3. Mitochondrial Transplantation in CNS Disorder Models
During the past decade, studies examining the therapeutic potential of transplantation of isolated extracellular mitochondria in a variety of general and CNS disease models have thrived (for reviews see
[52][53][54][55] and
Table 1). The beneficial effects of exogenous mitochondrial transplantation have been demonstrated in diverse pathological models including cardiac, lung, liver, and CNS pathologies
[56][57][58][59][60][61][62][63]. In humans, a few clinical trials showed beneficial effects of autologous mitochondrial transplantation, but the follow-up period was relatively short. In infants who required ECMO support for ischemia–reperfusion-associated myocardial dysfunction, autologous mitochondrial transplantation led to an improvement in ventricular function and release from ECMO support. However, there is no information on how stable the improvement was
[64]. Another human study was performed on six children with single large-scale mitochondrial DNA (mtDNA) de novo deletion syndromes (SLSMDs), a rare and severe multisystemic disease. Mitochondrial augmentation therapy, in which the maternal mitochondria, mostly similar to those of the recipient, were transplanted into the patients’ enriched hematopoietic cells following leukapheresis, was employed. Following the transplantation procedure, partial and limited improvement in mitochondrial number and clinical symptoms was observed during 6–12 months of follow-up
[65]. In women with recurrent pregnancy failures, transplantation of autologous mitochondria to mature human oocytes with sperm at the time of intracytoplasmic sperm injection resulted in a significant improvement in the ratio of good-quality embryos and healthy normal babies
[66]. All of these studies used autologous or allogeneic maternal-derived mitochondria for transplantation rather than allogeneic mitochondria to reduce immune response and avoid heteroplasmy.
Several studies have transplanted exogenous mitochondria in various CNS experimental models. In 6-OHDA Parkinson’s disease rat model, transplantation of exogenous allogeneic and xenogeneic mitochondria coupled with Pep-1 into the medial forebrain bundle (MFB) reduced loss of dopaminergic neurons in the substantia nigra three months later, suggesting that the effect of the transplanted mitochondria spread beyond the injection site, probably due to the characteristics of the MFB, being a neural pathway containing fibers. The restoration of the dopaminergic neurons was associated with enhanced mitochondrial functions, reduced neuroinflammation, and enhanced locomotive activity
[53]. In this study, no significant difference was observed between Pep-1-coupled xenogeneic and allogeneic mitochondria-induced effects. The same group showed similar beneficial bioenergetical and behavioral effects at three to four weeks following repeated chronic (once a week for three months) intranasal injection of Pep-1-labeled mitochondria
[63]. Another study used the MPTP null mouse model of PD and intravenously injected them with exogenous mitochondria. The GFP-labeled transplanted mitochondria were distributed in various organs including the liver, kidney, muscle, and brain. MPTP mice systemically injected with mitochondria showed improved locomotion, reduced ROS generation, and restored ATP levels and complex I activity. Systemically injected mitochondria in healthy mice did not affect ATP levels nor spontaneous locomotion but significantly increased latency to immobility in the forced swimming test
[67]. Both studies showed improvements in cell survival and mitochondrial functions in cell cultures treated with the relevant toxins. Injection of exogenous mitochondria into the tail vein was also performed in a mouse model of AD, produced by intracerebroventricular injection with amyloid-beta 1–42 peptide. One to two weeks after the intravenous injections of fresh human-isolated mitochondria, AD mice exhibited significantly improved cognitive performance. Furthermore, there was a notable reduction in neuronal loss and gliosis in the hippocampus and increased activities of citrate synthase and cytochrome c oxidase in treated AD mice compared to non-treated AD mice
[60]. Acute effects of intravenous repeated transplantation of mitochondria isolated from young mice into aged mice included improved mitochondrial bioenergetics and reduced redox state, associated with ameliorated learning and motor functions in the aged mice
[68]. The protective effect of exogenous mitochondrial transplantation was also studied in experimental spinal cord injury (SCI). One study reported that up to 7 days post-transplantation, mitochondria were observed in multiple resident cell types but not in neurons. The other study detected the transplanted mitochondria up to 28 days post-transplantation in the vicinity of the lesion. One day after transplantation, a partial restoration of mitochondrial respiration as well as amelioration of mitochondrial fragmentation and cellular apoptosis were observed. Partial functional protection, assessed by tissue paring and recovery of sensory and motor function, was observed four weeks after transplantation; however, it faded after 6 weeks of follow-up
[69][70]. In traumatic brain injury, which caused mitochondrial impairments, anxiety and cognitive deficits, transplantation of allogeneic liver-isolated mitochondria restored astrocytic brain-derived neurotrophic factor (BDNF) levels and the behavioral deficits
[71].
The past decade has witnessed an abundance of studies focusing on mitochondrial abnormalities in several mental disorders including major depression and schizophrenia. A wide array of methodologies ranging from imaging through genetic, biochemical, and molecular to histological and structural techniques were used to reveal multifaceted mitochondrial dysfunction in mental disorders, specifically in schizophrenia
[72][73][74]. Hence, mitochondrial transplantation effects were also assessed in experimental models of mental disorders. In a lipopolysaccharide-induced mouse model of inflammation-induced depression, intravenous injection of exogenous mitochondria acutely reduced depressive-like behaviors assessed by forced swim, tail suspension, and sucrose preference tests. This was associated with an acute reduction in astrocyte and microglia activation and cytokines levels, higher levels of BDNF transcripts and neurogenesis, and restored mitochondrial dysfunction measured by ATP and ROS production in mouse hippocampi
[75]. We have studied the effect of exogenous allogeneic mitochondrial transplantation in schizophrenia patient-derived iPSCs (SZ-iPSCs) and in the maternal immune activation Poly I:C rat model of schizophrenia. Transplantation of mitochondria into SZ-iPSCs restored mitochondrial deficits including mitochondria respiration, ΔΨ
m, mitochondrial network dynamics, and transcript levels of specific subunits of complex I and of OPA1. Concomitantly, an enhanced efficiency of SZ-iPSCs differentiating into functional dopaminergic and glutamatergic neurons was observed. In the rat model of SZ, intra-medial prefrontal cortex (mPFC) single injection of mitochondria, in adolescent rats (34 days old), restored mitochondrial impairments and neuronal outgrowth and activity. assessed by monoamines’ transmission. in adulthood (100–120 days old). Proteomics analysis of the mPFC showed an association between the beneficial neuronal and mitochondrial effects and improved metabolic and neuronal development and plasticity pathways. Finally, mitochondrial transplantation in Poly I:C rats restored schizophrenia-related behavioral deficits such as attentional deficit and spontaneous locomotor activity in a novel environment. The behavioral changes showed a significant correlation with changes in monoamine and neuronal structural alterations. Unlike the intra-MFB injection in the PD model, the data suggest a localized effect of the transplanted mitochondria. Unexpectedly, a similar injection protocol to healthy rats induced detrimental effects in all parameters mentioned above, including behavioral, bioenergetical, and neuronal-related features. These data emphasize the importance of the bioenergetical and physiological states of the recipient in the outcome of mitochondrial transplantation. Furthermore, the opposite effects induced by mitochondrial transplantation in the schizophrenia model and healthy rats advocate for a causal link between the mitochondria and behavior, neuronal activity and plasticity
[61][62].
Table 1. Research reports on mitochondrial transplantation in CNS disease models.
Disease |
Species/Applied Model |
Source of Mitochondria |
Route of Transplantation |
Ref. |
Parkinson’s disease |
Rat |
Allogeneic/xenogeneic Pep-1-labeled mitochondria |
Injection into the medial forebrain bundle |
[76] |
Parkinson’s disease |
Mouse |
Human hepatoma cells |
Intravenous injection |
[67] |
Parkinson’s disease |
Rat |
Liver allogeneic mitochondria conjugated with Pep-1 |
Intranasal infusion |
[63] |
Alzheimer’s disease |
Mouse |
HeLa cell-derived mitochondria |
Tail intravenous injection |
[60][77] |
Cognitively impaired aged mice |
Mouse |
Liver allogeneic mitochondria isolated from young mice |
Injected into the hippocampus of aged mice |
[78] |
Diabetes-associated cognitively impaired mice |
Mouse |
Platelet-derived mitochondria |
Intracerebroventricular injection |
[79] |
Chronic mild stressed—aged rats |
Rat |
Brain-derived mitochondria from young rats |
Injected intracerebroventricularly in aged rats |
[80] |
Aging |
Mouse |
Liver-derived allogeneic mitochondria from young rats |
Intravenous injection |
[68] |
CNS injury |
Mouse |
Cerebral cortex-derived allogeneic mitochondria whose DJ1 protein was modified with O-GlcNAcylation |
Intraventricular injection |
[81] |
Traumatic brain injury |
Mouse |
Liver/muscle-derived autologous mitochondria |
Injected into the cerebral cortex |
[71] |
Brain stroke |
Mouse |
Bone marrow mesenchymal stem cell-derived allogenic mitochondria |
Intranasal administration |
[82] |
Schizophrenia |
Rat |
Rat brain-derived allogeneic mitochondria |
Bilateral injection of into medial prefrontal cortex |
[61][62] |
Lipopolysaccharide (LPS)-induced model of depression |
Mouse |
Hippocampus-derived allogeneic mitochondria |
Intravenous injection |
[75] |
Spinal cord injury |
Rat |
Soleus muscle-derived allogeneic mitochondria |
Injected into spinal cord |
[69] |
Spinal cord ischemia |
Rat |
Soleus muscle-derived allogeneic mitochondria |
Intravenous transplantation via the jugular vein |
[83] |
Spinal cord injury |
Rat |
Soleus muscle-derived allogenic mitochondria |
Injection into spinal cord via intraparenchymal route |
[70] |
Neuromuscular limb injury |
Mouse |
NR |
Systemic injection |
[84] |
Lower limb ischemia–reperfusion injury |
Mouse |
Human umbilical cord mesenchymal stem cell-derived mitochondria |
Gastrocnemius muscle injection |
[85] |
Optic nerve injury |
Rat |
Liver-derived allogeneic mitochondria |
Intravitreal injections |
[86] |
Mitochondria transplantation in humans |
Recurrent pregnancy failure cases |
Human |
Ovarian cortical tissue-derived autologous mitochondria |
Mitochondria transferred to human oocytes, intracytoplasmic sperm injection |
[66] |
Ischemia–reperfusion-associated myocardial dysfunction |
Human (infants) |
Rectus abdominis muscle-derived autologous mitochondria |
Injected into the myocardium affected by ischemia–reperfusion |
[64] |
Single large-scale mitochondrial DNA (mtDNA) de novo deletion syndromes (SLSMDs) |
Human (infants) |
Maternal PBMC-derived mitochondria transplanted into the patients’ enriched CD34+ cells after leukapheresis |
Transfused into patients |
[65] |