Mitochondrial Transcription Factor Research Articles

Ginsenoside-Enriched Extract from Black Ginseng Anti-Fatigue Effects by Improving Antioxidant Capacity and Mitochondrial Function

In this study, we investigated the anti-fatigue effects of black ginseng ginsenosides using exercise performance tests, serum analyses, and gene expression profiling. No significant differences in dietary intake or body weight were observed between groups. The low-dose black ginseng (LBG) group showed no significant improvements in swimming and rotating rod tests. In contrast, the medium (MBG)- and high-dose (HBG) groups showed notable increases in swimming time and significant improvements in the rotating rod test. All treatment groups exhibited longer running times, particularly the HBG group. Serum analysis revealed increased muscle and hepatic glycogen, catalase, and lactate dehydrogenase levels in the MBG and HBG groups, whereas lactate, lipid peroxide, and superoxide dismutase levels were decreased. Additionally, gene expression analysis showed significant upregulation of key antioxidant and mitochondrial function genes, including those encoding cationic amino acid transporter 2, stearoyl-CoA desaturase-2, nuclear respiratory factor 1, nuclear factor erythroid 2-related factor 2, mitochondrial transcription factor A, cytochrome c oxidase II, and NADH–ubiquinone oxidoreductase core subunit 1, particularly in the HBG group, indicating enhanced antioxidant capacity and improved mitochondrial function. These findings suggested that black ginseng ginsenosides effectively mitigated fatigue.

Mitochondrial maintenance as a novel target for treating steroid-induced osteonecrosis of femoral head: a narrative review.

The pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) remains unclear; however, emerging evidence suggests that mitochondrial injury plays a significant role. This review aims to elucidate the involvement of mitochondrial dysfunction in SONFH and explore potential therapeutic targets. A comprehensive literature search was conducted in PubMed, Web of Science, and Elsevier ScienceDirect, focusing on mitochondrial homeostasis, including mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and oxidative stress in SONFH. Ultimately, we included and analyzed a total of 16 studies. Glucocorticoids initially promote but later inhibit mitochondrial biogenesis in osteoblasts, leading to excessive ROS production and mitochondrial dysfunction. This dysfunction impairs osteoblast survival and bone formation, contributing to SONFH progression. Key proteins such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) are potential therapeutic targets for promoting mitochondrial biogenesis and reducing ROS-induced damage. Enhancing mitochondrial function and reducing oxidative stress in osteoblasts may prevent or slow the progression of SONFH. Future research should focus on developing these strategies.

Protopine Exerts Neuroprotective Effects on Neonatal Hypoxic-Ischemic Brain Damage in Rats via Activation of the AMPK/PGC1α Pathway.

Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear. In this study, we established a CoCl2-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms. Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro. Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.

Oxct1 regulates cardiomyocyte PANoptosis in acute myocardial infarction via succinylating Tfam

Abstract Background Myocardial ischemia leads to various forms of programmed cell death in cardiomyocytes, resulting in acute myocardial infarction (AMI) and the development of heart failure in the long term. PANoptosis is a unique cell death regulatory mechanism orchestrated by the PANoptosome complex, which regulates and intersects multiple forms of programmed cell death. Oxct1 has been demonstrated to play crucial roles in tumors, pressure-overloaded hearts, and cardiac endothelial cells. However, whether Oxct1 is involved in the regulation of PANoptosis and correlated mechanisms during AMI remains unclear. Purpose To elucidate the role of Oxct1 in cardiomyocytes during AMI and uncover the potential mechanisms. Methods The myocardial infarction model induced by anterior descending branch ligation and the primary cardiomyocytes hypoxia model were employed in our experiments. Small interfering RNA (siRNA) and adenovirus were constructed to knock down and overexpress Oxct1 for altering its expression in cardiomyocytes in vitro. Cardiomyocyte-specific knockout mice were constructed to alter Oxct1 expression in vivo. PANoptosis characteristic measurement, including Z-DNA binding protein 1(Zbp1), pyroptosis markers, apoptosis markers, necroptosis markers, ROS, and mitochondrial morphology, were performed to verify the ability of Oxct1 to regulate the PANoptosis of cardiomyocytes. Cardiac morphological, structural, and functional changes were measured to assess the effect of Oxct1 on AMI. RNA sequencing was performed to identify downstream pathways. Immunoprecipitation +Mass spectrometry and co-immunoprecipitation were performed to identify the specific binding factors of Oxct1. Results We found that the expression of Oxct1 was significantly elevated after AMI. Besides, gain- and loss-of-function experiments were constructed both in vitro and in vivo. Functionally, Oxct1 knockdown significantly enhanced cardiomyocyte vitality, reduced ROS production and mtDNA cytoplasmic release in hypoxic cardiomyocytes. In vivo, Oxct1cko mice manifested reduced infarct size, improved cardiac function and alleviated cardiac fibrosis by mitigating PANoptosis. However, Oxct1 overexpression resulted in the opposite effects. Afterwards, RNA-seq analysis results showed that cytosolic DNA-sensing pathway was significantly enriched in Oxct1 knockdown cardiomyocytes. Mechanistically, Oxct1 could bind to mitochondrial transcription factor A(Tfam) and increased its succinylation, promoting Tfam degradation. Downregulation of Tfam resulted in ROS production and mtDNA damage, while mtDNA released into cytoplasm could activate Zbp1 and induce cascade reaction of PANoptosis. Conclusion This study demonstrates that Oxct1 promotes Tfam degradation through succinylation, exacerbating ROS production, mtDNA damage and cytoplasmic release, ultimately leading to cardiomyocyte PANoptosis in AMI.

MARCHF1 promotes breast cancer through accelerating REST ubiquitylation and following TFAM transcription.

Breast cancer has become the leading cause of death in women. Membrane associated ring-CH-type finger 1 (MARCHF1) is associated with the development of various types of cancer, but the exact role of MARCHF1 in breast cancer remains unclear. In our study, the higher MARCHF1 expression was observed in tumor samples of patients with breast cancer and then the role of MARCHF1 in breast cancer was further evaluated. Overexpression of MARCHF1 contributed to proliferation of cancer cells and inhibition of oxidative stress. Knockdown of MARCHF1 reduced breast cancer cell proliferation, increased mitochondrial dysfunction induced by oxidative stress, eventually aggravating cell death. In vivo, MARCHF1 promoted the tumor growth and oppositely, MARCHF1 silencing suppressed the tumor development. Moreover, MARCHF1 interacted with repressor Element-1 silencing transcription factor (REST) and facilitated its ubiquitylation and degradation. Subsequently, REST negatively regulated the transcription of mitochondrial transcription factor A (TFAM). The subcutaneous tumor formation assay in nude mice also supported these conclusions. In details, knockdown of MARCHF1 upregulated the protein expression of REST and downregulated the mRNA level of TFAM. On the contrary, MARCHF1 overexpression exhibited opposite effects. Thus, MARCHF1 is conducive to the progression of breast cancer via promoting the ubiquitylation and degradation of RSET and then the transcription of TFAM. Downregulating MARCHF1 could provide a novel direction for treating breast cancer.

The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.

Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.

Dietary niacin supplementation improves meat quality, muscle fiber type, and mitochondrial function in heat-stressed Taihe black-bone silky fowls.

A recent study has shown that niacin supplementation induces the conversion of type II to type I muscle fibres, thereby promoting a phenotypic shift in oxidative metabolism in porcine skeletal muscle. These effects may be mediated by modulation of the AMPK1/SIRT1 pathway, which activates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of fibre conversion, thereby promoting skeletal muscle mitochondrial biogenesis and myofibre conversion. In this study, we explored how niacin (NA) supplementation impacts the quality of meat and the characteristics of muscle fibers in Taihe Black-bone Silky Fowls (TBsf) exposed to heat conditions. Chickens were rationally assigned to five different treatment groups with five replicates of six chickens each: thermophilic (TN), heat stress (HS) and HS + NA (HN) groups, with the HN group being supplemented with 200, 400 and 800 mg/kg (HS + NA0.02, HS + NA0.04 and HS + NA0.08) NA in the premix, respectively. The results of the experiment showed that addition of 800 mg/kg NA to the diet significantly improved TBsf muscle tenderness compared to HS. Dietary enrichment with 200-800 mg/kg NA significantly increased total antioxidant capacity, superoxide dismutase, and glutathione peroxidase activities, while significantly decreasing malondialdehyde compared to HS. Incorporation of 200-800 mg/kg NA into the diet significantly reduced lactate dehydrogenase activity and myosin heavy chain (MyHC-IIB) gene expression. Furthermore, adding 800 mg/kg NA can significantly enhance the mRNA expression of mitochondrial transcription factors (TFAM and TFB1M) in TBsf skeletal muscle. Adding 400 and 800 mg/kg of NA significantly increased the mRNA expression of AMP-activated protein kinase 1 (AMPK1), PGC-1α, cytochrome c oxidase (Cytc), and nuclear respiratory factor (NRF-1) in the skeletal muscle of TBsf. Supplementing NA at 200-400 mg/kg significantly increased the expression of Sirtuin 1 (SIRT1) mRNA in TBsf skeletal muscle. The experimental results showed that the addition of NA to the diet reduced the shear force of TBsf muscle under heat exposure conditions. It increased the proportion of type I muscle fibres by increasing the antioxidant capacity of the muscle and by promoting mitochondr fibreial biogenesis. Considering the results of this study, it is recommended that TBsf be supplemented with 400-800 mg/kg of NA in the diet to reduce the adverse effects of heat stress on meat quality.

Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells.

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8-NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase-γ by 2'-3'-dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.

Selenoprotein o as a regulator of macrophage metabolism in selenium deficiency-induced lung inflammation

Selenium (Se) deficiency induces an inflammatory response in the lungs, but the underlying mechanisms are unknown. Selenoprotein O (SelO) is the largest selenoprotein in terms of molecular weight, yet its potential biological functions have yet to be characterized. Our study revealed that Se deficiency leads to an imbalance in the expression of pro-inflammatory “M1” macrophages and anti-inflammatory “M2” macrophages in alveolar macrophages (AMs) and interstitial macrophages (IMs) and contributed to the development of lung inflammation. Through the analysis of differentially expressed selenoproteins, we identified SelO as a potential regulator of the imbalance in pulmonary macrophage polarization caused by Se deficiency. In vitro experiments showed that SelO knockdown enhanced the polarization of M1 macrophages while suppressing that of M2 macrophages. In addition, SelO knockdown reprogrammed macrophage metabolism to glycolysis, disrupting oxidative phosphorylation (OXPHOS). Mechanistically, SelO primarily targets mitochondrial transcription factor A (TFAM), which plays a crucial role in the transcription and replication of mitochondrial DNA (mtDNA) and is essential for mitochondrial biogenesis and energy metabolism. The deficiency of SelO affects TFAM, resulting in its uncontrolled degradation, which compromises mitochondrial function and energy metabolism. In summary, the findings presented here offer significant theoretical insights into the physiological functions of SelO.

Myricanol represses renal fibrosis by activating TFAM and ZNRF1 to inhibit tubular epithelial cells ferroptosis

BackgroundMitochondrial dysfunction induces ferroptosis in renal tubular epithelial cells (TECs). Studies have shown that myricanol maintains muscle cell function by enhancing mitochondrial energy metabolism. HypothesisMyricanol delays renal fibrosis by maintaining mitochondrial integrity and inhibiting ferroptosis in TECs. MethodsMice kidney lacking mitochondrial transcription factor A (TFAM), blood specimens, or pathological sections of renal tissue from patients with renal failure were used to explore the relationship between mitochondrial and renal functions. Erastin induced-TECs ferroptosis was used to study the potential mechanism by which TFAM regulates renal fibrosis. Chronic kidney disease (CKD) mice were utilized to explore the anti-fibrotic effects of myricanol. ResultsThe number of mitochondria and TFAM expression were decreased in human blood samples and pathological sections. Renal TFAM-deficient mice exhibited abnormalities in renal function, including ferroptosis and fibrosis. Ferrostatin-1 significantly inhibited renal fibrosis by preventing TECs ferroptosis. Transcriptional sequencing results indicated that zinc and ring finger 1 (ZNRF1) were important downstream genes of TFAM that regulate ferroptosis. We demonstrated that TFAM deficiency and ferroptosis, which destroyed interaction between ZNRF1 and the iron transport-related protein lipocalin-2 (LCN2), but myricanol clould reverse this effect. Overexpression of ZNRF1 efficiently maintained mitochondrial integrity and inhibited renal fibrosis. Myricanol ameliorated transforming growth factor β1-induced mitochondrial impairment. We firstly confirmed that myricanol efficiently improved renal function and suppresses fibrosis in CKD mice. ConclusionsMyricanol efficiently inhibit fibrosis through activating TFAM to stimulate the interaction between ZNRF1 and LCN2.

4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis

Objectives: The aim of this study was to investigate the mechanism of itaconate’s potential effect in diabetic kidney disease. Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy. Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions. Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Melatonin protects against sarcopenia in middle-aged mice.

Sarcopenia is a common age-related disease. Melatonin (MEL) is an age-related endocrine hormone, which displays a crucial role in resisting oxidative stress during aging. Importantly, the antioxidant properties of MEL can be mediated by mitochondria. Therefore, we wondered whether MEL could mitigate oxidative stress caused by mitochondria in sarcopenia. The middle-aged mice were administered 5 mg/kg/d and 10 mg/kg/d of MEL for 2 months. Young mice were used as the control group. After treatment with MEL, the grip strength of the fore/hind limbs, running time, and distance were elevated, and the weights of the gastrocnemius (GA), tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) were enhanced in middle-aged mice. Additionally, MEL was observed to alleviate histological damage and increase the cross-sectional area of muscle fibers in GA tissues of middle-aged mice. Furthermore, following MEL treatment, there was an increase in the percentage and size of normal mitochondria as well as mtDNA copy number but a reduction in the levels of malondialdehyde (MDA), protein carbonyl, and reactive oxygen species (ROS) in the GA tissues of middle-aged mice. At the molecular level, MEL repressed the levels of ATROGIN-1, muscle RING-finger protein-1 (MURF-1), and the ratio of p-P38/P38, but elevated the expression of cytochrome c oxidase subunit 4 (COX4), cystatin C (CYTC), nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in the GA tissues of middle-aged mice. Importantly, 10 mg/kg MEL was more efficacious in the treatment of sarcopenia than 5 mg/kg MEL. MEL attenuates sarcopenia in middle-aged mice, and the mechanism may relate to mitochondria-induced oxidative stress and the PGC-1α/TFAM pathway.

Concurrent detection of the mitochondrial DNA copy number and the +35G/C polymorphism in the mitochondrial transcription factor A gene in endometriosis

Background and aimEndometriosis is a chronic gynecological inflammatory disease. The mitochondrial DNA copy number (mtDNA CN) and mitochondrial transcription factor A (TFAM) are known to contribute to human pathologies and cancer. Therefore, this study aims to reveal the association of mtDNA CN and TFAM+35G/C (rs1937) polymorphism with the risk of endometriosis in Egyptian females. Materials and methodsThis case-control study involved 160 Egyptian females divided into two groups: 80 endometriosis cases and 80 controls. The mtDNA CN was quantified using a real-time quantitative PCR (qPCR), and the TFAM +35G/C SNP (rs1937) was genotyped using the TaqMan allelic discrimination assay technique. ResultsThe mtDNA CN was markedly decreased in endometriosis cases compared to controls (P < 0. 001). TFAM rs1937 genotypes and allele distributions were all in Hardy-Weinberg equilibrium. The GC genotype and the ‘C’ allele frequency (P = 0.015 and P = 0.017, respectively) were substantially greater in endometriosis cases. ConclusionDecreased mtDNA CN and the GC genotype of TFAM +35G/C polymorphism were significantly associated with the risk of endometriosis in Egyptian females.

The protective effects of chitosan and curcumin nanoparticles against the hydroxyapatite nanoparticles-induced neurotoxicity in rats

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.

Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.

By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."

Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.

"Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.

Discovery of NFκB2-Coordinated Dual Regulation of Mitochondrial and Nuclear Genomes Leads to an Effective Therapy for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial-nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific "TTGGGGGGTG" region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2's novel function of regulating mitochondrial-nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.

Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/− mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.

Replication and Transcription of Human Mitochondrial DNA.

Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.

Astaxanthin ameliorated isoproterenol induced myocardial infarction via improving the mitochondrial function and antioxidant activity in rats.

The present study evaluated the cardioprotective effect of astaxanthin (ASX) against isoproterenol (ISO) induced myocardial infarction in rats via the pathway of mitochondrial biogenesis as the possible molecular target of astaxanthin. The control group was injected with normal physiological saline subcutaneously for 2 days. The second group was injected with ISO at a dose of 85 mg/kg bwt subcutaneously for 2 days. The third, fourth and fifth groups were supplemented with ASX at doses of 10, 20, 30 mg/kg bwt, respectively daily by oral gavage for 21 days then injected with ISO dose of 85 mg/kg bwt subcutaneously for 2 successive days. Isoproterenol administration in rats elevated the activities of Creatine kinase-MB (CK-MB), aspartate transaminase (AST), lactate dehydrogenase (LDH), and other serum cardiac biomarkers Troponin-I activities, oxidative stress biomarkers, malondialdehyde(MDA), Nuclear factor-kappa B (NF-KB), while it decreased Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), Nuclear factor erythroid-2-related factor 2 (Nfe212), mitochondrial transcriptional factor A (mt TFA), mitochondrial DNA copy number and glutathione system parameters. However, Astaxanthin decreased the activities of serum AST, LDH, CK-MB, and Troponin I that elevated by ISO. In addition, it increased glutathione peroxidase and reductase activities, total glutathione and reduced GSH content, and GSH/GSSG ratio, mtDNA copy number, PGC-1α expression and Tfam expression that improved mitochondrial biogenesis while it decreased GSSG and MDA contents and NF-KB level in the cardiac tissues. This study indicated that astaxanthin relieved isoproterenol induced myocardial infarction via scavenging free radicals and reducing oxidative damage and apoptosis in cardiac tissue.