2 November 2010. In a paper published in the October 12 issue of PNAS, a team of researchers at Pohang University of Science and Technology in Korea propose that the schizophrenia susceptibility gene DISC1 interacts with the mitochondrial inner-membrane protein mitofilin, and that underexpression or mutation of DISC1 may cause mitochondrial defects underlying some of the neurodevelopmental and neurophysiological phenotypes seen in schizophrenia.
Mitochondria serve such diverse and vital cellular roles that any compromise in their function may have profound effects. Besides their well-known job as ATP-generating “power plants,” mitochondria are involved in cell differentiation and growth, apoptosis, calcium regulation, and more. Researchers have identified a number of intriguing correlations between various forms of mitochondrial dysfunction and schizophrenia, but there has been little evidence of causal links.
Members of David Porteous’s University of Edinburgh lab, where DISC1 was cloned in 2000 (Millar et al., 2000), reported four years later that DISC1 protein is primarily expressed in mitochondria (James et al., 2004), and they proposed that DISC1 mutations affecting the normal function of this essential organelle could play a fundamental role in schizophrenia.
At about the same time, Akira Sawa’s group at Johns Hopkins showed that DISC1 exerts its effects by forming complexes with proteins including the cytoskeletal protein NUDEL, or NDEL1. Mice carrying a truncated form of DISC1 that did not bind with NDEL1 exhibited abnormal neurite outgrowth and cortical development (Ozeki et al., 2003; also see SRF related news story). In a subsequent genomic study of patients, Sawa, Anil Malhotra, and colleagues reported an association between a DISC1 allele that reduces NDEL1 binding and schizophrenia (Burdick et al., 2008).
In parallel, many differences in mitochondrial structure and function have been observed in populations of patients with schizophrenia and with bipolar disorder. These findings, cataloged in a forthcoming review by Christine Kondradi and colleagues at Vanderbilt University (Clay et al., 2010), include reduced mitochondrial respiration; morphological abnormalities; more frequent mutations in mitochondrial DNA; and higher pH levels in postmortem brain samples.
Mark Vawter’s group at the University of California, Irvine, reported recently that synonymous base-pair substitutions in mitochondrial DNA were 22 percent more common in samples of dorsolateral prefrontal cortex from patients with schizophrenia compared to controls. In another postmortem study, Rosalinda Roberts and colleagues found that the overall number of mitochondria in striatal cells was similar in controls and patients with schizophrenia, but the number of mitochondria at striatal synapses was significantly reduced in patients (Somerville et al., 2010). (However, the researchers could not rule out that this difference is not an effect of antipsychotic medication or a compensatory response to the greater numbers of striatal synapses in patients with schizophrenia that they had reported in an earlier postmortem study.)
This accumulating evidence for an important mitochondrial role in schizophrenia is accompanied by a compelling reverse correlation: the physical symptoms in mitochondrial diseases are often accompanied by psychiatric disorders (Fattal et al., 2006).
First identified and characterized in the 1990s (Odgren et al., 1996; Gieffers et al., 1997), mitofilin is essential to normal mitochondrial function and morphology; knockdown of mitofilin results in reduced cell proliferation, increased apoptosis, and disorganization of the distinctive folds of the mitochondrial inner membrane known as cristae (John et al., 2005).
In the new work, led by Sang Ki Park, the researchers used several assays to screen for proteins that interact with NDEL1, then tested whether any of these proteins also interact with DISC1. One, mitofilin, interacted strongly with a region of DISC1, a finding that was corroborated by several additional assays. The group then established that a DISC1-mitofilin complex was selectively expressed in mitochondria.
With these findings in hand, the team generated short hairpin RNAs (shRNAs) to suppress DISC1 or mitofilin expression in a mouse neural cell line. Either shRNA significantly reduced activity of mitochondrial NADH hydrogenase and sharply reduced levels of ATP in cell samples, effects also seen in mice carrying a truncated form of DISC1. These disruptions of mitochondrial metabolism could be partially rescued by the coexpression of human DISC1 or mitofilin. The shRNAs against DISC1 and mitofilin also significantly reduced monoamine oxidase A (MAO-A) activity, but MAO-A activity was not significantly lower in cells with the truncated form of DISC1.
Because of the known effects of reduced expression of mitofilin on cell proliferation and apoptosis, the authors ruled out that the lower levels of ATP, NADH hydrogenase, or MAO-A might be due to smaller cell populations in the tested samples. Despite observations of abnormal mitochondrial morphology, they found no reduction in the number of cells or increase in apoptotic activity compared to controls.
Finally, the group used time-lapse imaging to measure DISC1-mitofilin effects on mitochondrial calcium regulation. When the researchers induced rapid increases in intracellular calcium concentration, calcium levels smoothly decreased to basal levels within five minutes. But shRNA-transfected cells exhibited an abnormal pattern of fluctuating calcium levels and a significantly delayed return to basal levels.
Of these various findings, the authors single out the reduction in MAO-A activity as the most interesting in a clinical context, since this observation dovetails well with the dopamine hypothesis of schizophrenia. “Downregulation of MAO-A by compromised functioning of the DISC1-mitofilin complex, which is likely to cause upregulated monoamine contents in monoaminergic neurons, may help explain the cellular basis underlying schizophrenia-associated neurochemical disturbances,” they write. “Thus, a direct link between abnormalities of DISC1 and dopamine homeostasis should be of immediate interest.”—Pete Farley.
Park YU, Jeong J, Lee H, Mun JY, Kim JH, Lee JS, Nguyen MD, Han SS, Suh PG, Park SK. Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17785-90. Abstract