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WCPG 2015—A Moment for Mitochondria in Schizophrenia Etiology

19 Oct 2015

October 20, 2015. The idea that problems with mitochondria drive brain pathology in schizophrenia and other psychiatric disorders was an emergent theme at the 23rd annual World Congress of Psychiatric Genetics in Toronto, Canada, with a symposium and a plenary talk devoted to the possibility. Given that the brain is an energy-hungry organ, any problems with energy production would have consequences. Genetic studies could help get at whether metabolism problems are cause or consequence, but while they probe over 1,000 mitochondria-related genes contained in nuclear DNA, they don't typically survey the circular DNA (mtDNA) that resides within each mitochondrion. MtDNA contains 37 genes, which encode proteins essential for oxidative-phosphorylation reactions that produce cellular energy, in the form of ATP.

In the symposium on Sunday, October 18, Vanessa Goncalves of University of Toronto presented her attempt to find signals in mtDNA associated with schizophrenia in a Swedish case-control sample of 10,000 people. Using an exome array, Goncalves probed both common and rare variants but came up with nothing significant. Because mtDNA reflects ancestry, looking at "haplogroups"—people with shared patterns of SNPs in mtDNA—may prove important. Goncalves reported a nominally significant association in a subgroup of Europeans but suggested the search needs a larger sample size.

Marquis Vawter of University of California, Irvine, followed with a compilation of results supporting a link between mitochondria and schizophrenia. Applying next-generation sequencing to mtDNA has turned up a surplus of non-synonymous mutations in schizophrenia compared to controls (Sequeira et al., 2015), and a spectrum of as-yet uninvestigated deletions has also emerged. Vawter also presented microscopy results showing that the tight association between synaptic junctions and mitochondria location is disrupted in schizophrenia and suggested that mitochondrial hypofunction characterizes the disorder.

Noting that the brain needs a lot of ATP to support neurotransmission, Dost Ongur of Harvard Medical School presented a brainwide view of energy metabolism using a technique called phosphorus magnetic resonance spectroscopy. This approach obtains a readout of how well the brain draws from energy sources: specifically, it probes the activity of creatine kinase, which converts phosphocreatine into ATP. Ongur's previous work has shown that the brains of people with schizophrenia are less efficient at this conversion (Du et al., 2014), and his preliminary results suggest a somewhat similar situation in the early days of illness. He suggested that this deficit in baseline energy metabolism might be further exacerbated with stimulation-induced brain activation.

The final speaker of the symposium, Dorit Ben-Shachar of Rambam Health Campus and Technion Israel Institute of Technology, Israel, reviewed her previous work associating abnormal energy production in neurons with schizophrenia, including data from hair follicle-derived induced pluripotent stem cells (iPSCs) differentiated into neurons. Neurons from people with schizophrenia failed to differentiate or mature properly, and mitochondrial abnormalities occurred alongside these deficits (Robicsek et al., 2013). Ben-Shachar presented new results showing that introducing healthy mitochondria to these derived neurons in vitro normalized their metabolism and resulted in improved neural differentiation and maturation, highlighting a relationship between cell metabolism and neural development.

On Monday morning, October 19, Doug Wallace of Children's Hospital of Philadelphia gave a plenary talk proposing that problems with bioenergetics could underpin complex diseases. He also offered an explanation for the variable expressivity that accompanies many disorders in the form of heteroplasmy: The mtDNA present in each mitochondrion may vary, with some containing mutations not shared with others. Using Leber's Optic Neuropathy as an example, he suggested that a cell could compensate for an mtDNA mutation deleterious to metabolism to some extent, but once enough mitochondria contained the mutation, the cell would struggle. In the question period, he maintained that attempts to find associations with mtDNA and other disorders often fail because the analyses do not take into account the fact that mtDNA is inherited differently from nuclear DNA.—Michele Solis.