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Kir6.2 is essential to maintain neurite features by modulating PM20D1-reduced mitochondrial ATP generation
- Source :
- Redox Biology, Redox Biology, Vol 47, Iss, Pp 102168-(2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- Kir6.2, a pore-forming subunit of the ATP-sensitive potassium (KATP) channels, regulates the functions of metabolically active tissues and acts as an ideal therapeutic target for multiple diseases. Previous studies have been conducted on peripheral kir6.2, but its precise physiological roles in the central nervous system (CNS) have rarely been revealed. In the current study, we evaluated the neurophenotypes and neuroethology of kir6.2 knockout (kir6.2−/−) mice. We demonstrated the beneficial effects of kir6.2 on maintaining the morphology of mesencephalic neurons and controlling the motor coordination of mice. The mechanisms underlying the abnormal neurological features of kir6.2 deficiency were analyzed by RNA sequencing (RNA-seq). Pm20d1, a gene encoding PM20D1 secretase that promotes the generation of endogenous mitochondria uncouplers in vivo, was dramatically upregulated in the midbrain of kir6.2−/− mice. Further investigations verified that PM20D1-induced increase of N-acyl amino acids (N-AAAs) from circulating fatty acids and amino acids promoted mitochondrial impairments and cut down the ATP generation, which mediated the morphological defects of the mesencephalic neurons and thus led to the behavioral impairments of kir6.2 knockout mice. This study is the first evidence to demonstrate the roles of kir6.2 in the morphological maintenance of neurite and motor coordination control of mice, which extends our understanding of kir6.2/KATP channels in regulating the neurophysiological function.<br />Graphical abstract Graphical abstract of the physiological roles of kir6.2 in the CNS. Kir6.2 deficiency induces predominant deficits in the architecture of midbrain neurites via PM20D1-induced N-AAAs increase and ATP shortage, thus decreasing movement abilities of mice.Image 1
- Subjects :
- Kir6.2
Medicine (General)
endocrine system
Neurite
QH301-705.5
Clinical Biochemistry
Central nervous system
Mitochondrion
Biochemistry
Amidohydrolases
Mice
R5-920
Adenosine Triphosphate
Downregulation and upregulation
KATP Channels
medicine
Neurites
Animals
Biology (General)
Potassium Channels, Inwardly Rectifying
PM20D1
Mice, Knockout
biology
Chemistry
Organic Chemistry
Motor coordination
Cell biology
Mitochondria
Mitochondrial uncoupling
medicine.anatomical_structure
Knockout mouse
biology.protein
cardiovascular system
Amyloid precursor protein secretase
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....2442c052f94ac2c17b7ea876c268ec57