TY - JOUR
T1 - Alcohol withdrawal and cerebellar mitochondria
AU - Jung, Marianna E.
N1 - Funding Information:
This work was supported by grants from the National Institute of Health (AA018747) and UNTHSC Institute for Aging and Alzheimer’s disease (IAADR-002). I wish to thank Daniel Metzger for his editorial assistance. I apologize to research groups whose contributions are not referred in this review due to space limitation.
Publisher Copyright:
© Springer Science+Business Media New York 2014.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Cerebellar disorders trigger the symptoms ofmovement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca2+ level and a decrease in a Ca2+-binding protein, both of which result in the excessive entry of Ca2+ to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellumunder the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondriatargeting research may help develop a powerful new therapy to manage cerebellar disorders associated with hyperexcitatory CNS disorders like ethanol withdrawal.
AB - Cerebellar disorders trigger the symptoms ofmovement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca2+ level and a decrease in a Ca2+-binding protein, both of which result in the excessive entry of Ca2+ to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellumunder the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondriatargeting research may help develop a powerful new therapy to manage cerebellar disorders associated with hyperexcitatory CNS disorders like ethanol withdrawal.
KW - Apoptosis. Ca. Cerebellum
KW - Ethanol withdrawal
KW - Glutamate
KW - Granular cells
KW - Mitochondria
KW - Purkinje neurons
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=84943175102&partnerID=8YFLogxK
U2 - 10.1007/s12311-014-0598-8
DO - 10.1007/s12311-014-0598-8
M3 - Review article
C2 - 25195804
AN - SCOPUS:84943175102
SN - 1473-4222
VL - 14
SP - 421
EP - 437
JO - Cerebellum
JF - Cerebellum
IS - 4
M1 - A001
ER -