hippocampal HT22 cells. Following stimulation with H2O2, we observed downregulation of miR-125b expression, upregulation of p53 expression, mitochondria were damaged and increased cell death. Overexpression of miR-125b alleviated mitochondrial damage and inhibited p53 expression. Furthermore, confocal and electron microscopy showed that overexpression of p53 eliminated the protective effect of miR-125b on the mitochondria. Thus, miR-125b alleviates abnormal mitochondrial homeostasis in H2O2-treated HT22 cells by suppressing p53 expression. Our data reveal a new model by which miR-125b influences mitochondrial dynamics.

Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer

The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.

Defective Autophagy and Mitophagy in Aging and Alzheimer's Disease.

Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer’s disease (AD), Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.