Unveiling OSCP as the potential therapeutic target for mitochondrial dysfunction-related diseases.

Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.

ATP synthase inhibitory factor subunit 1 regulates islet ß-cell function via repression of mitochondrial homeostasis.

Mitochondrial homeostasis is crucial for the function of pancreatic ß-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in ß-cells. IF1 knockdown in cultured INS-1E ß-cells enhances glucose-induced insulin release. However, the role of IF1 in islet ß-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within ß-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- ß-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 ß-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 ß-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in ß-cells. Therefore, inhibiting IF1 to improve ß-cell function in patients can be a novel therapeutic strategy to treat diabetes.

Mitochondrial respiration in C57BL/6 substrains varies in response to myocardial infarction.

The C57BL/6 mouse strain have been commonly used for the genetic background animal models and experimental research. There are several major sources of C57BL/6 substrains for the biomedical research community which display genetic and phenotypic differences. Previous studies have suggested that the varies in baseline of cardiovascular phenotypes as well as in response to pressure overload by transverse aortic constriction (TAC). To investigate whether there exist substrain specific differences in response to heart failure post myocardial infarction (MI), consequently the impaired mitochondrial respiration, we performed MI surgery on two commonly used C57BL/6 substrains: C57BL/6J (BL/6J) and C57BL/6NCrl (BL/6N) mice. Subsequently, measurements about cardiac function, histology and mitochondrial respiration capacities were conducted to evaluate the differences. The data showed that C57BL/6J(BL/6J) mice is more resistant to the attack of MI, evidenced by lower mortality, less infarct size and better preserved cardiac function after MI, especially exhibited better mitochondrial respiration capacities, compared with the C57BL/6NCrl(BL/6N) mice.

Sustained Oligomycin Sensitivity Conferring Protein Expression in Cardiomyocytes Protects Against Cardiac hypertrophy Induced by Pressure Overload via Improving Mitochondrial Function.

Cardiac hypertrophy is a major risk factor for congestive heart failure, a leading cause of morbidity and mortality. Abrogating hypertrophic progression is a well-recognized therapeutic goal. Mitochondrial dysfunction is a hallmark of numerous human diseases, including cardiac hypertrophy and heart failure. F1Fo-ATP synthase catalyzes the final step of oxidative energy production in mitochondria. Oligomycin sensitivity conferring protein (OSCP), a key component of the F1Fo-ATP synthase, plays an essential role in mitochondrial energy metabolism. However, the effects of OSCP-targeted therapy on cardiac hypertrophy remain unknown. In the present study, we found that impaired cardiac expression of OSCP is concomitant with mitochondrial dysfunction in the hypertrophied heart. We used cardiac-specific, adeno-associated virus-mediated gene therapy of OSCP to treat mice subjected to pressure overload induced by transverse aortic constriction (TAC). OSCP gene therapy protected the TAC-mice from cardiac dysfunction, cardiomyocyte hypertrophy, and fibrosis. OSCP gene therapy also enhanced mitochondrial respiration capacities in TAC-mice. Consistently, OSCP gene therapy attenuated reactive oxygen species and opening of mitochondrial permeability transition pore in the hypertrophied heart. Together, adeno-associated virus type 9-mediated, cardiac-specific OSCP overexpression can protect the heart via improving mitochondrial function. This result may provide insights into a novel therapy for cardiac hypertrophy and heart failure.

Honokiol protects against doxorubicin cardiotoxicity via improving mitochondrial function in mouse hearts.

Honokiol is a key component of a medicinal herb, Magnolia bark. Honokiol possesses potential pharmacological benefits for many disease conditions, especially cancer. Recent studies demonstrate that Honokiol exerts beneficial effects on cardiac hypertrophy and doxorubicin (Dox)-cardiotoxicity via deacetylation of mitochondrial proteins. However, the effects and mechanisms of Honokiol on cardiac mitochondrial respiration remain unclear. In the present study, we investigate the effect of Honokiol on cardiac mitochondrial respiration in mice subjected to Dox treatment. Oxygen consumption in freshly isolated mitochondria from mice treated with Honokiol showed enhanced mitochondrial respiration. The Dox-induced impairment of mitochondrial respiration was less pronounced in honokiol-treated than control mice. Furthermore, Luciferase reporter assay reveals that Honokiol modestly increased PPARγ transcriptional activities in cultured embryonic rat cardiomyocytes (H9c2). Honokiol upregulated the expression of PPARγ in the mouse heart. Honokiol repressed cardiac inflammatory responses and oxidative stress in mice subjected to Dox treatment. As a result, Honokiol alleviated Dox-cardiotoxicity with improved cardiac function and reduced cardiomyocyte apoptosis. We conclude that Honokiol protects the heart from Dox-cardiotoxicity via improving mitochondrial function by not only repressing mitochondrial protein acetylation but also enhancing PPARγ activity in the heart. This study further supports Honokiol as a promising therapy for cancer patients receiving Dox treatment.

Adipose induces myoblast differentiation and mediates TNFα-regulated myogenesis.

Skeletal muscle formation is controlled by multiple processes. These processes are tightly regulated by muscle regulatory factors. Genes that are highly and specifically expressed during myogenesis need to be identified. In the present study, the role of an anti-adipogenic gene adipose (Adp) in myogenesis is demonstrated. We discover that the expression of Adp is increased during myoblast differentiation. Overexpression of Adp in mouse myoblast C2C12 cells leads to an increase of myogenesis and up-regulation of MyoG expression. The inhibition effect of tumor necrosis factor α (TNFα) on myogenic differentiation is reversed by Adp-overexpression. Further research showed that TNFα significantly decreases Adp expression at both the mRNA and protein levels. Luciferase reporter assays showed that TNFα can inhibit Adp gene promoter activity and impair gene transcription. KLF15 was found to regulate the transcription of Adp. Furthermore, the expression of KLF15 and its binding to Adp promoter were reduced due to TNFα treatment. The reduced KLF15 expression after TNFα treatment is responsible for the repression of Adp gene promoter activity. KLF15 was also found to participate in Adp-mediated myogenic differentiation. Taken together, these data identify Adp as a positive modulator of myoblast differentiation and provide new insights for Adp function research.

Molecular cloning and characterization of the porcine Ero1L and ERp44 genes: potential roles in controlling energy metabolism.

Disulfide bond formation is a pivotal step in the maturation and release of secretory proteins that is controlled by specific endoplasmic reticulum (ER) resident enzymes. An important element in this process is Ero (ER oxidoreduction), a glycosylated flavoenzyme tightly associated with oxidative protein folding that lacks the known ER retention motifs. ER resident protein 44kDa (ERp44) is an ER resident protein that mediates ERo1 localization in ER and also prevents the secretion of unassembled cargo proteins with unpaired cysteine. These proteins are not only the key participants in the disulfide-bond formation process, but they also control the secretory pathway on both qualitative and quantitative levels. Here, we cloned full-length cDNA sequences of the porcine Ero1L (1448bp) and ERp44 (1361bp) genes. Isolation and characterization of their genomic sequences revealed that Ero1L contains 16 exons and 15 introns almost 150 kp in length, whereas ERp44 contains 12 exons and 11 introns more than 140 kp in length, and they are located on porcine chromosome 1q21 and 1q29, respectively. Tissue distribution analysis of the two genes revealed extremely high expression in adipose tissue, and the topology of their phylogenic tree indicates a high degree of conservation among different species. We looked at transcription factors binding sites in the 5'-flanking regions of Ero1L and ERp44, and many adipose differentiations related factors reflect the tight relationship to energy metabolism.

Resistin up-regulates COX-2 expression via TAK1-IKK-NF-kappaB signaling pathway.

The hormone resistin, which was originally shown to induce insulin resistance, has been implicated in the regulation of inflammatory processes, but the molecular mechanism underlying such regulation has not been clearly defined. The goal of our study was to determine whether the expression of COX-2 can be induced by resistin and what the potential signaling pathway involved in this process is. Compared with controls, resistin significantly upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could significantly reduce this effect. Induction of COX-2 by resistin was also markedly reduced in the presence of either dominant negative mutant IkappaBalpha or PDTC, a pharmacological inhibitor of NF-kappaB. On the other hand, NF-kappaB subunit p65 was upregulated by resistin. Moreover, we found that transforming growth factor-beta-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin. These results suggest that resistin enhances COX-2 expression in mouse macrophage cells in a TAK1-IKK-NF-kappaB-dependent manner and therefore plays a critical role in inflammatory processes.

Arachidonic acid induces acetyl-CoA carboxylase 1 expression via activation of CREB1.

Acetyl-CoA carboxylase (ACC; EC 6.4.1.2) is the major enzyme of fatty acid synthesis and oxidation in response to dietary changes. In animals, there are two major isoforms of ACCs, ACC1 and ACC2, which are encoded by different genes and display distinct tissue and cellular distribution. We examined the effect of high concentration of arachidonic acid (AA) on the expression of ACC1 mRNA in HepG2 hepatoma cells cultured in the absence of insulin. After 12 h of treatment, AA was found to significantly up-regulate ACC1 mRNA level as well as that of cAMP regulatory element binding protein 1 (CREB1), implying the possible interactions between ACC1 and CREB1. In support of the hypothesis, several potential CREB1 binding sites were identified within the PII promoter of ACC1. Further experiments demonstrated that transient over-expression of CREB1 in HepG2 cells activates ACC1 PII promoter and induces the production of triacylglycerol in response to AA, indicating that the effect of AA on ACC1 is possibly regulated via CREB1.