Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease

Abstract

By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intracellular calcium fluxes, Mortalin is a chaperone protein that plays crucial roles in neuronal homeostasis and activity. However, its expression and stability are strongly modified in response to cellular stresses, in particular upon altered oxidative conditions during neurodegeneration. Here, we report and discuss the abundant literature that has highlighted its contribution to the pathophysiology of Parkinson's disease, as well as its therapeutic and prognostic potential in this still incurable pathology.

Keywords: Hspa9; Mortalin; Parkinson’s disease; chaperone; mitochondria; neurodegeneration; oxidative stress; prognostic and therapeutic potential.

Figure 1

Mortalin functions in neurons under physiological conditions. Mortalin functions depend on its subcellular localization and protein partners. Its two main functions rely on (1) tethering ER and mitochondrial membranes (MAM, in orange) that mostly enable intracellular calcium storage and fluxes, and (2) controlling the quality of proteins imported into the mitochondrial matrix, in association with the Tom/Tim mitochondrial import complexes (green). AMPA: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CAv: voltage-gated calcium channels; ER: endoplasmic reticulum; IP3R: inositol trisphosphate receptor; KA: kainate; MAM: mitochondria-associated endoplasmic reticulum membranes; MCU: mitochondrial calcium uniporter; NMDA: N-methyl-D-aspartate; OXPHOS: oxidative phosphorylation; PTP: permeability transition pore; ROS: reactive oxygen species; SERCA: sarco/endoplasmic reticulum Ca²⁺-ATPase; Tim: translocase of the inner membrane; Tom: translocase of the outer membrane; VDAC: voltage-dependent anion channel.

Figure 2

Implication of Mortalin in the degenerative DA neuron during PD. Intrinsic dopamine metabolites and synuclein aggregation generate a ROS overload in the DA neurons of PD patients, which is further augmented with the inhibition of the mitochondrial electron transport chain (OXPHOS). Dopamine metabolites and synuclein aggregates also trigger Mortalin degradation, which amplifies the impact of oxidative stress in neuronal homeostasis. C.I: Mitochondrial respiratory complex I; DAT: dopamine transporter; L-Dopa: levodopa; MAM: mitochondria-associated endoplasmic reticulum membranes; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; Tyr: tyrosine.