Mitochondria and mitochondria-mediated signalling pathways are known to control synaptic signalling, as well as long-lasting changes in neuronal structure and function. Mitochondrial impairment is linked to synaptic dysfunction in normal ageing and age-associated neurodegenerative ailments, including Parkinson's disease (PD) and Alzheimer's disease (AD). Both proteolysis and mitophagy perform a major role in neuroprotection, by maintaining a healthy mitochondrial population during ageing. Mitophagy, a highly evolutionarily conserved cellular process, helps in the clearance of damaged mitochondria and thereby maintains the mitochondrial and metabolic balance, energy supply, neuronal survival and neuronal health. Besides the maintenance of brain homeostasis, hippocampal mitophagy also helps in synapse formation, axonal development, dopamine release and long-term depression. In contrast, defective mitophagy contributes to ageing and age-related neurodegeneration by promoting the accumulation of damaged mitochondria leading to cellular dysfunction. Exercise, stress management, maintaining healthy mitochondrial dynamics and administering natural or synthetic pharmacological compounds are some of the strategies used for neuroprotection during ageing and age-related neurological diseases. The current review discusses the impact of defective mitophagy in ageing and age-associated neurodegenerative conditions, the underlying molecular pathways and potential therapies based on recently elucidated mitophagy-inducing strategies.
Keywords: ageing; mitochondrial dysfunction; mitophagy; neurodegeneration; pharmacological compounds; therapeutic interventions.
© 2023 British Pharmacological Society.