Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder

Abstract

Dysfunction of mitochondria, key players in various essential cell processes, has been repeatedly reported in schizophrenia (SZ). Recently, several studies have reported functional recovery and cellular viability following mitochondrial transplantation, mostly in ischemia experimental models. Here, we aimed to demonstrate beneficial effects of isolated active normal mitochondria (IAN-MIT) transfer in vitro and in vivo, using SZ-derived induced pluripotent stem cells (iPSCs) differentiating into glutamatergic neuron, as well as a rodent model of SZ. First, we show that IAN-MIT enter various cell types without manipulation. Next, we show that IAN-MIT transfer into SZ-derived lymphoblasts induces long-lasting improvement in various mitochondrial functions including cellular oxygen consumption and mitochondrial membrane potential (Δ ψ m). We also demonstrate improved differentiation of SZ-derived iPSCs into neurons, by increased expression of neuronal and glutamatergic markers β3-tubulin, synapsin1, and Tbr1 and by an activation of the glutamate-glutamine cycle. In the animal model, we show that intra-prefrontal cortex injection of IAN-MIT in adolescent rats exposed prenatally to a viral mimic prevents mitochondrial Δ ψ m and attentional deficit at adulthood. Our results provide evidence for a direct link between mitochondrial function and SZ-related deficits both in vitro and in vivo and suggest a therapeutic potential for IAN-MIT transfer in diseases with bioenergetic and neurodevelopmental abnormalities such as SZ.

Mitochondrial Dysfunction in Schizophrenia

“…[ 108,109 ] In addition to the genetic models of mitochondria abnormalities, the maternal immune activation (MIA) model of SCZ presents a significant mitochondrial dysfunction [ 110 ] that leads to multiple SCZ‐relevant neurobehavioral deficits, [ 111,112 ] which were restored by the intra‐PFC injection of isolated normal mitochondria. [ 113 ] The above studies suggest that mitochondrial dysfunction plays a causal role in generating SCZ‐like neurobehavioral deficits.…”

“…Furthermore, not only do chemicals that boost mitochondrial function result in recovery in SCZ‐like behavioral deficits, but the transfer of isolated active normal mitochondria into the brains of MIA model rats also resulted in neurobehavioral recovery, accompanied by the functional restoration of mitochondria. [ 113 ] The fact that disturbance of mitochondrial function results in SCZ‐relevant neurobehavioral abnormalities, and that one can rescue SCZ‐like behavioral deficits by restoring mitochondrial function further suggests the causal role of mitochondrial dysfunction in various SCZ‐relevant neurobehavioral abnormalities. All these animal studies point to the fact that chemicals that enhance mitochondrial function can serve as a valid therapeutic target for mitochondria‐related deficits in SCZ ( Table 5 ).…”

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

“…A mitochondria transfer to patient’s cells with SZ showed the cells receiving mitochondria transfer from controls had a higher mitochondria membrane potential compared to the same cells that did not receive a mitochondria transfer [77]. Mitochondria membrane potential is maintained at sufficiently high levels to promote ADP to ATP conversion.…”

Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells

“…To assess the cause-effect relationship for mitochondrial dysfunction in SCZ, Robicek et al [ 84 ] most recently investigated mitochondria transfer to SCZ-iPSC derived neurons [ 78 ]. Several studies have shown that mitochondria can transfer between cells via various contact modes, comprising cell fusion, junction, and tunneling nanotube formation [ 103 ].…”