Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

Abstract

G72 is a strong candidate susceptibility gene for schizophrenia and bipolar disorder, whose function remains enigmatic. Here we show that one splicing isoform of the gene (LG72 ) encodes for a mitochondrial protein. We also provide convergent lines of evidence that increase of endogenous or exogenous G72 levels promotes robust mitochondrial fragmentation in mammalian cell lines and primary neurons, which proceeds in a manner that does not depend on induction of apoptosis or alteration in mitochondrial transmembrane potential. Finally, we show that increase in G72 levels in immature primary neurons is accompanied by a marked increase in dendritic arborization. By contrast, we failed to confirm the originally proposed functional interaction between G72 and D-amino acid oxidase (DAO) in two tested cell lines. Our results suggest an alternative role for G72 in modulating mitochondrial function.

N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice

“…G72 gene in schizophrenia and BPAD D-M Otte et al localization signal at the N terminus and is located in the mitochondria (Kvajo et al, 2008). This is supported by our results showing a mitochondrial localization of LG72 upon expression in mouse neuroblastoma cells.…”

“…Given the mitochondrial localization of heterologously expressed LG72 in human (Kvajo et al, 2008) and mouse cells (Supplementary Figure S1A), these findings suggested the possibility that LG72 affected mitochondrial function and lead to an increased production of ROS. We therefore investigated mitochondrial density and expression of mitochondrial marker enzymes in G72Tg mice.…”

“…Experiments performed in neuronal cultures also showed that it affects mitochondrial morphology (Kvajo et al, 2008).…”

“…It encodes two genes, G72 and G30, that are transcribed contrariwise from overlapping DNA strands (reviewed in Abou Jamra et al, 2006). LG72, the longest open reading frame, represents an exceptional case of a primate-specific gene with a rapidly changing protein structure, probably related to a rapid evolution of underlying brain function (Kvajo et al, 2008). Although the N terminus of the protein is well conserved among anthropoid primates, variations in the C terminus result in proteins of different sizes.…”

Mitochondrial involvement in psychiatric disorders

“…There have been no studies to date examining morphological or morphometric abnormalities in BPD or MDD lymphocytes. Interestingly, two strong schizophrenia candidate genes, Disrupted in Schizophrenia 1 (DISC1) and G72, have splicing isoforms that are targeted to mitochondria although the exact functions of these proteins in the mitochondria remain unknown (41,42).…”