PGC-1α, short for peroxisome proliferator-activated receptor gamma coactivator 1 alpha, is a transcriptional co-activator. It is a master regulator of mitochondrial biogenesis, playing a crucial role in regulating mitochondrial function, energy metabolism, and antioxidant defense. PGC-1α is involved in pathways related to mitochondrial network dynamics, autophagic removal of damaged mitochondria, and also impacts insulin-stimulated glucose uptake in skeletal muscle [1]. It is regulated by factors like SIRT1/3, TFAM, and AMPK, and is closely linked to the mitochondrial lifecycle and ROS stress response [2]. The PGC-1 family, including PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), is essential for many cellular events such as oxidative stress, endoplasmic reticulum homeostasis, and inflammation [3].

In a mouse model of vascular dementia (VaD) induced by chronic cerebral hypoperfusion, hippocampal PGC-1α expression was down-regulated. However, neuron-specific overexpression of PGC-1α (using PGC-1αf/f Eno2-Cre mice) significantly ameliorated cognitive deficits. PGC-1α improved energy metabolism of neurons under hypoxic conditions, increased metabolic activity, boosted expressions of mitochondrial antioxidants and uncoupling proteins, reduced ROS production, and decreased the activation of microglia and astrocytes in the hippocampus, protecting hippocampal neurons against ischemic insults [4].

In conclusion, PGC-1α is a key regulator in multiple biological processes, especially those related to mitochondrial function and energy metabolism. Model-based research, such as the PGC-1α-related mouse models in the study of VaD, has revealed its potential as a therapeutic target for cognitive impairment. Additionally, PGC-1α is implicated in various diseases including cancers, cardiac and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders, highlighting its importance in understanding disease mechanisms and developing new therapies [3].

References:

1. Halling, Jens Frey, Pilegaard, Henriette. 2020. PGC-1α-mediated regulation of mitochondrial function and physiological implications. In Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme, 45, 927-936. doi:10.1139/apnm-2020-0005. https://pubmed.ncbi.nlm.nih.gov/32516539/

2. Abu Shelbayeh, Othman, Arroum, Tasnim, Morris, Silke, Busch, Karin B. 2023. PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response. In Antioxidants (Basel, Switzerland), 12, . doi:10.3390/antiox12051075. https://pubmed.ncbi.nlm.nih.gov/37237941/

3. Qian, Lu, Zhu, Yanli, Deng, Chao, Tian, Ye, Yang, Yang. 2024. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. In Signal transduction and targeted therapy, 9, 50. doi:10.1038/s41392-024-01756-w. https://pubmed.ncbi.nlm.nih.gov/38424050/

4. Han, Bin, Jiang, Wei, Liu, Haijie, Ju, Zhenyu, Hao, Junwei. 2020. Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. In Theranostics, 10, 2832-2848. doi:10.7150/thno.37119. https://pubmed.ncbi.nlm.nih.gov/32194838/