Mitochondrial fission in Huntington’s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca efflux and Reactive Oxygen Species (ROS) homeostasis.

Publication date: Jan 10, 2020

Mitochondria-associated membranes (MAMs) are dynamic structures that communicate endoplasmic reticulum (ER) and mitochondria allowing calcium transfer between these two organelles. Since calcium dysregulation is an important hallmark of several neurodegenerative diseases, disruption of MAMs has been speculated to contribute to pathological features associated with these neurodegenerative processes. In Huntington’s disease (HD), mutant huntingtin induces the selective loss of medium spiny neurons within the striatum. The cause of this specific susceptibility remain unclear. However, defects on mitochondrial dynamics and bioenergetics have been proposed as critical contributors, causing accumulation of fragmented mitochondria and subsequent Ca homeostasis alterations. In the present work, we show that aberrant Drp1-mediated mitochondrial fragmentation within the striatum of HD mutant mice, forces mitochondria to place far away from the ER disrupting the ER-mitochondria association and therefore causing drawbacks in Ca efflux and an excessive production of mitochondria superoxide species. Accordingly, inhibition of Drp1 activity by Mdivi-1 treatment restored ER-mitochondria contacts, mitochondria dysfunction and Ca homeostasis. In sum, our results give new insight on how defects on mitochondria dynamics may contribute to striatal vulnerability in HD and highlights MAMs dysfunction as an important factor involved in HD striatal pathology.

Open Access PDF

Cherubini, M., Lopez-Molina, L., and Gines, S. Mitochondrial fission in Huntington’s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca efflux and Reactive Oxygen Species (ROS) homeostasis. 06877. 2020 Neurobiol Dis.

Concepts Keywords
Bioenergetics Huntingtin
Calcium Mitochondrial fission
Endoplasmic Reticulum DNM1L
ER Mitochondrion
Fragmentation Mitochondria associated membranes
Homeostasis Molecular biology
Huntingtin Cell biology
Huntington Mitochondria
Medium Spiny Neurons Branches of biology
Mice
Mitochondria
Mitochondrial
Mitochondrial Fission
Mutant
Neurodegenerative
Neurodegenerative Diseases
Organelles
Oxygen
Pathology
ROS
Species
Striatal
Striatum
Superoxide

Semantics

Type Source Name
disease MESH pathologic processes
disease MESH cognitive decline
disease MESH movement disorders
drug DRUGBANK Inositol
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK ATP
drug DRUGBANK Oxygen
disease MESH pathology
disease MESH defects
disease MESH neurodegenerative diseases
drug DRUGBANK Calcium
disease MESH Amyotrophic lateral sclerosis
disease MESH death
drug DRUGBANK 1D-myo-inositol 1 4 5-trisphosphate
drug DRUGBANK Huperzine B
disease MESH oxidative stress
drug DRUGBANK L-Glutamine
drug DRUGBANK Water
drug DRUGBANK L-Lysine
drug DRUGBANK Phosphate ion
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Glycine
drug DRUGBANK Tromethamine
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Glycerin
drug DRUGBANK Potassium Chloride
drug DRUGBANK Poloxamer 188
pathway KEGG Oxidative phosphorylation
drug DRUGBANK Sucrose
disease MESH multiple

Original Article

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