Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations.

Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations.

Publication date: Jun 09, 2019

PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson’s disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing.We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions.In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions.The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.

, Gonz’alez-Casacuberta, Ju’arez-Flores, D.L., Ezquerra, M., Fucho, R., Catal’an-Garc’ia, M., Guitart-Mampel, M., Tob’ias, E., Garc’ia-Ruiz, C., Fern’andez-Checa, J.C., Tolosa, E., Mart’i, M.J., Grau, J.M., Fern’andez-Santiago, R., Cardellach, F., Mor’en, C., and Garrabou, G. Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations. 21110. 2019 Aging (Albany NY).

Concepts Keywords
Albany Branches of biology
Autophagic Cellular respiration
Autophagy Cell biology
Basal Programmed cell death
Bioenergetics Autophagy
Dopaminergic Immunology
E3 Ubiquitin Ligase Parkin
Fibroblasts Mitochondrion
Flux Glycolysis
Galactose Autophagosome
Glucose Ageing
Glycolytic
Homeostasis
Mitochondrial
Mutation
Neuron
Neurons
Oxidative Stress
Parkinson
Pathogenesis
Phenotype
PRKN
Respiration
Substrate

Semantics

Type Source Name
pathway BSID Oxidative Stress
disease MESH oxidative stress
drug DRUGBANK Galactose
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
disease MESH multiple
gene UNIPROT PRKN
drug DRUGBANK Profenamine
drug DRUGBANK Trihexyphenidyl
disease DOID Parkinson disease
disease MESH Parkinson disease

Original Article

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