Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) is a core member of the PGC-1 family and serves as a transcriptional coactivator, playing a crucial regulatory role in various diseases. Mitochondria, the main site of cellular energy metabolism, are essential for maintaining cell growth and function. Their function is regulated by various transcription factors and coactivators. PGC-1α regulates the biogenesis, dynamics, energy metabolism, calcium homeostasis, and autophagy processes of mitochondria by interacting with multiple nuclear transcription factors, thereby exerting significant effects on mitochondrial function. This review explores the biological functions of PGC-1α and its regulatory effects and related mechanisms on mitochondria, providing important information for our in-depth understanding of the role of PGC-1α in cellular metabolism. The potential role of PGC-1α in metabolic diseases, cardiovascular diseases, and neurodegenerative diseases was also discussed, providing a theoretical basis for the development of new treatment strategies.
Humans ; Mitochondria/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/physiology* ; Animals ; Energy Metabolism/physiology* ; Neurodegenerative Diseases/physiopathology* ; Autophagy/physiology* ; Transcription Factors/physiology* ; Metabolic Diseases/physiopathology* ; Cardiovascular Diseases/physiopathology*

Parkinson's disease (PD) is a common neurodegenerative disorder mainly related to mitochondrial dysfunction of dopaminergic neurons in the midbrain substantia nigra. This study aimed to investigate the effects of exercise preconditioning on motor deficits and mitochondrial function in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Eight-week-old male C57BL/6J mice were randomly divided into four groups: sedentary + saline (SS), sedentary + MPTP (SM), exercise + saline (ES), and exercise + MPTP (EM) groups. Mice in the ES and EM groups received 4 weeks of treadmill training, and then SM and EM groups were treated with MPTP for 5 days. Motor function was assessed by behavioral tests, and morphological and functional changes in dopaminergic neurons and mitochondria in the substantia nigra of the midbrain were evaluated using immunohistochemistry, Western blot, and transmission electron microscopy technology. The results showed that, compared with the SM group, the EM group exhibited significantly improved motor ability, up-regulated protein expression levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the midbrain, and down-regulated protein expression of α-synuclein (α-Syn) in the mitochondria of substantia nigra. Compared with the SM group, the EM group showed up-regulated protein expression levels of mitochondrial fusion proteins, including optical atrophy protein 1 (OPA1) and mitofusin 2 (MFN2), and biogenesis-related proteins, including peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), while the protein expression levels of dynamin-related protein 1 (DRP1) and mitochondrial fission protein 1 (FIS1) were significantly down-regulated. Compared with the SM group, the EM group showed significantly reduced damage to substantia nigra mitochondria, restored mitochondrial membrane potential and ATP production, and decreased levels of reactive oxygen species (ROS). These results suggest that 4-week treadmill pre-training can alleviate MPTP-induced motor impairments in PD mice by improving mitochondrial function, providing a theoretical basis for early exercise-based prevention of PD.
Animals ; Male ; Physical Conditioning, Animal/physiology* ; Mice ; Mice, Inbred C57BL ; Mitochondria/physiology* ; Dopaminergic Neurons ; MPTP Poisoning/physiopathology* ; Substantia Nigra ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

OBJECTIVETo observe the effect of Cornus Officinalis total glycosides (COTG) and Cornus polysaccharides (CP) on myocardial mitochondria and expression levels of glycogen synthase kinase-3β (GSK-3β) of acute myocardial infarction (AMI) rats.

METHODSThe AMI rat model was established by ligating the left anterior descending branch of coronary artery. Rats were divided into 5 groups according to random digit table, i.e., the sham-operation group, the model group, the COTG prevention group, the CP treatment group, the COTG treatment group, 12 in each group. Normal saline was administered to rats in the normal control group and the model group by gastrogavage. Corresponding medication was respectively administered to rats in the rest 3 groups by gastrogavage. The cardiac function was detected by echocardiography and hemodynamics. The infarct size was determined by Masson trichrome staining. The expression of mitochondrial biogenesis genes such as a subunit of peroxisome proliferators-activated receptor-γ coactivator-1 (PGC-1α), PGC-1β, nuclear respiratory factor-1 (NRF-1), and GSK-3P mRNA were detected by Real-time PCR.

RESULTSCompared with the sham-operation group, the myocardial infarction size increased, cardiac function decreased, the expression of PGC-1&alpha;, PGC-1β, and NRF-1 mRNA decreased, and the expression of GSK-3β mRNA increased (all P <0. 05). Compared with the model group, myocardial infarction sizes were reduced, cardiac function was improved, the expression of NRF-1 mRNA was elevated in the COTG prevention group, the CP treatment group, the COTG treatment group; the expression of the PGC-1&alpha; and PGC-1β mRNA was elevated in the COTG prevention group and the CP treatment group; the expression of GSK-3β mRNA was reduced in the CP treatment group (all P <0. 05). Compared with the CP prevention group, fractional shortening (FS) and aortic systolic blood pressure (SBP) increased in the CP treatment group; ejection fraction (EF) decreased in the CP treatment group; the expression of PGC-1&alpha;, PGC-1β, NRF-1 mRNA were reduced in the the CP treatment group and the COTG treatment group; the expression of GSK-3β mRNA decreased in the CP treatment group (all P <0. 05). Compared with the COTG treatment group, FS, EF, left ventricular end systolic pressure (LVESP), SBP, and the expression of GSK-3β mRNA were reduced in the CP treatment group (P <0. 05).

CONCLUSIONSCOTG and CP could improve cardiac function, reduce the myocardial infarction area, and promote biogenesis of myocardial mitochondria. Their protective effects on the mitochondria of cadiocytes might be achieved by GSK-3β signalina pathway.

Animals ; Cornus ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glycogen Synthase Kinase 3 ; Glycogen Synthase Kinase 3 beta ; Glycosides ; Heat-Shock Proteins ; Mitochondria, Heart ; physiology ; Myocardial Infarction ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Polysaccharides ; Protective Agents ; pharmacology ; therapeutic use ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Transcription Factors

Death following situations of intense emotional stress has been linked to the cardiac pathology described as stress cardiomyopathy, whose pathomechanism is still not clear. In this study, we sought to determine, via an animal model, whether the transcriptional coactivator peroxisome proliferator-activated receptor &gamma; coactivator-1alpha (PGC-1&alpha;) and the amino peptide neuropeptide Y (NPY) play a role in the pathogenesis of this cardiac entity. Male Sprague-Dawley rats in the experimental group were subjected to immobilization in a plexy glass box for 1 h, which was followed by low voltage electric foot shock for about 1 h at 10 s intervals in a cage fitted with metallic rods. After 25 days the rats were sacrificed and sections of their hearts were processed. Hematoxylin-eosin staining of cardiac tissues revealed the characteristic cardiac lesions of stress cardiomyopathy such as contraction band necrosis, inflammatory cell infiltration and fibrosis. The semi-quantitative RT-PCR analysis for PGC-1&alpha; mRNA expression showed significant overexpression of PGC1-&alpha; in the stress-subjected rats (P<0.05). Fluorescence immunohistochemistry revealed a higher production of NPY in the stress-subjected rats as compared to the control rats (P=0.0027). Thus, we are led to conclude that following periods of intense stress, an increased expression of PGC1-&alpha; in the heart and an overflow of NPY may lead to stress cardiomyopathy and even death in susceptible victims. Moreover, these markers can be used to identify stress cardiomyopathy as the cause of sudden death in specific cases.
Animals ; Cardiomyopathies ; metabolism ; Myocytes, Cardiac ; metabolism ; Neuropeptide Y ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Rats ; Rats, Sprague-Dawley ; Stress, Physiological ; physiology ; Transcription Factors ; metabolism

BACKGROUNDPrenatal hyperglycaemia may increase metabolic syndrome susceptibility of the offspring. An underlying component of the development of these morbidities is hepatic gluconeogenic molecular dysfunction. We hypothesized that maternal hyperglycaemia will influence her offsprings hepatic peroxisome proliferator-activated receptor coactivator-1&alpha; (PGC-1&alpha;) expression, a key regulator of glucose production in hepatocytes.

METHODWe established maternal hyperglycaemia by streptozotocin injection to induce the maternal hyperglycaemic Wistar rat model. Offspring from the severe hyperglycemia group (SDO) and control group (CO) were monitored until 180 days after birth. Blood pressure, lipid metabolism indicators and insulin resistance (IR) were measured. Hepatic PGC-1&alpha; expression was analyzed by reverse transcription polymerase chain reaction and Western blotting. mRNA expression of two key enzymes in gluconeogenesis, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), were analyzed and compared.

RESULTSIn the SDO group, PGC-1&alpha; expression at protein and mRNA levels were increased, so were expression of G-6-Pase and PEPCK (P < 0.05). The above effects were seen prior to the onset of IR.

CONCLUSIONThe hepatic gluconeogenic molecular dysfunction may contribute to the metabolic morbidities experienced by this population.

Animals ; Female ; Hyperglycemia ; chemically induced ; physiopathology ; Insulin Resistance ; physiology ; Liver ; metabolism ; Male ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Peroxisome Proliferator-Activated Receptors ; metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; RNA-Binding Proteins ; Rats ; Rats, Wistar ; Streptozocin ; toxicity ; Transcription Factors

BACKGROUNDUncoupling protein (UCP) 2 is related to the dysfunction of beta cells induced by fatty acids. However, whether UCP2 has similar effects on alpha cell is still not clear. This study aimed to investigate the effects of UCP2 and its possible mechanisms in lipotoxicity-induced dysfunction of pancreatic alpha cells.

METHODSThe alpha TC1-6 cells were used in this study to evaluate the effects of palmitate and/or UCP2 inhibit factors on the glucagon secretory function, glucagon content, the glucagon mRNA level and the nitrotyrosine level in the supernatant. Meantime, the expression levels of UCP2 and peroxisome proliferator-activated receptor-&gamma; coactivator-1 alpha (PGC-1 alpha) were measured by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Furthermore, the possible relationship between UCP2 and insulin signal transduction pathway was analyzed.

RESULTSPalmitate stimulated alpha cell glucagon secretion and the expression of UCP2 and PGC-1 alpha, which could be partially decreased by the inhibition of UCP2. Palmitate increased nitrotyrosine level and suppressed insulin signal transduction pathway in alpha cells. Inhibition of UCP2 influenced the effects of free fatty acid on alpha cells and may relate to glucagon secretion.

CONCLUSIONUCP2 played an important role on alpha cell dysfunction induced by free fatty acid in vitro, which may be related to its effects on oxidative stress and insulin signal transduction pathway.

Animals ; Cells, Cultured ; Glucagon ; secretion ; Glucagon-Secreting Cells ; drug effects ; physiology ; Insulin ; pharmacology ; Insulin Receptor Substrate Proteins ; metabolism ; Ion Channels ; genetics ; physiology ; Iridoid Glycosides ; pharmacology ; Iridoids ; Mice ; Mitochondrial Proteins ; genetics ; physiology ; Oxidative Stress ; Palmitic Acid ; toxicity ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphorylation ; RNA, Messenger ; analysis ; Signal Transduction ; Trans-Activators ; genetics ; physiology ; Transcription Factors ; Tyrosine ; analogs & derivatives ; metabolism ; Uncoupling Protein 2