Mitochondrial control of cell bioenergetics in Parkinson's disease

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics.

Keywords: Autophagy; Glycolysis; Lysosome; Mitochondria; Neurodegeneration; Parkinson’s disease; Pentose-phosphate pathway; Redox.

Figure 1. Cellular pathways associated with bioenergetics in PD

Genetic mutations in PD-related genes and/or exposure to environmental toxins lead to an increased oxidative stress and mitochondrial failure that affect several metabolic pathways. Dysfunctional mitochondria induce the aggregation of proteins, such as α-synuclein, due to impairment in the ubiquitin/proteasome and autophagy/lysosome pathways. This also leads to alterations in the cross-talk between mitochondria and ER, contributing to increased mROS. Additional factors, such as dopamine metabolism or glial activation may also contribute to increased ROS. Excessive ROS interfere with ATP synthesis and contribute to the stabilization of proteins, such as HIF-1, which mediates glycolytic up-regulation in order to compensate for the mitochondrial energy impairment. However, increased glycolysis may have adverse effects in neurons. Thus, glycolysis facilitates a failed attempt of post-mitotic cells to re-enter the cell cycle, a feature that may be important in genetic PD-related mutations affecting p53. Also, certain glycolytic intermediates may interact with dopamine derivatives generating neurotoxins. Finally, increased glycolysis impairs antioxidant PPP. Thus, the compensative increase in glycolysis contributes to the cascade of events leading to selective degeneration of dopaminergic neurons.

Figure 2. Metabolic shift in familial parkinsonism

Mutations in familial PD-linked genes encoding α-synuclein, parkin, DJ-1, PINK1 and LRRK2 are associated with PD pathogenesis. These mutations contribute to PD causing mitochondrial dysfunction, oxidative damage and abnormal protein aggregation and phosphorylation, compromising neuronal function and survival. α-Synuclein undergoes aggregation as a consequence of its mutation or indirectly by mutation of other PD-related genes, endangering protein degradation pathways and inducing ER stress and mitochondrial dysfunction. Mitochondrial dysfunction and oxidative damage lead to deficits in ATP, which activates glycolysis. This glycolytic increase can also be consequence of genetic mutations in Parkin, PINK1 and DJ-1, which act on specific glycolytic regulatory proteins. In addition, Parkin, being an E3 ubiquitin ligase, promotes proteasomal degradation, participates in mitochondrial fusion and fission processes, and reverses PINK1-induced mitochondrial dysfunction. DJ-1 protects mitochondria against oxidative stress, it functions as a transcriptional co-activator of PINK1, amongst others, and blocks α-synuclein aggregation. PINK1 protects against mitochondrial dysfunction, preventing mitochondrial ROS production and recruiting Parkin into mitochondria, thus controlling mitochondrial dynamics. LRRK2 seems to play a role in synaptic vesicles formation. LRRK2 causes abnormal protein phosphorylation, which induces mitochondrial-dependent cell death. Furthermore, familial PD-linked genes such as Parkin, PINK1, DJ-1 and α-synuclein favour ER-mitochondria crosstalk through maintenance of contact sites, thus promoting cell survivalGreen arrows indicate activating effects, and red lines with blunt ends inhibitory effects).