Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease

Abstract

Parkinson's disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis. Indeed, data obtained from genetic and genome association studies have implicated interactive contributions of genes controlling protein quality control and metabolism. For example, loss of key proteins that are responsible for clearance of dysfunctional mitochondria through a process called mitophagy has been found to cause PD, and a significant proportion of genes associated with PD encode proteins involved in the autophagy-lysosomal pathway. In this review, we highlight the evidence for the targeting of mitochondria by proteotoxic, redox and metabolic stress, and the role autophagic surveillance in maintenance of mitochondrial quality. Furthermore, we summarize the role of α-synuclein, leucine-rich repeat kinase 2, and tau in modulating mitochondrial function and autophagy. Among the stressors that can overwhelm the mitochondrial quality control mechanisms, we will discuss 4-hydroxynonenal and nitric oxide. The impact of autophagy is context depend and as such can have both beneficial and detrimental effects. Furthermore, we highlight the potential of targeting mitochondria and autophagic function as an integrated therapeutic strategy and the emerging contribution of the microbiome to PD susceptibility.

Keywords: 4-hydroxynonenal; bioenergetic health index; endosome-lysosomes; glucose metabolism; microglia; post-translational modification.

Figure 1. Mitochondrial function and autophagy: integrating redox, metabolic and proteotoxic stress in Parkinson’s disease

Mitochondria and the autophagy machinery are essential for neuronal function and health. Mitochondria are not only the major source of cellular energy but also a signaling nexus for metabolites and modulating redox status and the bioenergetic health may be used as biomarkers for disease prognosis and response to thereapeutics. Because of the high demand of cellular energy and the high content of fatty acids in neurons, reactive oxygen and nitrogen species can be generated intracellularly, as well as from neighboring glia cells, or even due to exposure to environmental toxins. Metabolic regulation of redox signaling, mitochondrial function and autophagy is of importance in the central nervous system via pathways including but not limited to glycolysis, hexoamine biosynthesis, and fatty acid oxidation. Furthermore, protein homeostasis, as represented by α-synuclein and tau homeostasis is important for Parkinson’s disease. α-synuclein can target to and inhibit mitochondrial function, and itself is subject to HNE modification and nitration. Autophagy is a major pathway for α-synuclein degradation and the clearance of damaged mitochondria, but is also targeted by proteotoxic proteins including α-synuclein, tau and LRRK2. In this review, we highlight the evidence of how mitochondria are targeted by proteotoxic, redox and metabolic stress, while maintained by the autophagic surveillance. These areas present opportunities to better understand Parkinson’s disease pathogenesis and potential for development of effective therapies.

Figure 2. Assessment of autophagic and mitophagic flux

A. The amount of LC3II in the presence and absence of inhibitors that blocks lysosomal degradation of LC3II, and the p62 accumulation in the absence of enhanced p62 transcription activation is used to assess autophagic flux. B. Cells or animals expressing reporter gene RFP-GFP-LC3 can also be examined for autophagic flux based on the amount of LC3 that reaches the lysosomes due to the pH sensitivity of GFP. C. Cells or animals expressing reporter gene mitochondrial matrix targeted Cherry-GFP-LC3 can be examined for mitophagic flux based on the amount of LC3 that reaches the lysosomes due to the pH sensitivity of GFP.

Figure 3. Potential targets and therapeutic strategies for treating Parkinson’s disease based on autophagy-lysosomal pathway, bioenergetics and metabolism, as well as redox signaling and oxidative-reductive stress

Major efforts have been made in recent years to develop broad spectrum and/or organelle targeted antioxidant strategies, and enhanced autophagy, mitophagy, and lysosomal activities. Highlighted in this figure are some of the key events of metabolic, oxidative-reductive, and proteotoxic stress (in boxes), as well as molecules that have been tested in in vitro and animal models (in green) that target metabolism and autophagy/mitophagy/lysosomal pathways.