Key result
22q11.2 haploinsufficiency is linked to altered mitochondrial function, implying a causal role in schizophrenia.
Why the study?
Schizophrenia is associated with altered energy metabolism, but the cause and potential impact of these metabolic changes remain unknown.
Haploinsufficiency of genes within the 22q11.2 region leads to mitochondrial dysfunction, suggesting a causal role in the development of schizophrenia in 22q11.2 deletion syndrome.
Supports mitochondrial hypotheses in 22q11.2DS; hypothesis-generating and should not yet change practice.
BACKGROUND AND HYPOTHESIS: Schizophrenia is associated with altered energy metabolism, but the cause and potential impact of these metabolic changes remain unknown. 22q11.2 deletion syndrome (22q11.2DS) represents a genetic risk factor for schizophrenia, which is associated with the loss of several genes involved in mitochondrial physiology. Here we examine how the haploinsufficiency of these genes could contribute to the emergence of schizophrenia in 22q11.2DS. STUDY DESIGN: We characterize changes in neuronal mitochondrial function caused by haploinsufficiency of mitochondria-associated genes within the 22q11.2 region (PRODH, MRPL40, TANGO2, ZDHHC8, SLC25A1, TXNRD2, UFD1, and DGCR8). For that purpose, we combine data from 22q11.2DS carriers and schizophrenia patients, in vivo (animal models) and in vitro (induced pluripotent stem cells, IPSCs) studies. We also review the current knowledge about seven non-coding microRNA molecules located in the 22q11.2 region that may be indirectly involved in energy metabolism by acting as regulatory factors. STUDY RESULTS: We found that the haploinsufficiency of genes of interest is mainly associated with increased oxidative stress, altered energy metabolism, and calcium homeostasis in animal models. Studies on IPSCs from 22q11.2DS carriers corroborate findings of deficits in the brain energy metabolism, implying a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS. CONCLUSIONS: The haploinsufficiency of genes within the 22q11.2 region leads to multifaceted mitochondrial dysfunction with consequences to neuronal function, viability, and wiring. Overlap between in vitro and in vivo studies implies a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS.
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Kolář et al. (2023) conducted a review in Schizophrenia and 22q11.2 deletion syndrome. Haploinsufficiency of mitochondria-associated genes within the 22q11.2 region was evaluated on Mitochondrial function, oxidative stress, energy metabolism, and calcium homeostasis. Haploinsufficiency of genes within the 22q11.2 region is associated with increased oxidative stress, altered energy metabolism, and calcium homeostasis, implying a causal role in schizophrenia.
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