Review: Genes Involved in Mitochondrial Physiology Within 22q11.2 Deleted Region and Their Relevance to Schizophrenia

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.

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.

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.

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.