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1.1 Energy Metabolism in the Brain Although the brain accou...
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![1.1 Energy Metabolism in the Brain
Although the brain accounts for only about 2% of body weight, it consumes 20% of the body's total daily energy expenditure [17]. The brain primarily uses glucose and fatty acids for energy. Under resting conditions, the brain's preferred metabolic pathway is mitochondrial oxidative phosphorylation. However, high-demand activities such as synaptic plasticity, learning, and memory require additional contributions from glycolysis or lactate metabolism [13, 18, 19]. This highlights the crucial role of mitochondria in brain energy metabolism. Lactate acts as a "double-edged sword" in the brain; it is a substrate required for maintaining energy metabolism in the central nervous system (CNS), but excessive lactate accumulation in the brain can cause inflammatory responses, leading to neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) [20].
1.2 The Role of Mitochondria in Brain Energy Metabolism
Here, we primarily discuss the role of mitochondria in oxidative phosphorylation (OXPHOS) and glycolysis. OXPHOS mainly provides energy to the CNS when oxygen supply is sufficient or under resting conditions. This physiological process occurs in the inner mitochondrial membrane of eukaryotic cells or the cytoplasm of prokaryotes. It is the coupled reaction of ATP synthesis from ADP and inorganic phosphate, powered by the energy released during the oxidation of substances in the body via the respiratory chain. OXPHOS has the following functions in the CNS: (1) maintaining neuronal function; (2) supporting glial cell function; and (3) influencing the development and repair of the nervous system [21, 22].
Glycolysis in the CNS mainly provides energy when oxygen supply is insufficient or when energy supply is urgently needed. In this physiological process, glucose is broken down into pyruvate in the cytoplasm, producing two molecules of pyruvate and two molecules of ATP for each molecule of glucose broken down. Pyruvate is further metabolized by lactate dehydrogenase (LDH) to produce lactate, which can then enter the mitochondria and be oxidized to carbon dioxide and water. Glycolysis can rapidly provide energy to maintain the normal operation of neurons and other cells when the CNS is active. At the same time, the intermediate products of glycolysis can provide substrates for other physiological activities. For example, pyruvate can be converted into non-essential amino acids such as alanine, participating in protein synthesis; it can also be converted into glucose in organs such as the liver, maintaining stable blood glucose levels. In addition, although glycolysis takes place in the cytoplasm, it closely cooperates with mitochondria [23, 24].
Glycolysis and OXPHOS are interdependent, and this interdependence stems from mitochondria. Glucose-driven OXPHOS requires glycolysis to occur. Mitochondria cannot directly oxidize glucose; therefore, glucose initially needs to undergo glycolysis, where it produces pyruvate (or lactate in astrocytes), which can be imported into mitochondria and completely oxidized [25].
1.3 Energy Metabolism Disorders in the Brains of AD Patients
The main reasons for energy metabolism disorders in the AD brain can be summarized as follows: (1) glucose metabolism dysregulation; (2) impaired mitochondrial fatty acid oxidation (FAO);](/_next/image?url=https%3A%2F%2Fpub-8c0ddfa5c0454d40822bc9944fe6f303.r2.dev%2Fai-drawings%2FIcV7vcnomT4yUr2cR2ybs0iHyXlGgSRn%2F905f8239-cc7a-4506-a92b-cad88e820407%2F81ca34d8-7e4b-41ed-ac88-93fe3e8d434b.png&w=3840&q=75)
