Decrease In Mitochondrial Biogenesis Research Articles

Different Effects of High-Fat/High-Sucrose and High-Fructose Diets on Advanced Glycation End-Product Accumulation and on Mitochondrial Involvement in Heart and Skeletal Muscle in Mice

Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet.

Effect of DNA damage mediating psychosocial stress on aging

Adversity and psychosocial stress are involved in aging through the following pathways. psychological stress enhances the nerve system to secrete endocrine mediators (hormones). Mitochondrial respiration mediates energy production stimulated by binding to these hormones to their receptors. Energy produced by mitochondria accelerates metabolism and, in its turn, leads to increases in reactive oxygen species (ROS) of free radicals. Cellular stress and accumulation of damage can result from an excess of ROS. Accumulation of damage comprises damages in telomeric and nontelomeric DNA, in addition to mitochondrial DNA. Mitochondrial DNA damage plays an important role in increasing the pathway of p53/p21. The expression of the PGC-1α gene is inhibited by activation of the previous pathway that generates a decrease in mitochondrial biogenesis. The low level of mitochondrial biogenesis generates mitophagy defects and increases the level of dysfunctional mitochondria that lead to a high level of ROS production. Nuclear DNA damage and mitochondrial dysfunction stimulate necrosis or cell senescence. Necrotic cells enhance the inflammatory activity by which damage-associated molecular patterns (DAMPs) are continuously secreted. Senescent cells secrete high levels of the senescence-associated secretory phenotype (SASP) that includes tumor necrosis factor TNF-α and interleukin-6 (IL-6) as inflammatory cytokines, and MCP-2 and interleukin-8 (IL-8) as chemokines. All these processes work together to accelerate the biological aging process by causing defects related to aging such as diabetes and cardiovascular disease.

Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice.

Aging is a physiological process that generates progressive decline in many cellular functions. There are many theories of aging, and one of great importance in recent years is the mitochondrial theory of aging, in which mitochondrial dysfunction that occurs at advanced age could be responsible for the aged phenotype. In this context, there is diverse information about mitochondrial dysfunction in aging, in different models and different organs. Specifically, in the brain, different studies have shown mitochondrial dysfunction mainly in the cortex; however, until now, no study has shown all the defects in hippocampal mitochondria in aged female C57BL/6J mice. We performed a complete analysis of mitochondrial function in 3-month-old and 20-month-old (mo) female C57BL/6J mice, specifically in the hippocampus of these animals. We observed an impairment in bioenergetic function, indicated by a decrease in mitochondrial membrane potential, O2 consumption, and mitochondrial ATP production. Additionally, there was an increase in ROS production in the aged hippocampus, leading to the activation of antioxidant signaling, specifically the Nrf2 pathway. It was also observed that aged animals had deregulation of calcium homeostasis, with more sensitive mitochondria to calcium overload and deregulation of proteins related to mitochondrial dynamics and quality control processes. Finally, we observed a decrease in mitochondrial biogenesis with a decrease in mitochondrial mass and deregulation of mitophagy. These results show that during the aging process, damaged mitochondria accumulate, which could contribute to or be responsible for the aging phenotype and age-related disabilities.

Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood.

Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.

PSIX-33 Docosahexaenoic Acid (DHA) but not Eicosapentaenoic Acid (EPA) induces the trans-differentiation of C2C12 into white-like adipocytes phenotype

Abstract Muscle-derived stem cells (MDSCs, or myoblasts) play an important role in myotubes regeneration. However, these cells can differentiate into adipocytes once exposed to EPA and DHA, which are highly suggested during pregnancy. The objective of this study aims at determining the effect of isolated EPA and DHA on C2C12 cells undergoing white and brown adipogenic differentiation. Confluent cultured cells were treated with white and brown adipocyte induction medium (WIM and BIM respectively) with 50µM EPA and 50µM DHA separately. DHA treated groups differentiated into white-like adipocyte by down-regulating the expression of myogenic genes such as MyoD, MyoG, and Mrf4; but promoted white adipocyte marker genes(P < 0.05). Moreover, cells treated with WIM and DHA exhibited a decrease in mitochondrial biogenesis through suppressing PGC1a and TFAM expression (P < 0.05). Also, DHA promoted the expression of lipolysis regulating genes. DHA impaired C2C12 cells browning through reducing the mitochondrial biogenesis by significantly suppressing the expression of COX7a1, PGC1a, and UCP3 genes (P < 0.05). DHA treated groups showed an increased accumulation of lipid droplets and suppressed maximal mitochondrial respiration and spare capacity. EPA treatment reduced myogenesis regulating genes (P < 0.05) but did not affect adipogenic genes (P >0.05). Likewise, EPA suppressed the expression of WAT signature genes (P < 0.05), indicating its antagonism to DHA. EPA and WIM treatment suppressed the expression of TFAM and PGC1a, but did not affect PGC1a protein level. Although mitochondrial biogenic gene expression was reduced in EPA and BIDM treated group, no changes in mitochondrial function were observed. EPA supplementation did not affect the differential route of C2C12 into brown adipocytes. To conclude, EPA and DHA may similarly affect the integrity of muscle tissue, but DHA is a potent adipogenic and lipogenic factor that can change the metabolic profile of the body by increasing intramuscular fat.

Respiratory muscle senescence in ageing and chronic lung diseases.

Ageing is a progressive condition that usually leads to the loss of physiological properties. This process is also present in respiratory muscles, which are affected by both senescent changes occurring in the whole organism and those that are more specific for muscles. The mechanisms of the latter changes include oxidative stress, decrease in neurotrophic factors and DNA abnormalities. Ageing normally coexists with comorbidities, including respiratory diseases, which further deteriorate the structure and function of respiratory muscles. In this context, changes intrinsic to ageing become enhanced by more specific factors such as the impairment in lung mechanics and gas exchange, exacerbations and hypoxia. Hypoxia in particular has a direct effect on muscles, mainly through the expression of inducible factors (hypoxic-inducible factor), and can result in oxidative stress and changes in DNA, decrease in mitochondrial biogenesis and defects in the tissue repair mechanisms. Intense exercise can also cause damage in respiratory muscles of elderly respiratory patients, but this can be followed by tissue repair and remodelling. However, ageing interferes with muscle repair by tampering with the function of satellite cells, mainly due to oxidative stress, DNA damage and epigenetic mechanisms. In addition to the normal process of ageing, stress-induced premature senescence can also occur, involving changes in the expression of multiple genes but without modifications in telomere length.

Muscle denervation reduces mitochondrial biogenesis and mitochondrial translation factor expression in mice

The mitochondrial translation process, in which mitochondrial DNA (mtDNA)-encoded genes are translated into their corresponding proteins, is crucial for mitochondrial function, biogenesis, and integrity. This process is divided into four phases—initiation, elongation, termination, and mitoribosome recycling—which are regulated by specific translation factors, including mitochondrial initiation factor 2 and 3 (mtIF2 and mtIF3), mitochondrial elongation factor Tu, Ts, and G1 (mtEFTu, mtEFTs, and mtEFG1), mitochondrial translational release factor 1-like (mtRF1L), and mitochondrial recycling factor 1 and 2 (mtRRF1 and mtRRF2). Muscle denervation downregulates mitochondrial biomass and induces skeletal muscle atrophy. However, it is unknown whether denervation affects the expression of mitochondrial translation factors in skeletal muscle. In this study, we hypothesized that denervation decreases the expression of mitochondrial translation factors. Therefore, we investigated the effect of muscle denervation on mitochondrial protein and mitochondrial translation factor expression in soleus muscle after surgery. Denervation induced muscle atrophy and activated the ubiquitin-proteasome pathway in soleus muscle. Additionally, muscle denervation decreased the expression of mitochondrial translation factors as well as nuclear DNA and mtDNA-encoded mitochondrial proteins in soleus muscle. Further, a correlation was found between the expression of mitochondrial translation factors and mtDNA-encoded proteins three and seven days after denervation. Taken together, these results demonstrated that the denervation-induced decrease in mitochondrial biogenesis corresponded with changes in mitochondrial translation factors in murine skeletal muscle, providing novel molecular-level insight into the effects of muscle denervation on the mitochondrial translation process.

Sustained mitochondrial biogenesis is essential to maintain caloric restriction-induced beige adipocytes

BackgroundCaloric restriction (CR) delays the onset of metabolic and age-related disorders. Recent studies have demonstrated that formation of beige adipocytes induced by CR is strongly associated with extracellular remodeling in adipose tissue, decrease in adipose tissue inflammation, and improved systemic metabolic homeostasis. However, beige adipocytes rapidly transition to white upon CR withdrawal through unclear mechanisms. Materials and methodsSix-week old C57BL6 mice were fed with 40% CR chow diet for 6 weeks. Subsequently, one group of mice was switched back to ad libitum chow diet, which was continued for additional 2 weeks. Adipose tissues were assessed histologically and biochemically for beige adipocytes. ResultsBeige adipocytes induced by CR rapidly transition to white adipocytes when CR is withdrawn independent of parkin-mediated mitophagy. We demonstrate that the involution of mitochondria during CR withdrawal is strongly linked with a decrease in mitochondrial biogenesis. We further demonstrate that beige-to-white fat transition upon β3-AR agonist-withdrawal could be attenuated by CR, partly via maintenance of mitochondrial biogenesis. ConclusionIn the model of CR, our study highlights the dominant role of mitochondrial biogenesis in the maintenance of beige adipocytes. We propose that loss of beige adipocytes upon β3-AR agonist withdrawal could be attenuated by CR.

High‐Fat Diet Causes Mitochondrial Dysfunction and Renal Fibrosis in Minipigs

Obesity is a common and complex health problem which has been dramatically increasing in the world. It is also considered as an independent risk factor for chronic kidney disease. Kidney is one of the most energy‐demanding organs in the human body, which has the second highest mitochondrial content and oxygen consumption only next to the heart. The purpose of this study was to investigate the nexus between mitochondrial function and kidney injury by using dietary‐induced obese minipig model.Materials and methodsSix‐month‐old Lee‐Sung minipigs were assigned randomly into 2 groups and fed either a control diet (C) or a high‐fat diet (HFD) for six months, the kidney was collected for the analysis.ResultsCompared with C group, HFD group had heavier body weight, thicker back fat, higher plasma levels of glucose, triacylglycerol and total cholesterol. Furthermore, the biomarkers of kidney injury, including blood creatinine, urine creatinine, urine urea, and urine protein were higher in the HFD group than the C ones. A heavier kidney was observed in the HFD pigs; whereas a smaller ratio of kidney weight to body weight was found in the HFD group than C group, implying a less effective loading in the kidney function of HFD pig. In histologic section of kidney, disarranged structure and more glomerular fibrosis were observed in the HFD pigs. Moreover, HFD caused a decreased antioxidant capacity in the kidney, indicating an oxidative stress. Whether HFD caused the renal injury through mitochondrial mechanisms, we analyzed the ATP generation and found that HFD kidney displayed a lower ATP production than C group did. The mitochondrial‐related genes in kidney were analyzed as well. The mRNA expression of SIRT1, which has a role in variety of mitochondrial processes, including redox homeostasis and mitochondrial biogenesis was downregulated by HFD. PGC1‐1a, a nutritional sensor in the kidney, was inhibited by HFD, suggesting a decrease in mitochondrial biogenesis. UCP2, activated by mitochondrial ROS, was upregulated in HFD group compare with C group. The mRNA expressions of Opa1 and Fis1, markers of mitochondrial dynamics, were downregulated by HFD, suggesting a mitochondrial dysfunction.In conclusion, long term HFD feeding in Lee‐Sung minipigs induced obesity, dyslipidemia and renal injury. Mitochondrial dysfunction might partially contribute to the progression of obesity‐related renal damage.Support or Funding InformationThis study was sponsored by the Ministry of Science and Technology, Taiwan (MOST107‐2313‐B‐002‐049).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Metformin on Lymphoid Cancer Cells

Metformin is a commonly prescribed drug for metabolic disorders particularly in type 2 diabetes. In addition to Metformin’s established antidiabetic effect it has a potential for use as an anti-cancer medication, via mitochondrial complex inhibition. Methods: In order to determine what effect Metformin could have on a common cancer such as lymphoma at a cellular level, we performed a 14 day experiment on the effect of 3 different doses of Metformin (0mM, 0.025mM, 0.25mM) on two different lymphoid cell lines, Jurkat and Jeko. Metformin at 0.025mM, is considered physiological. Cells in culture were collected on Days 3, 7, 10, and 14 and RT-PCR targeted gene expression was carried out focusing on mitochondrial and apoptosis related genes such as cytochrome oxidases (COX2 and 4), nuclear respiratory factor (NRF1), apoptosis gene (P53) and other mitochondrial genes such as PGC1A, SOD2, and TFAM. Results: Jeko cells showed initial significant mitochondrial gene suppression with Metformin. The suppression in mRNA gene expression however appear to reverse by day 7. By Day 10 there is a uniform up-regulation in mRNA expressions and the effects stabilized by day 14. Our Jurkat cells showed less consistent mRNA level changes, though the pattern was similar. In summary, Jeko cells, upon initial exposure to Metformin, show a decrease in mitochondrial biogenesis and increased apoptosis. This initial suppression seems to be replaced by over-expression of mitochondrial genes over a period of time and its effects stabilizes by day 10 of exposure. This phenomenon appears to be shown in both cell lines. We plan to corroborate our gene expression findings with Sea-Horse cell respiration studies. Conclusion: We believe that Metformin initially causes cancer cell damage, however with time the cells are able to escape that phenomenon by up-regulating mitochondrial genes particularly at physiological doses. In order for Metformin to be an effective pro-apoptotic agent in a cancer scenario, brief pulses of supra-physiological doses may be more effective. Disclosure N. Ahmadi: None. S. Sen: None.

ER stress induces cardiac dysfunction through cardiomyocytes architectural modifications and alteration of mitochondrial function

Endoplasmic reticulum (ER) stress has recently emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. However, the molecular mechanisms by which ER stress leads to cardiac dysfunction remain poorly understood. In the present study, we evaluated the early cardiac effects of ER stress induced by tunicamycin (TN) in mice. Electrocardiographic analysis indicated that TN-induced ER stress led to a significant impairment of the cardiac function. Electron microscopic observations revealed that ultrastructural changes of cardiomyocytes in response to ER stress manifested extensively at the level of the sarco-endoplasmic reticulum membranes. Smooth tubules of sarcoplasmic reticulum in connection with short sections of rough endoplasmic reticulum were observed. The presence of rough instead of smooth reticulum was increased at the interfibrillar space, at the level of dyads and in the vicinity of mitochondria. At a functional level, ER stress resulted in a substantial decrease in mitochondrial biogenesis as demonstrated by the decrease of the expression of PGC-1α and of its targets NRF1, Tfam, CS and COXIV. ER stress also led to an impairment of mitochondrial oxidative phosphorylation and to a metabolic remodeling characterized by a shift from fatty acid to glycolytic substrate consumption. Our findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases.

Time Course of Decrease in Skeletal Muscle Mitochondrial Biogenesis after Discontinuation of High-Fat Diet.

It is known that a high-fat diet induces an increase in mitochondrial biogenesis in skeletal muscle. To examine the time course of decrease in mitochondrial biogenesis in skeletal muscle after discontinuing a high-fat diet feeding, C57BL/6 mice were fed a high-fat diet for 4 wk and then switched to the control diet for another 3 or 7 d. During the high-fat diet withdrawal period, the protein content of the mitochondrial respiratory chain decreased faster than the fatty acid oxidation enzymes. The mitochondrial DNA copy number remained high for at least 1 wk after withdrawing the high-fat diet. These results suggested that after switching to the control diet following a period of high-fat diet, the increased mitochondrial biogenesis levels are maintained for a few days, and the rate of decline is divergent between the different mitochondrial components.

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload-Induced Left Ventricular Remodeling.

BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis through unclear means. Here we demonstrate that, unlike the canonical iron-induced alterations to transcript stability, loss of iron dampens the transcription of genes encoding mitochondrial proteins with no change to transcript half-life. Using mass spectrometry, we demonstrate that these transcriptional changes are accompanied by dynamic alterations to histone acetylation and methylation levels that are largely reversible upon readministration of iron. Moreover, histone deacetylase inhibition abrogates the decreased histone acetylation observed upon iron deprivation and restores normal transcript levels at genes encoding mitochondrial proteins. Collectively, we demonstrate that deprivation of an essential nutrient induces transcriptional repression of organellar biogenesis involving epigenetic alterations.

Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25ppm for 12weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.

Mitochondrial anomalies: driver to age associated degenerative human ailments.

Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to maintain adequate energy balance for cellular existence. To orchestrate these functions, an undisturbed mitochondrial dynamics is imperative through a set of tightly guided mechanisms. Interference in key signature processes by several genetic, epigenetic and age-linked factors triggers mitochondrial dysfunction through decrease in mitochondrial biogenesis, reduced mitochondrial content, aberrant mtDNA mutations, increased oxidative stress, deficient mitophagy, energy dysfunction, decrease in anti oxidant defense and impaired calcium homeostasis. Mitochondrial dysfunction is widely implicated in origin and development of various age associated degenerative human ailments including metabolic syndromes, cardiovascular diseases, cancer, diabetes and neurodegenerative disorders. The present review revisits the mitochondrial anomalies involved in aetiology of different human diseases and also highlights the translational significance of nano-vectors aimed for selective mitochondrial engineering which might pave way for development of novel therapeutics.

Protective effects of DHEA and Metformin on the viability of early embryos under oxidative stress are mediated by sustaining mitochondrial biogenesis

To test whether DHEA and Metformin can improve the quality of zygotes from mice with antiphospholipid syndrome (APS). Cardiolipin, the major phospholipid in mitochondrial membrane, regulates the stability of respiratory supercomplex. Lycat is a enzyme that converts the cardiolipin precursor to mature form. This remodeling process shows prompt responses to oxidative stress. Transgenic mice overexpressing Lycat recapitulated APS-related recurrent pregnancy failure. Oxidative stress induced by high AP-abs impairs the differentiation of extraembryonic tissues. Exogenous DHEA at low doses inhibits lipid peroxidation and restores oxidative balance. Similarly, Metformin (Met) reduces DNA damage-induced aneuploidy in reproduction by attenuating reactive oxygen species (ROS) production. 1) ROS detection. Ovaries from 2-month old Lycat-Tg (n=8) and WT (n=6) mice were collected for cryosectioning. Rehydrated tissue sections were incubated with 10 μM fluorogenic H2DCF for 20 min. After DAPI counter staining, ROS+ cells were photographed (Ex/Em = 468/560 nm) and quantified by NIH ImageJ. Data were presented as percentage of ROS+ cells among total cells on each section.2) Quantifing mitochondrial (mt) copy number and In Vitro rescue. One-cell embryos (n=111) from Tg ♂ x Tg ♀s matings were collected and cultured in M16 supplemented with 10 nM DHEA + 5 μM Met to blastocysts (DM-Tg); among them, 71 embryos were pooled for SYBR green Q-PCR on an ABI-7900HT. A 650pb DNA fragment encoding NADH Dehydrogenase Subunit I was amplified. Absolute mtDNA copy number in a single blastocyst was derived by a linear regression model using standard curves calculated between Ct and the logarithm of the concentration of standards.Effects of DHEA/Met on embryo quality was further tested in vivo by uterine transfer of the remaining DM-Tg embryos to WT foster females at 10 embryos/mouse with 4 repeats. Pregnancy was verified on day 12.5 p.c. Comparable numbers of WT and untreated Tg blastocysts were included as controls in each assay. Unpaired t-test was used for statistical analysis. DCF-staining showed that elevated Lycat led to ovarian hypersensitivity (WT, 11.3±5.3 vs. Tg, 28.7±6.0%; p=0.01) to ROS. Unlike the untreated Tg controls that showed a 27% decrease in mitochondrial biogenesis (WT, 3.42±0.54 x 105 vs Tg 2.48±0.64 x 105 copies/blastocyst; p<0.01), the DM-Tg embryos showed no difference in mtDNA copy number as compared with the WT controls (WT, 3.42±0.54 x105 vs. DM-Tg 3.30±0.60 x105; p=0.6). Moreover, in vitro cultivation of Tg embryos to blastocyst stage, in the presence of DHEA/Met, did enhance the viability of the embryos (DM-Tg, 7.3±1.0 vs. Tg, 4.8±1.0 pups/litter; p=0.008), resulting in an implantation rate comparable to WT embryos (DM-Tg 7.3±1.0 vs. WT, 8.5±1.3; p=0.17). Beneficial effects of DHEA/Met cocktail on embryo viability are, at least in part, achieved by preventing premature mitochondria degradation.

Arsenic induced oxidative stress and mitochondrial dysfunction in rat brain

The present study was undertaken to reveal the effects of chronic arsenic exposure (25ppm intragastrically for 12 weeks) on mitochondrial functions and oxidative stress in male Wister rats. Chronic arsenic exposure resulted in decrease in the activities of the mitochondrial complexes. There was increased generation of ROS followed by decrease in MnSOD activity. The generation of oxidative stress was associated with increased protein oxidation and lipid peroxidation in rat brain as evident by FTIR spectra. The RT-PCR analysis of NRF 1, NRF 2 and PGC 1α revealed decrease in gene expression suggesting decreased biogenesis following chronic exposure in rat brain. Thus, the findings of the present study reveal that arsenic induced decrease in mitochondrial biogenesis may be responsible for the decreased metabolic response that may be further involved in the generation of oxidative stress and neurodegeneration in rat brain.

High fat diet-induced obesity augments H2S in perivascular adipose tissue by cannabinoid-mediated decrease in mitochondrial biogenesis

Background: Hydrogen sulfide (H2S) synthesized in perivascularadipose tissue (PVAT) decreases vascular tone and inhibits atherogenesis. H2Ssignaling in PVAT is determined by the rate of its synthesis by cystathionineγ-lyase (CSE) and its mitochondrial oxidation. Recenty, we have demonstrated that administration of cannabinoid CB1 agonists augments H2Ssignaling in PVAT by suppressing mitochondrial biogenesis. Because endogenouscannabinoids are produced in the adipose tissue, we examined the effect ofdiet-induced obesity on PVAT H2S system.