Mitophagy in neurodegeneration and aging

Abstract

Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD⁺ precursors and urolithins.

Figure 1. Overview of Mitophagy Pathways

A. PINK1/Parkin-mediated pathway. PINK1 is stabilized on the outer mitochondrial membrane of damaged mitochondria where it phosphorylates ubiquitin, leading to the activation of parkin. Parkin polyubiquitinates mitochondrial proteins, leading to the association with autophagy receptors and the formation of the autophagosome. The autophagosome then fuses with the lysosome, leading to degradation. Alternatively, PINK1 can recruit autophagy receptors directly in a parkin-independent manner, leading to low levels of mitophagy. B. Reticulocyte mitophagy. Upon maturation signal, NIX localizes to the outer mitochondrial membrane of reticulocyte mitochondria. NIX binds to LC3, leading to the formation of the autophagosome. C. Mammalian sperm mitophagy. Ubiquitinated paternal sperm associates with VCP. VCP facilitates the presentation of ubiquitinated (Ub) sperm mitochondrial proteins to the 26S proteasome, leading to degradation. Synchronously, SQSTM1 binds to other ubiquitinated mitochondrial proteins leading to sequestration within an autophagosome. D. Mitochondria-derived vesicles. Unfolded oxidized proteins lead to aggregation. Cardiolipin is locally oxidized to phosphatidic acid, leading to membrane curvature. PINK1 is localized to the outer mitochondrial membrane where it recruits parkin. The vesicle is formed and the cargo is transported to the lysosome for degradation. E. C. elegans somatic tissue. PINK1 is stabilized on the OMM of damaged/superfluous mitochondria, leading to the recruitment of parkin. Parkin ubiquitinates DCT-1 (homolog of NIX/BNIP3L), which associates with LGG-1 (homolog of LC3), leading to the formation of the autophagosome. F. C. elegans sperm. Loss of membrane integrity triggers the release of endonuclease G from inner mitochondrial membrane space to the mitochondrial matrix, where it degrades mtDNA. G. Yeast. Association of OMM protein Atg32 to isolation membrane-bound Atg8 directly or through its interaction with Atg11 recruits targeted mitochondria to the autophagosome.

Fig 2. Mitophagy in neurodegeneration and aging

Mitophagy can be inhibited by a reduction of autophagic protein activity or by depletion of metabolites such as NAD⁺ due to increased DNA damage and consumption or due to a decline in NAD⁺ synthesis. A reduction in mitophagy leads to an accumulation of dysfunctional mitochondria, which can induce a variety of damage contributing to neurodegeneration and aging. These pathologies can be restored by targeting mitophagy through genetic editing, mitophagy-inducing compounds, and NAD⁺ supplementation.