Open AccessDefects in GABA metabolism affect selective autophagy pathways and are alleviated by m TOR inhibition
Author(s) -
Lakhani Ronak,
Vogel Kara R,
Till Andreas,
Liu Jingjing,
Burnett Sarah F,
Gibson K Michael,
Subramani Suresh
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303356
Subject(s) - mitophagy , autophagy , microbiology and biotechnology , biology , mitochondrion , tor signaling , glutamate receptor , gamma aminobutyric acid , kinase , signal transduction , oxidative stress , biochemistry , receptor , apoptosis
Abstract In addition to key roles in embryonic neurogenesis and myelinogenesis, γ‐aminobutyric acid ( GABA ) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6 K 1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase ( SSADH )‐deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced m TOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA .