👤 Vasundhra Bhandari

Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Show less

Mitochondrial uncoupling proteins (UCP) are a part of the large family of mitochondrial solute carriers (SLC25s), concentrated in the inner mitochondrial membrane that carries protons from intermembrane space to the matrix. Further, some UCPs are also involved in the transportation of the fatty acid anions and catalyzed the proton transport by fatty acid cycling across the membrane. Out of the 5 UCPs, UCP 2, 4, and 5 are localized in the central nervous system (CNS), and alteration within the expression of these UCPs results in neuronal dysfunction and, ultimately, death of neurons. UCPs play a vital role in regulating mitochondrial membrane potential, preventing reactive oxygen species (ROS) production, alteration in neuronal activity, and the regulation of calcium homeostasis that ultimately results in the prevention of neuronal loss. These changes in mitochondria impact the function and survival of neurons playing a critical role in the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, UCP2 regulates the microglia response towards neuroinflammation by modulating microglia's M1 and M2 phenotypes. These microglia cells are further involved in regulating inflammatory response and synaptic functions. Moreover, UCP2, 4, and 5 are ubiquitously present in all brain regions that negatively regulate ROS production and inflammation, leading to the prevention of neuronal cell death. Increased ROS production is a common symptom reported in neurodegenerative diseases that affect several pathways concerned with neuronal death, either apoptosis or autophagy. These accumulating evidence suggested UCPs as a possible therapeutic target for the management of neurodegenerative diseases. Show less