Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain.
Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the alpha-ketoglutarate dehydrogenase complex of the Krebs cycle. While studying how the DLST genotype contributes to the pathogenesis of Alzheimer's disease (AD), we found a novel mRNA that is transcribed starting from intron 7 in the DLST gene. The novel mRNA level in the brain of AD patients was significantly lower than that of controls. The truncated gene product (designated MIRTD) localized to the intermembrane space of mitochondria. To investigate the function of MIRTD, we established human neuroblastoma SH-SY5Y cells expressing a maxizyme, a kind of ribozyme, that specifically digests the MIRTD mRNA. The expression of the maxizyme specifically eliminated the MIRTD protein and the resultant MIRTD-deficient cells exhibited a marked decrease in the amounts of subunits of complexes I and IV of the mitochondrial respiratory chain, resulting in a decline of activity. A pulse-label experiment revealed that the loss of the subunits is a post-translational event. Thus, the DLST gene is bifunctional and MIRTD transcribed from the gene contributes to the biogenesis of the mitochondrial respiratory complexes.
Kanamori
Takashi
T
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan.
Nishimaki
Kiyomi
K
Asoh
Sadamitsu
S
Ishibashi
Yoshitomo
Y
Takata
Iichiro
I
Kuwabara
Tomoko
T
Taira
Kazunari
K
Yamaguchi
Haruyasu
H
Sugihara
Shiro
S
Yamazaki
Tsuneo
T
Ihara
Yasuo
Y
Nakano
Kyoko
K
Matuda
Sadayuki
S
Ohta
Shigeo
S
D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000502:physiology; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D018384:Oxidative Stress; D016716:PC12 Cells; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016337:RNA, Catalytic / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured
D021122:Protein Subunits; D016337:RNA, Catalytic; D012333:RNA, Messenger; D000217:Acyltransferases; C021515:dihydrolipoamide succinyltransferase