Melatonin's Protective Effects on Neurons in an in Vitro Cell Injury Model.

BACKGROUND: Currently, the role of melatonin (MT) in neuronal damage remains unclear and this study aimed to explore the protective effects of MT on neurons in an in vitro cell injury model. METHODS: The Sprague Dawley (SD) rat traumatic brain injury (TBI) model was prepared, and brain tissue extract (BTE) from the injured area were generated. To establish a cell injury model in vitro, the BTE was added to the culture medium during the neuron culture process. MT was introduced into the culture medium of the cell injury model to observe its protective effects on neurons. Relevant molecular biology experiments were conducted to observe cellular oxidative stress status, inflammation, endoplasmic reticulum (ER) stress, mitochondrial damage, and neuronal apoptosis. RESULTS: When compared to the control group, the BTE group exhibited a significant increase in cellular oxidative stress, inflammation, neurofilament light polypeptide (NEFL) expression, and ER stress. Additionally, the mitochondrial DNA (mtDNA) copy number significantly decreased, and there was a higher count of apoptotic cells (p < 0.05). Upon the addition of MT to the culture medium of the in vitro cell injury model, there was a significant reduction in cellular oxidative stress, inflammation, and NEFL levels. This addition also mitigated ER stress, increased mtDNA copy numbers, and decreased the ratio of cell apoptosis (p < 0.05). CONCLUSIONS: In the in vitro cell injury model, MT demonstrates the capacity to inhibit cellular oxidative stress, inflammation, and ER stress levels. Additionally, it diminishes mtDNA damage, fosters cell viability, and serves as a protective agent against both apoptosis and necrosis in neurons.

[Research advance on the role of mitochondrial dysfunction and releasing mitochondrial DNA in sepsis-induced acute lung injury].

Sepsis-induced acute lung injury (ALI) is a serious condition with a high incidence. Mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA) play a crucial role in the occurrence and development of sepsis-induced ALI. In sepsis, mitochondrial dysfunction causes energy depletion of cells and dysfunction of tissue cell repair mechanisms, leading to ALI. In addition, the release of mtDNA leads to a more intense inflammatory response, exacerbating sepsis-induced ALI. This article reviews the pathophysiological mechanism of mitochondrial dysfunction and mtDNA release in sepsis and the current research status, in order to provide direction for the evaluation, treatment and prevention of sepsis-induced ALI.

Germacrone protects renal tubular cells against ferroptotic death and ROS release by re-activating mitophagy in diabetic nephropathy.

Mitophagy is a critical intracellular event during the progression of diabetic nephropathy (DN). Our previous study demonstrated that germacrone has anti-ferroptotic properties and is a potential therapeutic agent for DN. However, the relationship among germacrone, mitophagy, and ferroptosis in DN remains unclear. In this study, the data confirmed that germacrone ameliorates high glucose (HG)-induced ferroptosis through limiting Fe (2+) content and lipid reactive oxygen species (ROS) accumulation in human kidney 2 (HK-2) cells. Germacrone reversed HG-mediated inhibition of mitophagy. Mitophagy inhibition and anabatic mitochondrial ROS abrogate germacrone-mediated protective effects against ferroptotic death, resulting in the subsequent activation of mitochondrial DNA (mtDNA) cytosolic leakage-induced stimulator of interferon response CGAMP interactor 1 (STING) signaling. The combination of a mitochondrial ROS antagonist and germacrone acts synergistically to alleviate the ferroptotic death of tubular cells and DN symptoms. In summary, germacrone ameliorated ferroptotic death in tubular cells by reactivating mitophagy and inhibiting mtDNA-STING signaling in DN. This study provides a novel insight into germacrone-mediated protection against DN progression and further confirms that antioxidant pharmacological strategies facilitate the treatment of DN.

Regulating Photosensitizer Metabolism with DNAzyme-Loaded Nanoparticles for Amplified Mitochondria-Targeting Photodynamic Immunotherapy.

Mitochondria-specific photosensitizer accumulation is highly recommended for photodynamic therapy and mitochondrial DNA (mtDNA) oxidative damage-based innate immunotherapy but remains challenging. 5-Aminolevulinic acid (ALA), precursor of photosensitizer protoporphyrin IX (PpIX), can induce the exclusive biosynthesis of PpIX in mitochondria. Nevertheless, its photodynamic effect is limited by the intracellular biotransformation of ALA in tumors. Here, we report a photosensitizer metabolism-regulating strategy using ALA/DNAzyme-co-loaded nanoparticles (ALA&Dz@ZIF-PEG) for mitochondria-targeting photodynamic immunotherapy. The zeolitic imidazolate framework (ZIF-8) nanoparticles can be disassembled and release large amounts of zinc ions (Zn2+) within tumor cells. Notably, Zn2+ can relieve tumor hypoxia for promoting the conversion of ALA to PpIX. Moreover, Zn2+ acts as a cofactor of rationally designed DNAzyme for silencing excessive ferrochelatase (FECH; which catalyzes PpIX into photoinactive Heme), cooperatively promoting the exclusive accumulation of PpIX in mitochondria via the "open source and reduced expenditure" manner. Subsequently, the photodynamic effects derived from PpIX lead to the damage and release of mtDNA and activate the innate immune response. In addition, the released Zn2+ further enhances the mtDNA/cGAS-STING pathway mediated innate immunity. The ALA&Dz@ZIF-PEG system induced 3 times more PpIX accumulation than ALA-loaded liposome, significantly enhancing tumor regression in xenograft tumor models.

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats.

BACKGROUND: Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. METHODS: The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. RESULTS: The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. CONCLUSIONS: The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs' development. These effects may be mediated through modulating mitochondrial homeostasis and functions.

The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy.

Periodontitis is an inflammatory and destructive disease of tooth-supporting tissue and has become the leading cause of adult tooth loss. The most central pathological features of periodontitis are tissue damage and inflammatory reaction. As the energy metabolism center of eukaryotic cells, mitochondrion plays a notable role in various processes, such as cell function and inflammatory response. When the intracellular homeostasis of mitochondrion is disrupted, it can lead to mitochondrial dysfunction and inability to generate adequate energy to maintain basic cellular biochemical reactions. Recent studies have revealed that mitochondrial dysfunction is closely related to the initiation and development of periodontitis. The excessive production of mitochondrial reactive oxygen species, imbalance of mitochondrial biogenesis and dynamics, mitophagy and mitochondrial DNA damage can all affect the development and progression of periodontitis. Thus, targeted mitochondrial therapy is potentially promising in periodontitis treatment. In this review, we summarize the above mitochondrial mechanism in the pathogenesis of periodontitis and discuss some potential approaches that can exert therapeutic effects on periodontitis by modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in periodontitis might provide new research directions for pathological intervention or treatment of periodontitis.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Mangiferin Protects DNase 2 Abundance via Nrf2 Activation to Prevent Cytosolic mtDNA Accumulation during Liver Injury.

SCOPE: Mitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage-associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aims to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on deoxyribonuclease 2 (DNase 2) protection from oxidative damage. METHODS AND RESULTS: Mangiferin administration effectively protects against hepatotoxicity in mice subjected to CCl4 challenge or bile duct ligation (BDL) surgery. Moreover, mangiferin activates nuclear factor erythroid 2-related factor (Nrf2)-antioxidant signaling, reduces cytosolic mtDNA accumulation, and suppresses Toll-like receptor 9 (TLR-9)/myeloid differentiation factor 88 (MyD88)-dependent inflammation in the liver. The study prepares hepatic mtDNA to stimulate hepatocytes, and finds that mangiferin protects DNase 2 protein abundance. mtDNA induces reactive oxygen species (ROS) production to promote DNase 2 protein degradation through oxidative modification, but mangiferin protects DNase 2 protein stability in a Nrf2-dependent manner. In hepatic Nrf2 deficiency mice, the study further confirms that Nrf2 induction is required for mangiferin to clear cytosolic mtDNA and block mtDNA-mediated TLR9/MyD88/nuclear factor kappa-B (NF-κB) inflammatory signaling cascades. CONCLUSION: These findings provide new insights into the role of mangiferin as a liver protecting agent, and suggest protection of DNase 2 as a novel therapeutic strategy for pharmacological intervention to prevent liver damage.

Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.

Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.

The evaluation of reactive oxygen species generation and free mitochondrial DNA in platelet concentrates during 5 days of storage.

Oxidative stress and mitochondrial damage are causes of platelet storage lesions (PSLs). Mitochondrial damage causes mitochondrial DNA (mtDNA) to be released into the extracellular space. MtDNA in platelet concentrates is considered damage-associated molecular patterns (DAMPs) and is one of the major causes of PSLs. The mechanism of mtDNA release in platelet concentrates has not been thoroughly investigated. This study aimed to determine the effect of reactive oxygen species (ROS) on mtDNA release in platelet concentrates during storage. Ten platelet concentrates from healthy donors were obtained in this investigation. Platelet concentrates were prepared by platelet-rich plasma (PRP) and stored at 22 ±â€Š2 C° with gentle agitation. Platelet concentrates were subjected to flow cytometry and real-time PCR to evaluate total ROS and free mtDNA on days 0, 3, and 5 of platelet concentrate storage. Total ROS detected significantly increased from day 0 to day 5 of platelet concentrate storage (P = 0.0079). The mean of copy numbers of free mtDNA on day 0 increased from 3.43 × 106 ±â€Š1.57 × 106 to 2.85 × 107 ±â€Š1.51 × 107 (molecules/µl) on the fifth day of platelet concentrate storage, and it was statistically significant (P = 0.0039). In addition, LDH enzyme activity significantly increased during platelet concentrate storage (P < 0.0001). Also, releasing mtDNA in platelet concentrates was directly correlated with total ROS generation (P = 0.021, r = 0.61) and LDH activity (P = 0.04, r = 0.44). The evidence from this study confirmed the increasing level mtDNA copy numbers in platelet concentrates during storage, and the amount of free mtDNA is directly correlated with ROS generation and platelet lysis during 5 days of platelet concentrate storage. Finally, these changes may be related to DAMPs in the platelet concentrates.

In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates.

Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM2.5) and NO2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIRONAGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM2.5 and NO2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO2 exposure and cord-blood mtDNA heteroplasmy. A 5 µg/m3 increment in NO2 was linked with MT-D-Loop16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB14766C>T was negatively associated with NO2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM2.5 exposure. This is the first study to show that prenatal NO2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.

Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.

Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.

Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear. METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC. RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2high OSCC patients showed better overall survival than CES2low OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2. CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC.

Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway.

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA's effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.

Autophagy and mitochondrial damage in the testis of high-fat diet fed rats.

High-fat diet (HFD) affects the physiology of reproduction in males, and many studies have investigated its detrimental effects. In this study, we investigated the cellular response induced by an HFD in the rat testis, focusing on the mitochondrial compartment. After five weeks of HFD, an increase in the levels of malondialdehyde and of reduced form of glutathione in the rat testis indicated an increase in lipid peroxidation. The results showed an increase in autophagy, apoptosis, and mitochondrial damage in the testis of HFD rats. We found a decrease in the protein expression of mitochondrial antioxidant enzymes, such as catalase and SOD2. Immunohistochemical analysis revealed a decrease in the immunofluorescent signal of SOD2, mainly in the spermatogonia and spermatocytes of HFD rats. HFD-induced mitochondrial damage caused a reduction in mitochondria, as evidenced by a decrease in the protein expression of TOM20, a mitochondrial outer membrane receptor. Consistently, HFD enhanced the levels of the PINK1 protein, a mitophagy marker, suggesting the removal of damaged mitochondria under these conditions. Induction of mtDNA damage and repair was stronger in the HFD rat testis. Finally, we found a decrease in the mtDNA copy number and expression of the POLG enzyme, which is involved in mtDNA replication. In conclusion, our results showed that autophagy and apoptosis are activated in the testis of HFD rats as a survival strategy to cope with oxidative stress. Furthermore, HFD-induced oxidative stress affects the mitochondria, inducing mtDNA damage and mtDNA copy number reduction. Mitophagy and mtDNA repair mechanisms might represent a mitochondrial adaptive response.

Mitochondrial targeting of potent nanoparticulated drugs in combating diseases.

Mitochondrial dysfunction, characterized by the electron transport chain (ETC) leakage and reduced adenosine tri-phosphate synthesis, occurs primarily due to free radicals -induced mutations in either the mitochondrial deoxyribonucleic acid (mtDNA) or nuclear (n) DNA caused by pathogenic infections, toxicant exposures, adverse drug-effects, or other environmental exposures, leading to secondary dysfunction affecting ischemic, diabetic, cancerous, and degenerative diseases. In these concerns, mitochondria-targeted remedies may include a significant role in the protection and treatment of mitochondrial function to enhance its activity. Coenzyme Q10 pyridinol and pyrimidinol antioxidant analogues and other potent drug-compounds for their multifunctional radical quencher and other anti-toxic activities may take a significant therapeutic effectivity for ameliorating mitochondrial dysfunction. Moreover, the encapsulation of these bioactive ligands-attached potent compounds in vesicular system may enable them a superb biological effective for the treatment of mitochondria-targeted dysfunction-related diseases with least side effects. This review depicts mainly on mitochondrial enzymatic dysfunction and their amelioration by potent drugs with the usages of nanoparticulated delivery system against mitochondria-affected diseases.

Basolateral Amygdala SIRT1/PGC-1α Mitochondrial Biogenesis Pathway Mediates Morphine Withdrawal-Associated Anxiety in Mice.

BACKGROUND: Anxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. Sirtuins 1 (SIRT1) has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety. METHODS: We established a mouse model of anxiety-like behaviors induced by morphine withdrawal and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mitochondrial DNA contents with quantitative real-time PCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by western blot. Then we used virus-mediated downregulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examined the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function. RESULTS: We found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules increased in BLA cells. Virus-mediated downregulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, whereas overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/ peroxisome proliferator activated receptor gamma coactivator 1-alpha pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal. CONCLUSION: Our results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioid withdrawal-associated anxiety.

Targeting mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases.

Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human health. Mitochondrial bioenergetics is considered an important measure to assess the pathogenesis of various diseases. Dysfunctional mitochondria affect or cause several conditions involving the most energy-intensive organs, including the brain, muscles, heart, and liver. This dysfunction may be attributed to an alteration in mitochondrial enzymes, increased oxidative stress, impairment of electron transport chain and oxidative phosphorylation, or mutations in mitochondrial DNA that leads to the pathophysiology of various pathological conditions, including neurological and metabolic disorders. The drugs or compounds targeting mitochondria are considered more effective and safer for treating these diseases. In this review, we make an effort to concise the available literature on mitochondrial bioenergetics in various conditions and the therapeutic potential of various drugs/compounds targeting mitochondrial bioenergetics in metabolic and neurodegenerative diseases.

Novel bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells.

Four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl2 (Zn(BQTC)), [Zn(BQA) (Cur)Cl] (Zn(BQACur)), [Zn (TC)]Cl2 (Zn(TC)), and [Zn (AP) (Cur)Cl] (Zn(APCur)), bearing curcumin (H-Cur), cyclen (TC), 1,10-phenanthrolin-5-amine (AP), and novel cryptolepine-cyclen derivatives (BQTC and BQA) were prepared for cell nucleus- and mitochondria-specific imaging. MTT assay results indicated that Zn(BQTC) and Zn(BQACur) exhibit stronger anticancer activity against cisplatin-resistant A549R lung tumor cells than ZnCl2, Zn(TC), Zn(APCur), H-Cur, TC, AP, BQTC, and BQA. Due to the dual fluorescence characteristic of Zn(BQTC), selective fluorescence imaging of the nucleus and mitochondria of A549R cancer cells was conducted. Further, Zn(BQTC), obtained by the functionalization of Zn(TC) with cryptolepine derivative substituents, efficiently inhibited DNA synthesis, thus resulting in high cytotoxicity (selective for A549R lung tumor cells) accompanied by DNA impairment in nuclear and mitochondrial fractions. Additionally, Zn(BQTC) caused severe damage to the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), sequentially disrupted mitochondrial and nuclear functions, and promoted the DNA damage-induced apoptotic signaling pathway and adenosine triphosphate depletion (ATP). Thus, Zn(BQTC) can be used as an anticancer drug by targeting mtDNA and nDNA. Most importantly, Zn(BQTC) showed higher efficacy in inhibiting cancer growth (55.9%) in A549R tumor-bearing mice than Zn(TC) (31.2%) and cisplatin, along with a promising in vivo safety profile. These results demonstrate the applicability of the developed novel bifluorescent Zn(II)-cryptolepine-cyclen complexes as promising DNA-targeting anticancer agents for cancer treatment.

Effects of exposure to environmental pollutants on mitochondrial DNA copy number: a meta-analysis.

Exposure to environmental pollutants has been associated with alteration on relative levels of mitochondrial DNA copy number (mtDNAcn). However, the results obtained from epidemiological studies are inconsistent. This meta-analysis aimed to evaluate whether environmental pollutant exposure can modify the relative levels of mtDNAcn in humans. We performed a literature search using PubMed, Scopus, and Web of Science databases. We selected and reviewed original articles performed in humans that analyzed the relationship between environmental pollutant exposure and the relative levels of mtDNAcn; the selection of the included studies was based on inclusion and exclusion criteria. Only twenty-two studies fulfilled our inclusion criteria. A total of 6011 study participants were included in this systematic review and meta-analysis. We grouped the included studies into four main categories according to the type of environmental pollutant: (1) heavy metals, (2) polycyclic aromatic hydrocarbons (PAHs), (3) particulate matter (PM), and (4) cigarette smoking. Inconclusive results were observed in all categories; the pooled analysis shows a marginal increase of relative levels of mtDNAcn in response to environmental pollutant exposure. The trial sequential analysis and rate confidence in body evidence showed the need to perform new studies. Therefore, a large-scale cohort and mechanistic studies in this area are required to probe the possible use of relative levels of mtDNAcn as biomarkers linked to environmental pollution exposure.