Regulation Of Mitochondrial Energy Metabolism Research Articles

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

Phosphatase and tensin homolog (PTEN) is a multifunctional gene that is involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here we report that circPTEN- mitochondria (MT) (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator (SRA) stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex Ι subunit and reduces mitochondrial membrane potential and adenosine triphosphate production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN, which produces both linear and circular RNAs with different and independent functions.

Alterations in mitochondrial structure and function in response to environmental temperature changes in Apostichopus japonicus

Global temperatures have risen as a result of climate change, and the resulting warmer seawater will exert physiological stresses on many aquatic animals, including Apostichopus japonicus. It has been suggested that the sensitivity of aquatic poikilothermal animals to climate change is closely related to mitochondrial function. Therefore, understanding the interaction between elevated temperature and mitochondrial functioning is key to characterizing organisms’ responses to heat stress. However, little is known about the mitochondrial response to heat stress in A. japonicus. In this work, we investigated the morphological and functional changes of A. japonicus mitochondria under three representative temperatures, control temperature (18 °C), aestivation temperature (25 °C) and heat stress temperature (32 °C) temperatures using transmission electron microscopy (TEM) observation of mitochondrial morphology combined with proteomics and metabolomics techniques. The results showed that the mitochondrial morphology of A. japonicus was altered, with decreases in the number of mitochondrial cristae at 25 °C and mitochondrial lysis, fracture, and vacuolization at 32 °C. Proteomic and metabolomic analyses revealed 103 differentially expressed proteins and 161 differential metabolites at 25 °C. At 32 °C, the levels of 214 proteins and 172 metabolites were significantly altered. These proteins and metabolites were involved in the tricarboxylic acid (TCA) cycle, substance transport, membrane potential homeostasis, anti-stress processes, mitochondrial autophagy, and apoptosis. Furthermore, a hypothetical network of proteins and metabolites in A. japonicus mitochondria in response to temperature changes was constructed based on proteomic and metabolomic data. These results suggest that the dynamic regulation of mitochondrial energy metabolism, resistance to oxidative stress, autophagy, apoptosis, and mitochondrial morphology in A. japonicus may play important roles in the response to elevated temperatures. In summary, this study describes the response of A. japonicus mitochondria to temperature changes from the perspectives of morphology, proteins, and metabolites, which provided a better understanding the mechanisms of mitochondrial regulation under environment stress in marine echinoderms.

COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.

Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

Pueraria protein extract inhibits melanogenesis and promotes melanoma cell apoptosis through the regulation of MITF and mitochondrial‑related pathways.

PuerariaLobata Radix (P.Lobata Radix) is an edible traditional Chinese medicine that contains various active compounds. Proteins from P.Lobata Radix have become the subject of increased interest in recent years. In evaluating the whitening effect on the skin, the present study found that the P.Lobata Radix water‑soluble total protein extract (PLP) had the strongest inhibitory effect on tyrosinase activity. In the present study, the anti‑melanogenic effect of PLP and the inhibitory effect on B16 melanoma cells were investigated. PLP significantly reduced the tyrosinase activity and melanin content in B16 melanoma cells. Mechanistically, PLP inhibited melanogenesis by decreasing the expression of tyrosinase, tyrosinase‑related protein (TRP)‑1 and TRP‑2 through downregulation of the microphthalmia‑associated transcription factor (MITF) gene, which was mediated by inhibition of p38 mitogen‑activated protein kinase signaling. In addition, PLP inhibited cell viability and triggered apoptosis of B16 cells in a dose‑dependent manner. Exposure to PLP reduced the mitochondrial membrane potential (MMP) and decreased ATP generation, leading to mitochondria‑related apoptosis of B16 melanoma cells. The expression levels of succinate dehydrogenase (SDH) and its two related subunits (SDHA and SDHB) were downregulated significantly by PLP, which may be associated with the regulation of mitochondrial energy metabolism by PLP. These results may explain why MMP collapse and reduced ATP generation were observed in B16 melanoma cells treated with PLP. Finally, the present study demonstrated that the inhibition of melanin synthesis by PLP was correlated with the regulation of antioxidant enzymes to reduce reactive oxygen species levels. These results suggested that PLP inhibits melanogenesis by downregulating the expression of MITF‑related melanogenic enzymes and triggering apoptosis through mitochondria‑related pathways.

Regulation of Mitochondrial Energy Metabolism by Glutaredoxin 5 in the Apicomplexan Parasite Neospora caninum.

Iron-sulfur [Fe-S] clusters are one of the most ancient and functionally versatile natural biosynthetic prosthetic groups required by various proteins involved in important metabolic processes, including the oxidative phosphorylation of proteins, electron transfer, energy metabolism, DNA/RNA metabolism, and protein translation. Apicomplexan parasites harbor two possible [Fe-S] cluster assembly pathways: the iron-sulfur cluster (ISC) pathway in the mitochondria and the sulfur formation (SUF) pathway in the apicoplast. Glutaredoxin 5 (GRX5) is involved in the ISC pathway in many eukaryotes. However, the cellular roles of GRX5 in apicomplexan parasites remain to be explored. Here, we showed that Neospora caninum mitochondrial GRX5 (NcGRX5) deficiency resulted in aberrant mitochondrial ultrastructure and led to a significant reduction in parasite proliferation and virulence in mice, suggesting that NcGRX5 is important for parasite growth in vitro and in vivo. Comparative proteomics and energy metabolomics were used to investigate the effects of NcGRX5 on parasite growth and mitochondrial metabolism. The data showed that disruption of NcGRX5 downregulated the expression of mitochondrial electron transport chain (ETC) and tricarboxylic acid cycle (TCA) cycle proteins and reduced the corresponding metabolic fluxes. Subsequently, we identified 23 proteins that might be adjacent to or interact with NcGRX5 by proximity-based protein labeling techniques and proteomics. The interactions between NcGRX5 and two iron-sulfur cluster synthesis proteins (ISCS and ISCU1) were further confirmed by coimmunoprecipitation assays. In conclusion, NcGRX5 is important for parasite growth and may regulate mitochondrial energy metabolism by mediating the biosynthesis of iron-sulfur clusters. IMPORTANCE Iron-sulfur [Fe-S] clusters are among the oldest and most ubiquitous prosthetic groups, and they are required for a variety of proteins involved in important metabolic processes. The intracellular parasites in the phylum Apicomplexa, including Plasmodium, Toxoplasma gondii, and Neospora caninum, harbor the ISC pathway involved in the biosynthesis of [Fe-S] clusters in mitochondria. These cofactors are required for a variety of important biological processes. However, little is known about the role of oxidoreductase glutaredoxins in these parasites. Our data indicate that NcGRX5 is an essential protein that plays multiple roles in several biological processes of N. caninum. NcGRX5 interacts with the mitochondrial iron-sulfur cluster synthesis proteins ISCS and ISCU1 and also regulates parasite energy metabolism. These data provide an insider's view of the metabolic regulation and iron-sulfur cluster assembly processes in the apicomplexan parasites.

Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium.

Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.

Taurine protects R28 cells from hypoxia/re-oxygenation-induced damage via regulation of mitochondrial energy metabolism

Oxidative-induced damage and hypoxia/re-oxygenation (H/R) injury are common causes of irreversible visual impairment. The goals of this study were to explore the effects of taurine on R28 cells under the two damage models and the underlying mechanisms. Low doses of taurine supplementation promoted cell viability, mitochondrial membrane potential (MMP), SOD levels, ATP contents and attenuated cytotoxicity and intracellular ROS generation of the R28 cells under the two kinds of damage. The expression level of GTPBP3, a mitochondrial-tRNA (mt-tRNA) modification enzyme that catalyzes the taurine involved modification, was decreased under the two damage and taurine could reverse the reduction. After knocking down GTPBP3, the R28 cells become vulnerable to damage. The viability, cytotoxicity, MMP and intracellular ROS level of knockdown cells changed more obviously under the H/R injury than those of control cell. We also found that knockdown of GTPBP3 significantly decreased mitochondrial energy metabolism by measuring the oxidative respiration rate by the Seahorse XFe24 extracellular flux analyzer. The protection of low doses of taurine disappeared on knockdown R28 cells, indicating that GTPBP3 is crucial in the protection mechanisms of taurine. However, the impacts of the reduction of GTPBP3 level can be reversed by relatively high doses of taurine, implying the protection effects of taurine were dose-dependent, and there were more complicated mechanisms remain to be explored. This study explored a new mechanism of the neuroprotective effects of taurine, which depend on the GTPBP3-mediated taurine modification of mt-tRNAs and the promotion of mitochondrial energy metabolism.

Progress in Nonalcoholic Fatty Liver Disease: SIRT Family Regulates Mitochondrial Biogenesis.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, mitochondrial dysfunction, inflammation, and oxidative stress. As a group of NAD+-dependent III deacetylases, the sirtuin (SIRT1–7) family plays a very important role in regulating mitochondrial biogenesis and participates in the progress of NAFLD. SIRT family members are distributed in the nucleus, cytoplasm, and mitochondria; regulate hepatic fatty acid oxidation metabolism through different metabolic pathways and mechanisms; and participate in the regulation of mitochondrial energy metabolism. SIRT1 may improve NAFLD by regulating ROS, PGC-1α, SREBP-1c, FoxO1/3, STAT3, and AMPK to restore mitochondrial function and reduce steatosis of the liver. Other SIRT family members also play a role in regulating mitochondrial biogenesis, fatty acid oxidative metabolism, inflammation, and insulin resistance. Therefore, this paper comprehensively introduces the role of SIRT family in regulating mitochondrial biogenesis in the liver in NAFLD, aiming to further explain the importance of SIRT family in regulating mitochondrial function in the occurrence and development of NAFLD, and to provide ideas for the research and development of targeted drugs. Relatively speaking, the role of some SIRT family members in NAFLD is still insufficiently clear, and further research is needed.

Overexpressed VDAC1 in breast cancer as a novel prognostic biomarker and correlates with immune infiltrates

BackgroundMore and more evidence suggests that cancer is a mitochondrial metabolic disease recently and mitochondria dysfunction is critical to tumorigenesis. As a gatekeeper of mitochondria, the voltage-dependent anion channel 1 (VDAC1) is associated with the development of breast cancer (BC). However, its potential mechanism and clinical significance remain unclear; thus, in this research, we aimed to explore it.MethodsVDAC1 expression in BC tissues and normal tissues was obtained from The Cancer Genome Atlas (TCGA) and validated by datasets from the gene expression omnibus (GEO) database. Then, the relationships between VDAC1 expression and clinicopathological features were analyzed. Receiver operating characteristics (ROC) curves were used to identify the diagnostic value of VDAC1. The prognostic value was evaluated by Kaplan-Meier survival curves and Cox regression analysis. VDAC1 with its co-expression genes were subjected to enrichment analysis to explore potential mechanisms in BC and the protein-protein interaction (PPI) network was constructed. At last, the association between VDAC1 expression and infiltration levels of immune cell infiltration by various methods, as well as their corresponding markers, was analyzed. We also analyzed the correction between VDAC1 expression and eight immune checkpoint genes and the tumor immune dysfunction and exclusion (TIDE) scores of each BC sample in TCGA were calculated and the differences between high and low VDAC1 expression groups were analyzed.ResultsVDAC1 expression was remarkably elevated in BC (p < 0.001), and high expression of VDAC1 was associated with the positive expression of ER (p = 0.004), PR (p = 0.033), and HER2 (p = 0.001). ROC analysis suggested that VDAC1 had diagnosed value in BC. The Kaplan-Meier analysis suggested that higher expression of VDAC1 was associated with shorter overall survival (OS), and further Cox regression analysis revealed that VDAC1 was an independent factor of unfavorable prognosis in BC patients. Enrichment analysis of VDAC1 and its co-expression suggested that VDAC1 was related to the regulation of mitochondrial energy metabolism and protein modification, and the HIF-1 singing pathway might be the potential mechanism in BC. Notably, we found that VDAC1 expression was infiltration levels of most types of immune cells, as well as the expression of marker genes of immune cells. The ICGs PDCD1, CTLA4, LAG3, SIGLEC15, and TIGIT were negatively corrected with VDAC1 expression in BC. TIDE scores between the low and high expression groups showed no difference.ConclusionOverexpressed VDAC1 in BC could be severed as a novel biomarker for diagnosis and VDAC1 was an independent factor for adverse prognosis prediction. Our study revealed that VDAC1 might inhibit tumor immunity and might be a novel therapeutic target in BC.

Comparative whole-genome transcriptome analysis in renal cell populations reveals high tissue specificity of MAPK/ERK targets in embryonic kidney

BackgroundMAPK/ERK signaling is a well-known mediator of extracellular stimuli controlling intracellular responses to growth factors and mechanical cues. The critical requirement of MAPK/ERK signaling for embryonic stem cell maintenance is demonstrated, but specific functions in progenitor regulation during embryonic development, and in particular kidney development remain largely unexplored. We previously demonstrated MAPK/ERK signaling as a key regulator of kidney growth through branching morphogenesis and normal nephrogenesis where it also regulates progenitor expansion. Here, we performed RNA sequencing-based whole-genome expression analysis to identify transcriptional MAPK/ERK targets in two distinct renal populations: the ureteric bud epithelium and the nephron progenitors.ResultsOur analysis revealed a large number (5053) of differentially expressed genes (DEGs) in nephron progenitors and significantly less (1004) in ureteric bud epithelium, reflecting likely heterogenicity of cell types. The data analysis identified high tissue-specificity, as only a fraction (362) of MAPK/ERK targets are shared between the two tissues. Tissue-specific MAPK/ERK targets participate in the regulation of mitochondrial energy metabolism in nephron progenitors, which fail to maintain normal mitochondria numbers in the MAPK/ERK-deficient tissue. In the ureteric bud epithelium, a dramatic decline in progenitor-specific gene expression was detected with a simultaneous increase in differentiation-associated genes, which was not observed in nephron progenitors. Our experiments in the genetic model of MAPK/ERK deficiency provide evidence that MAPK/ERK signaling in the ureteric bud maintains epithelial cells in an undifferentiated state. Interestingly, the transcriptional targets shared between the two tissues studied are over-represented by histone genes, suggesting that MAPK/ERK signaling regulates cell cycle progression and stem cell maintenance through chromosome condensation and nucleosome assembly.ConclusionsUsing tissue-specific MAPK/ERK inactivation and RNA sequencing in combination with experimentation in embryonic kidneys, we demonstrate here that MAPK/ERK signaling maintains ureteric bud tip cells, suggesting a regulatory role in collecting duct progenitors. We additionally deliver new mechanistic information on how MAPK/ERK signaling regulates progenitor maintenance through its effects on chromatin accessibility and energy metabolism.

Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease

Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

Kinetic and thermodynamic regulation of mitochondrial energy metabolism and ROS production

We have developed a thermodynamically balanced kinetic model of mitochondrial adenosine triphosphate (ATP) production and concomitant reactive oxygen species (ROS) production. The model is comprised of modules simulating the kinetics of: (1) transporters and exchangers of phosphate, adenine nucleotides, and tricarboxylic acid (TCA) cycle intermediates, (2) the catalytic steps of the TCA cycle, via which substrates are oxidized to generate the reducing equivalents NADH and FADH2, (3) the donation of electrons to the electron transport chain (ETC) by these reducing equivalents and the subsequent redox transfer through the four complexes of the ETC, (4) the pumping of protons out of the matrix coupled to the ETC, which energetically finances the maintenance of an electrical potential across the inner mitochondrial membrane (IMM), (5) the transduction of membrane potential to synthesize ATP via the F0F1-ATPase, and (6) the generation of ROS by various complexes of the ETC.

Estrogen-related receptor alpha (ERR\u03b1) is a key regulator of intestinal homeostasis and protects against colitis

The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERRα in the intestine. We found that mice deficient in ERRα were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.

Abstract 13357: Dhtkd1 Knock-out Alters Cellular Respiration by Preventing Electron Transport Chain Related Proteins From Entering Into Mitochondria

The metabolite α-aminoadipic acid (2-AAA) has been identified as a predictor of diabetes and atherosclerosis in large human prospective studies. However, the mechanisms linking this metabolite to disease pathophysiology remain unknown. DHTKD1 is a central gene in the 2-AAA pathway, and has been linked to variation in 2-AAA levels in humans and animals. However, little is known about the role of DHTKD1 in cellular metabolism. We hypothesized that DHTKD1 is an important regulator of mitochondrial energy metabolism, with potential involvement in cardiometablic disease. Methods and Results: We investigated the consequences of loss of DHTKD1 function in a human HAP-1 cell line. Treatment with 2-AAA increased mitochondrial respiration in wild-type (WT) cells, but had no effect in DHTKD1 knock-out (KO) cells. DHTKD1 KO cells had significantly lower mitochondrial respiration (Mito Stress Test, Seahorse Analyzer), with no differences in glycolytic function, supporting an important role for DHTKD1 in mitochondrial metabolism. Membrane potential and mitochondrial content were up-regulated in KO compared to WT cells, suggesting a potential compensatory mechanism. We investigated the mechanisms underlying impaired mitochondrial function, and found TOM40 and TIM23, the pivotal proteins required for the movement of proteins into mitochondria, were decreased in DHTKD1 KO cells. Further, DHTKD1 KO resulted in reduced expression of electron transport chain related proteins (NDUF88, SDHB, MTCO1, UQCRC2, ATP5A) in mitochondria, but increased expression in the cytosol, suggesting impaired ability to cross the mitochondrial membrane. Conclusions: Our data suggest that the absence of DHTKD1 leads to less TOM40 and TIM23 expression, preventing key proteins in the electron transport chain from entering into mitochondria, resulting in impaired mitochondrial respiration. These findings highlight the vital role of DHTKD1 in cellular metabolism, and establish DHTKD1-mediated mitochondrial dysfunction as a potential novel pathway in cardiometabolic disease. Elevated 2-AAA observed in individuals prior to onset of diabetes and atherosclerosis may be an early biomarker of dysfunction in this pathway.

Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function. We demonstrate that AETII cells from mouse lungs exposed to cigarette smoke (CS) increase the levels of the mitochondria-encoded non-coding RNA, mito-RNA-805, generated by the control region of the mitochondrial genome. The protective effects of mito-ncR-805 are associated with positive regulation of mitochondrial energy metabolism, and respiration. Levels of mito-ncR-805 do not relate to steady-state transcription or replication of the mitochondrial genome. Instead, CS-exposure causes the redistribution of mito-ncR-805 from mitochondria to the nucleus, which correlated with the increased expression of nuclear-encoded genes involved in mitochondrial function. These studies reveal an unrecognized mitochondria stress associated retrograde signaling, and put forward the idea that mito-ncRNA-805 represents a subtype of small non coding RNAs that are regulated in a tissue- or cell-type specific manner to protect cells under physiological stress.

1-Methylcyclopropene treatment controls ethanol accumulation associated with regulation of mitochondrial energy metabolism in kiwifruit (Actinidia deliciosa) cv. "Bruno" during storage at room temperature.

In this paper, the effects of 1-methylcyclopropene (1-MCP) treatment on the ethanol accumulation and mitochondrial energy metabolism in kiwifruit (Actinidia deliciosa) cv. "Bruno" were investigated during storage at room temperature (24±1°C). The results showed that 1-MCP treatment significantly reduced the ethanol accumulation, maintained higher levels of adenosine triphosphate (ATP) content and energy charge (EC), enhanced enzymes activities involved in mitochondrial energy metabolism, such as succinic dehydrogenase, cytochrome C oxidase, H+ -adenosine triphosphatase (H+ -ATPase), and Ca2+ -adenosine triphosphatase (Ca2+ -ATPase), and regulated the NADH/NAD+ ratio, and pyruvate to tricarboxylic acid cycle (TCA) by suppressing the glutamate-pyruvate transaminase and promoting the pyruvate dehydrogenase activity, and decarboxylation of citric acid in harvested kiwifruit. These shifts in mitochondrial energy metabolism and oxidative phosphorylation correlated the higher ATP yield and an elevated EC with lower ethanol accumulation (13.71% of those in the control fruit) under 1-MCP treatment, and reduced the susceptibility of ethanol related off-flavor disorder in kiwifruit during storage. PRACTICAL APPLICATIONS: A kiwifruit (Actinidia deliciosa) cv. "Bruno," a major cultivatedkiwifruit in China, is prone to accumulate ethanol sharply after respiratory climacteric during storage. Ethanol has been accounted as a vital aroma volatile metabolite in various fruits. However, over accumulation of ethanol often leads to the development of alcohol off-flavor disorder, particularly in typical climacteric fruit such as kiwifruit. This work was aimed to maintain the flavor quality of kiwifruit cv. "Bruno" via improving the mitochondrial energy metabolism and functional TCA cycle, and limiting the ethanol accumulation under 1-MCP treatment. Thus, 1-MCP treatment could be beneficial to prevent the occurrence of alcohol off-flavor disorder along with sustainment of the flavor quality of kiwifruit cv. "Bruno" during storage at room temperature.

Effects of electroacupuncture pretreatment on mitochondrial energy metabolism in the rats with myocardial ischemia reperfusion: 电针预处理对心肌缺血再灌注大鼠线粒体能量代谢的影响

ObjectiveTo explore the effects of electroacupuncture pretreatment on mitochondrial energy metabolism in the rats with myocardial ischemia reperfusion injury (MIRI). MethodsA total of 60 SPF Wistar rats were randomly divided into a sham-operation group (sham group), a myocardial ischemia reperfusion injury group (MIRI group) and an electroacupuncture pretreatment group (EA group), 20 rats in each one. The rats in the sham group and the MIRI group were binded for 7 days, once a day, 20 min each time. On the 8th day, the sample was collected after the heart exposed for 50 min in thoractomy in the sham group and the sample was collected after ischemia for 20 min and reperfusion for 30 min in thoractomy in the MIRI group. In the EA group, the pretreatment intervention with electroacupuncture was applied at "Nèiguān (内关PC6)", "Guānyuán (关元CV4)" and "Zúsānlĭ (足三里ST36)" in the rats for 7 days, once a day, 20 min each time. On the 8th day, after ischemia for 20 min and reperfusion for 30 min in thoractomy, the sample was collected in the EA group. The changes in STⅡ segment of electroacardiogram (ECG) were observed and measured. Using enzyme-linked immunosorbent assay (ELISA), the concentrations of cardiac troponin T (cTnT) and cardiac troponin I (cTnI)were detected. Using nitro blue tetrazolium chloride monohydrate (NBT) staining, the myocardial infarction weight percentage was measured. Using ELISA, the concentrations of mitochondrial adenosine monophosphate (AMP), adenosine diphosphate (ADP)and adenosine triphosphate (ATP)were detected. Results(1) STⅡ changes: in 20 min of ligation, compared with the sham group, the STⅡ segment of electrocardiograph (ECG) was elevated significantly in the MIRI group and EA group (both P < 0.01), but the elevation range in the EA group was lower than that of the MIRI group (P < 0.01). After reperfusion for 30 min, the STⅡ segment was fallen by over 50% in the MIRI group and the EA group. Simultaneously, the STⅡ segment in the EA group was lower than that of the MIRI group (P < 0.01). (2) Regarding myocardial infarction weight percentage, compared with the sham group, the infarction weight was larger in the MIRI group and the EA group (both P < 0.05) and the infarction weight in the EA group was lower than that of the MIRI group (P < 0.05). (3) Regarding the levels of serum cTnt and cTnI, compared with the sham group, the levels of serum cTnT and cTnI were higher in the MIRI group and the EA group (all P < 0.01) and the levels of cTnT and cTnI in the EA group were lower than that of the MIRI group (both P < 0.01). (4) Regarding the concentrations of AMP, ADP and ATP, compared with the sham group, ATP concentration was lower in the MIRI group and the EA group (both P < 0.01) and the concentrations of AMP and ADP were higher (P < 0.05, P < 0.01). Compared with the MIRI group, ATP concentration was higher in the EA group (P < 0.05) and the concentrations of AMP and ADP were lower (both P < 0.01). ConclusionsElectroacupuncture pretreatment reduces the elevation of ECG STⅡ segment, decreases the concentrations of myocardial injury markers, cTnT and cTnI and regulates the transfer among AMP, ATP and ADP. The protective effect of electroacupuncture pretreatment may result from the regulation of mitochondrial energy metabolism.

The Role of PGC-1α in Digestive System Malignant Tumours.

Cancer is increasingly becoming the leading cause of death in many countries, and malignant tumours of the digestive system account for majority of cancer incidence and mortality cases. Metabolism has been identified as a core hallmark of cancer. Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α) is a pivotal regulator of mitochondrial energy metabolism. Accumulating evidence reveals that PGC-1α is essential in cancer development. We summarize the latest research progress of PGC-1α in common digestive system malignant tumours. Some related modulators and pathways are analyzed as well. We conducted a literature review on the development of PGC-1α in common digestive system malignant tumours. In colorectal cancer, PGC-1α appears to provide growth advantages by different pathways, although it has also been reported to have opposite effects. The previous studies of PGC-1α on liver cancer also demonstrated different effects by sundry pathways. Concerning gastric cancer, PGC-1α promotes cell proliferation, apoptosis in vitro and tumour growth in vivo. AMPK/SIRT1/PGC-1α is related to the inhibition of apoptosis in pancreatic cancer cells. Pancreatic cancer stem cells are strongly dependent on mitochondrial oxidative phosphorylation. PGC-1α is required to maintain the stemness property of pancreatic cancer stem cells. We explore diverse mechanisms that explain the dichotomous functions of PGC-1α on tumorigenesis, and discuss the latest research concerning digestive system malignant tumours. This review would provide better comprehension of the field and a basis for further studies associated with PGC-1α in digestive system cancers.

C-Src kinase impairs the expression of mitochondrial OXPHOS complexes in liver cancer

Src family kinases (SFKs) play a crucial role in the regulation of multiple cellular pathways, including mitochondrial oxidative phosphorylation (OXPHOS). Aberrant activities of one of the most predominant SFKs, c-Src, was identified as a fundamental cause for dysfunctional cell signaling and implicated in cancer development and metastasis, especially in human hepatocellular carcinoma (HCC). Recent work in our laboratory revealed that c-Src is implicated in the regulation of mitochondrial energy metabolism in cancer. In this study, we investigated the effect of c-Src expression on mitochondrial energy metabolism by examining changes in the expression and activities of OXPHOS complexes in liver cancer biopsies and cell lines. An increased expression of c-Src was correlated with an impaired expression of nuclear- and mitochondrial-encoded subunits of OXPHOS complexes I and IV, respectively, in metastatic biopsies and cell lines. Additionally, we observed a similar association between high c-Src and reduced OXPHOS complex expression and activity in mouse embryonic fibroblast (MEF) cell lines. Interestingly, the inhibition of c-Src kinase activity with the SFK inhibitor PP2 and c-Src siRNA stimulated the expression of complex I and IV subunits and increased their enzymatic activities in both cancer and normal cells. Evidence provided in this study reveals that c-Src impairs the expression and function of mitochondrial OXPHOS complexes, resulting in a significant defect in mitochondrial energy metabolism, which can be a contributing factor to the development and progression of liver cancer. Furthermore, our findings strongly suggest that SFK inhibitors should be used in the treatment of HCC and other cancers with aberrant c-Src kinase activity to improve mitochondrial energy metabolism.

Ginsenoside Rb1 as an Anti-Diabetic Agent and Its Underlying Mechanism Analysis.

Panax ginseng and Panax notoginseng, two well-known medical plants with economic value, have a long history of use for managing various diseases in Asian countries. Accumulating clinical and experimental evidence suggests that notoginsenosides and ginsenosides, which are the major bioactive components of the plants, have a variety of beneficial effects on several types of disease, including metabolic, vascular, and central nervous system disease. Considerable attention has been focused on ginsenoside Rb1 derived from their common ownership as an anti-diabetic agent that can attenuate insulin resistance and various complications. Particularly, in vitro and in vivo models have suggested that ginsenoside Rb1 exerts various pharmacological effects on metabolic disorders, including attenuation of glycemia, hypertension, and hyperlipidemia, which depend on the modulation of oxidative stress, inflammatory response, autophagy, and anti-apoptosis effects. Regulation of these pathophysiological mechanisms can improve blood glucose and insulin resistance and protect against macrovascular/microvascular related complications. This review summarizes the pharmacological effects and mechanisms of action of ginsenoside Rb1 in the management of diabetes or diabetic complications. Moreover, a multi-target effect and mechanism analysis of its antidiabetic actions were performed to provide a theoretical basis for further pharmacological studies and new drug development for clinical treatment of type 2 diabetes. In conclusion, ginsenoside Rb1 exerts significant anti-obesity, anti-hyperglycemic, and anti-diabetic effects by regulating the effects of glycolipid metabolism and improving insulin and leptin sensitivities. All of these findings suggest ginsenoside Rb1 exerts protective effects on diabetes and diabetic complications by the regulation of mitochondrial energy metabolism, improving insulin resistance and alleviating the occurrence complications, which should be further explored. Hence, ginsenoside Rb1 may be developed as a potential anti-obesity, anti-hyperglycemic, and anti-diabetic agent with multi-target effects.