Mitochondrial deficits in human iPSC-derived neurons from patients with 22q11.2 deletion syndrome and schizophrenia

Abstract

Schizophrenia (SZ) is a highly heterogeneous disorder in both its symptoms and risk factors. One of the most prevalent genetic risk factors for SZ is the hemizygous microdeletion at chromosome 22q11.2 (22q11DS) that confers a 25-fold increased risk. Six of the genes directly disrupted in 22qDS encode for mitochondrial-localizing proteins. Here, we test the hypothesis that stem cell-derived neurons from subjects with the 22q11DS and SZ have mitochondrial deficits relative to typically developing controls. Human iPSCs from four lines of affected subjects and five lines of controls were differentiated into forebrain-like excitatory neurons. In the patient group, we find significant reductions of ATP levels that appear to be secondary to reduced activity in oxidative phosphorylation complexes I and IV. Protein products of mitochondrial-encoded genes are also reduced. As one of the genes deleted in the 22q11.2 region is MRPL40, a component of the mitochondrial ribosome, we generated a heterozygous mutation of MRPL40 in a healthy control iPSC line. Relative to its isogenic control, this line shows similar deficits in mitochondrial DNA-encoded proteins, ATP level, and complex I and IV activity. These results suggest that in the 22q11DS MRPL40 heterozygosity leads to reduced mitochondria ATP production secondary to altered mitochondrial protein levels. Such defects could have profound effects on neuronal function in vivo.

Zebrafish as a tool to study schizophrenia-associated copy number variants

“…Finally, hiPSC studies generally use few patient-derived lines, making it difficult to know how generalizable and robust results are, and the rules governing the self-organization of brain organoids are not yet fully understood, making it difficult to extrapolate findings to in vivo models. To date, several studies have generated hiPSCs from patients with 22q11.2 deletion with findings including disrupted microRNA processing (Zhao et al, 2015), cellular migration, neurite outgrowth, neural differentiation, neurogenic-to-gliogenic competence (Toyoshima et al, 2016) and mitochondrial dysfunction (Li et al, 2019). To our knowledge, brain organoids have not yet been used to study CNVs associated with schizophrenia.…”

“…These studies largely relied on transient gene knockdown with morpholinos (MOs) and overexpression experiments to mimic gene deletion and duplication and subsequently analyzed phenotypes of interest in early embryos/larvae in an attempt to identify genes causative for specific disorder phenotypes. In recent years, MO approaches have been called into question due to offtargeting effects (Li et al, 2019) and discrepancies between mutant and morphant phenotypes (Kok et al, 2015;Stainier et al, 2017). Furthermore, ubiquitous overexpression can lead to expression in a variety of cell types and, thus, phenotypic confounds.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…Activation of these reaction chains leads to increased ATP synthesis [216]. These disorders are associated with working memory deficits and changes in the short-term hippocampus strengthening [218] and impairment of motor skills [219].…”

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

“…In contrast, MRPL40 is a protein of the large subunit of the mitochondrial ribosome whose function is necessary for mitochondrial protein synthesis in eukaryotes (Amunts et al, 2014;Jia et al, 2009). MRPL40 function has been implicated in mitochondrial respiration in neurons and calcium buffering at the synapse (Devaraju et al, 2017;Li et al, 2019). We demonstrate that deletion of human SLC25A1 compromises the integrity of the mitochondrial ribosome, downregulating the expression of multiple ribosome subunits, including MRPL40.…”