NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia.

Mitochondria together with other cellular components maintain a constant crosstalk, modulating transcriptional and posttranslational processes. We and others demonstrated mitochondrial multifaceted dysfunction in schizophrenia, with aberrant complex I (CoI) as a major cause. Here we show deficits in CoI activity and homeostasis in schizophrenia-derived cell lines. Focusing on a core CoI subunit, NDUFV2, one of the most severely affected subunits in schizophrenia, we observed reduced protein level and functioning, with no change in mRNA transcripts. We further show that NDUFV2 pseudogene (NDUFV2P1) expression is increased in schizophrenia-derived cells and in postmortem brain specimens. In schizophrenia and controls pooled samples, NDUFV2P1 level demonstrated a significant inverse correlation with NDUFV2 pre- and matured protein level and with CoI-driven cellular respiration. Our data suggest a role for a pseudogene in its parent-gene regulation and possibly in CoI dysfunction in schizophrenia. The abnormal expression of the pseudogene may be one element of a vicious circle in which CoI deficits lead to mitochondrial dysfunction potentially affecting genome-wide regulation of gene expression, including the expression of pseudogenes.