Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice

Abstract

BackgroundPTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice.Methods and FindingsPurified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.ConclusionsIncreased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1−/− mice to inflammation and injury-induced cell death.

Parkinson’s disease and enhanced inflammatory response

“…Additionally, Akundi et al showed repression of PINK1 expression results in heightened susceptibility to inflammatory response-mediated DA neuron loss. 115 Elevated striatal levels of IL-1, IL-10, and IL-12 were detected in PINK1 null mice following LPS treatment. Furthermore, embryonic fibroblasts derived from PINK1 knockout mice exhibited repressed NF-kB activity in response to an inflammatory environment suggesting that PINK1 deficient neurons might have increased susceptibility to inflammatory response-mediated death.…”

“…Furthermore, embryonic fibroblasts derived from PINK1 knockout mice exhibited repressed NF-kB activity in response to an inflammatory environment suggesting that PINK1 deficient neurons might have increased susceptibility to inflammatory response-mediated death. 115 …”

Shared and Cell Type-Specific Mitochondrial Defects and Metabolic Adaptations in Primary Cells from PINK1-Deficient Mice

“…Subsequently, Parkin promotes the degradation of depolarized mitochondria through mitophagy [8,9,10]. Besides regulating mitochondrial quality control loss of PINK1 in mice directly compromises mitochondrial function [11,12,13], and PINK1 protects cells and mitochondria against oxidative stress [14,15]. We recently described PINK1 -/- mice that develop age-dependent loss of dopamine and showed that mitochondria from the brain of PINK1 -/- mice undergo increased calcium-induced permeability transition [12].…”

“…Besides regulating mitochondrial quality control loss of PINK1 in mice directly compromises mitochondrial function [11,12,13], and PINK1 protects cells and mitochondria against oxidative stress [14,15]. We recently described PINK1 -/- mice that develop age-dependent loss of dopamine and showed that mitochondria from the brain of PINK1 -/- mice undergo increased calcium-induced permeability transition [12]. Here, we further characterized mitochondrial function, structure and adaptive changes in primary mouse embryonic fibroblasts (MEF) from PINK1-deficient (PINK1 -/- ) mice.…”

Tigarb Causes Mitochondrial Dysfunction and Neuronal Loss in Pink1 Deficiency

“…29 Moderate microgliosis was reported in the only postmortem report on a brain of a PD patient with 2 PINK1 mutations. 30 Of note, several of the markedly upregulated genes in our gene expression analysis (see see Supplementary Table), such as complement factor H and calpain, are involved in immune mechanisms and activation of microglial cells.…”