Abstract
Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.
Highlights
Aging is accompanied by a decline in cognitive function in a significant part of the population and is a major risk factor for the development of most neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1]
It is assumed that this is due to the participation of Phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) and parkin in the long-term survival of dopaminergic neurons, and PINK1 and parkin defects lead to the rapid death of nigral neurons without the accumulation of pathological proteins, which is confirmed by experiments with PINK1 knockdown
Mitophagy pathways play an important role in maintaining physiological homeostasis, are involved in the mechanisms of aging and neurodegenerative disorders, and represent promising targets for the development of potential therapeutic agents aimed at regulating mitochondria quality control in neurons and glial cells (Table 1)
Summary
Aging is accompanied by a decline in cognitive function in a significant part of the population and is a major risk factor for the development of most neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1]. Mitochondrial dysfunction is a key pathological marker for neurodegenerative diseases It is a central player in sporadic and familial forms of PD, since dopaminergic neurons of the substantia nigra are especially vulnerable to energy deficiency due to their ability for autonomous activity, constant recirculation of synaptic vesicles, and developed axonal network [4]. Mitophagy restricts the production of reactive oxygen species, prevents the accumulation of mitochondrial DNA (mtDNA) mutations and the decrease in ATP production, and blocks apoptotic signaling and the activation of inflammasomes [5,6]. It is the progressive decline in this type of selective macroautophagy throughout life that appears to lead to mitochondrial dysfunction and aging [6]. Determination of the relationships between mitophagy markers and various parameters of neurodegenerative processes in PD, AD, and other age-related disorders seems to be highly promising from both a clinical and fundamental point of view
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