Mitochondrial Homeostasis and Signaling in Parkinson's Disease

Abstract

The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

Keywords: AKAP; PKA; Parkinson’s disease; cAMP; mitocondria.

Figure 1

Targeting mitochondria for the treatment of Parkinson’s disease (PD). Distinct experimental approaches can be used to selectively interfere with the mutation-induced deregulation of mitochondrial activities in PD neurons. Thus, deranged mitochondrial cAMP signaling can be restored using protein-protein interaction (PPI)/targeting molecules that support the assembly of A-Kinase Anchor Protein (AKAP) complexes at mitochondria. This would positively impact on cell survival and metabolism of PD neurons. Similarly, peptidomimetics that positively regulate X protein activity at mitochondria have been successfully used to prevent oxidative stress and apoptotic cell death induced by mitochondrial toxins. Similarly, inhibiting p13 or treating with necrosis inhibitors (Nec-1) in toxin-induced or familial forms of PD positively impacts on oxidative metabolism and neuronal survival. Moreover, restoring PINK1-Parkin pathway using selective agonists or preventing ubiquitin-specific protease (USP)-mediated deubiquitination of Parkin substrates with selective USP inhibitors could restore mitophagy in PD neurons, preventing accumulation of damaged mitochondria, oxidative stress, and neuronal apoptosis. Finally, sustaining the activity of respiratory enzymes as succinate dehydrogenase subunit B (SDHB) with chemical drugs represents a promising therapeutic approach to restore oxidative metabolism and mitochondrial permeability transition pore (PTP), preventing apoptotic or necroptotic neuronal loss.