Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and ALS, are characterized by the progressive loss of neurons in specific brain regions, leading to motor or cognitive impairments. Mitochondrial dysfunction plays a crucial role in the pathogenesis of these disorders, particularly through the mitochondrial permeability transition (mPT). The mPT is a non-selective pore that allows the passage of various ions and molecules, leading to mitochondrial swelling, protein release, and cell death. This review discusses the role of mPT in neuronal death in major neurodegenerative diseases, focusing on the factors that induce mPT opening, including free radicals and calcium. It also explores the challenges and perspectives in developing neuroprotective strategies based on mPT inhibition. Despite the promising results of mPT inhibitors like cyclosporine A, their clinical use is limited due to side effects and the need for more specific and effective agents. The review highlights the importance of understanding the molecular mechanisms of mPT and the potential of targeting it as a therapeutic approach to prevent neuronal loss in neurodegenerative disorders.Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and ALS, are characterized by the progressive loss of neurons in specific brain regions, leading to motor or cognitive impairments. Mitochondrial dysfunction plays a crucial role in the pathogenesis of these disorders, particularly through the mitochondrial permeability transition (mPT). The mPT is a non-selective pore that allows the passage of various ions and molecules, leading to mitochondrial swelling, protein release, and cell death. This review discusses the role of mPT in neuronal death in major neurodegenerative diseases, focusing on the factors that induce mPT opening, including free radicals and calcium. It also explores the challenges and perspectives in developing neuroprotective strategies based on mPT inhibition. Despite the promising results of mPT inhibitors like cyclosporine A, their clinical use is limited due to side effects and the need for more specific and effective agents. The review highlights the importance of understanding the molecular mechanisms of mPT and the potential of targeting it as a therapeutic approach to prevent neuronal loss in neurodegenerative disorders.