Abstract
Neurodegenerative diseases represent a major health threat, with dysfunction in energy metabolism and imbalance in glucose-lipid homeostasis constituting key pathogenic factors. As the cell's energy hub, mitochondria are closely associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, the precise mechanism by which mitochondrial energy metabolism affects glucose-lipid homeostasis remains unclear. This review summarizes currents insights into the role of mitochondrial function in energy metabolism and glucose-lipid regulation in neurodegenerative diseases. We examined how mitochondrial dynamics, oxidative phosphorylation, calcium homeostasis, and key signaling pathways-AMP-activated protein kinase/mammalian target of rapamycin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and Sirtuin 1-contribute to neuronal energy balance and metabolic regulation. We further explored the impact of other organelles on mitochondria and how the dynamic switching of mitochondrial morphology and function disrupts the critical glucose-lipid homeostasis. By focusing on mitochondrial dysfunction, metabolic disorders, and their interactions, we introduce the mitochondria-centered multi-organelle-energy metabolic-glucose-lipid homeostasis (MMH) network as a unifying theoretical framework that positions the progressive loss of metabolic flexibility as the fundamental essence of neurodegenerative disorders. The MMH network furnishes a novel lens through which the shared mechanistic underpinnings of neurodegenerative diseases can be deciphered, and thereby enable earlier diagnosis and precision therapeutics.