Abstract
Maintenance of neuronal homeostasis is a challenging task, due to unique cellular organization and bioenergetic demands of post-mitotic neurons. It is increasingly appreciated that impairment of mitochondrial homeostasis represents an early sign of neuronal dysfunction that is common in both age-related neurodegenerative as well as in neurodevelopmental disorders. Mitochondrial selective autophagy, known as mitophagy, regulates mitochondrial number ensuring cellular adaptation in response to several intracellular and environmental stimuli. Mounting evidence underlines that deregulation of mitophagy levels has an instructive role in the process of neurodegeneration. Although mitophagy induction mediates the elimination of damaged mitochondria and confers neuroprotection, uncontrolled runaway mitophagy could reduce mitochondrial content overstressing the remaining organelles and eventually triggering neuronal cell death. Unveiling the molecular mechanisms of neuronal mitophagy and its intricate role in neuronal survival and cell death, will assist in the development of novel mitophagy modulators to promote cellular and organismal homeostasis in health and disease.
Highlights
Mitochondria are remarkably dynamic organelles that divide, fuse and migrate in different cellular compartments
A recent study demonstrated that overexpression of wild type and disease-associated tau results in reduced Parkin recruitment onto mitochondrial surface and mitophagy inhibition in both nematodes and neuroblastoma cells (Cummins et al, 2019). These findings suggest that the impairment of basal mitophagy is an early event in Alzheimer’s disease (AD) human brain and a causative factor in the development and progression of disease pathophysiology (Kerr et al, 2017; Fang et al, 2019)
Mitophagy preserves energy homeostasis facilitating the elimination of defective organelles and, thereby, preventing the release of various harmful byproducts of mitochondrial activity
Summary
Mitochondria are remarkably dynamic organelles that divide, fuse and migrate in different cellular compartments. While the role of mitophagy in cellular and organismal physiology is essential, several pathological conditions, such as mitochondrial disorders, ischemic stroke, chronic cerebral hypoperfusion, and diabetes, are shown to stimulate uncontrolled mitochondrial elimination that subsequently leads to neuronal cell death (Shi et al, 2014; Su et al, 2018; Devi et al, 2019; Park et al, 2019; Zaninello et al, 2020).
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