The chapter discusses the regulation of mitochondrial biogenesis, emphasizing the role of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) in this process. PGC-1α activates transcription factors such as nuclear respiratory factors 1 and 2, which in turn activate mitochondrial transcription factor A (Tfam), driving the transcription and replication of mitochondrial DNA (mtDNA). Key factors regulating PGC-1α include AMPK (AMP-activated protein kinase), which acts as an energy sensor and is crucial for mitochondrial biogenesis. AMPK activity decreases with age, contributing to reduced mitochondrial function and dysfunction in aging and diseases like Type 2 diabetes and Alzheimer’s disease. Other factors, such as CaMKIV (calcium/calmodulin-dependent protein kinase IV), NO (nitric oxide), SIRT1 (silent information regulator protein 1), TORC1 (transducer of regulated CREB-binding protein), calcineurin, p38 MAPK (mitogen-activated protein kinase), and RIP140, also play roles in mitochondrial biogenesis. The chapter highlights the importance of understanding these molecular mechanisms for developing therapeutic targets to treat and prevent diseases associated with mitochondrial dysfunction.The chapter discusses the regulation of mitochondrial biogenesis, emphasizing the role of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) in this process. PGC-1α activates transcription factors such as nuclear respiratory factors 1 and 2, which in turn activate mitochondrial transcription factor A (Tfam), driving the transcription and replication of mitochondrial DNA (mtDNA). Key factors regulating PGC-1α include AMPK (AMP-activated protein kinase), which acts as an energy sensor and is crucial for mitochondrial biogenesis. AMPK activity decreases with age, contributing to reduced mitochondrial function and dysfunction in aging and diseases like Type 2 diabetes and Alzheimer’s disease. Other factors, such as CaMKIV (calcium/calmodulin-dependent protein kinase IV), NO (nitric oxide), SIRT1 (silent information regulator protein 1), TORC1 (transducer of regulated CREB-binding protein), calcineurin, p38 MAPK (mitogen-activated protein kinase), and RIP140, also play roles in mitochondrial biogenesis. The chapter highlights the importance of understanding these molecular mechanisms for developing therapeutic targets to treat and prevent diseases associated with mitochondrial dysfunction.