Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

Abstract

that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders.OBJECTIVE To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). DESIGN, SETTING, AND PARTICIPANTSThis case-control study compared measures of mitochondrial function and the expression of related genes in 14 induced pluripotent stem cell-derived neurons from typically developing control individuals (6 lines) and from adults with 22q11DS (8 lines). The individuals with 22q11DS included 2 groups, those carrying a diagnosis of schizophrenia and those without this diagnosis (4 lines each). Similar measures were made of lymphoblastic cells lines (LCLs) from a separate group of adults with 22q11DS with (10 lines) or without (8 lines) schizophrenia. The study included samples derived from a clinical setting. The induced pluripotent stem cell lines were derived from individuals with 22q11DS with or without a diagnosis of schizophrenia at Stanford University. The LCLs were from adults within the 22q and You Center at the Children's Hospital of Philadelphia. Data were analyzed between July 1, 2019, and January 24, 2021.MAIN OUTCOMES AND MEASURES Total adenosine triphosphate (ATP), oxidative phosphorylation (OXPHOS) complex activity, and messenger RNA expression via reverse transcription-polymerase chain reaction of selected genes encoding for mitochondrial proteins.RESULTS Study participants included men and women aged 18 to 37 years. Of 32 participants, the mean (SD) age of men was 27 (1.9) years and of women was 29 (1.2) years. Replicating a previous study, neurons from the 22q11DS and schizophrenia (22q+Sz) group had reduced ATP levels (mean [SD], 15.6 [1.5] vs 21.9 [1.4]; P = .02) and reduced OXPHOS activity (ie, complex I; 1.51 [0.1] vs 1.89 [0.1]; P = .01). These deficits were not present in neurons from individuals with 22q11DS without schizophrenia (22q[−]Sz). In this group, the expression of multiple genes encoding OXPHOS subunits was significantly upregulated. For example, compared with control individuals, NDUFV2 expression was increased by 50% in the 22q(−)Sz group (P < .001) but not significantly changed in the 22q+Sz group. Expression of genes driving mitochondrial biogenesis, including PGC1α, showed a similar pattern of upregulation in the 22q(−)Sz group compared with the control and the 22q+Sz groups. Stimulation of mitochondrial biogenesis normalizes the ATP deficit seen in 22q+Sz neurons. Finally, using LCLs from a separate group of adults with 22q11DS, evidence for enhanced mitochondrial biogenesis was again found in the 22q(−)Sz group. CONCLUSIONS AND RELEVANCEIn this study, an increase in mitochondrial biogenesis and function was associated with the absence of schizophrenia in neurons and LCLs from individuals with 22q11DS, but the deficit in the 22q+Sz group was reversible by agents that enhance mitochondrial biogenesis....

Emerging evidence for astrocyte dysfunction in schizophrenia

“…Consistent with a possible role of PGC-1α in the 22q11DS, recent results obtained from iPSC derived neurons of 22q11patients with or without SCZ have shown that variable penetrance to the development of SCZ is influenced by compensatory mitochondrial biogenesis that occurs in patients with 22q11DS without SCZ (Li et al, 2021). Indeed, in the 22q11DS without SCZ, expression of nuclear genes encoding ETC subunits, and of multiple mitochondrial encoded genes, were upregulated, as was mitochondrial DNA content and the expression of genes affecting mitochondrial biogenesis and function, such as PGC-1α and PPARα, in human induced pluripotent stem cells (hiPSC) from the 22q11DS without SCZ, thus suggesting that the 22q11DS group without SCZ is characterized by effective compensation for the various mitochondrial abnormalities present in the 22q11DS group with SCZ.…”

“…Among the most important risk factors for SCZ, abnormalities in energy mitochondrial metabolism have been found in functional assays and in magnetic resonance spectroscopy studies on SCZ patients (Jensen et al, 2006;Maurer et al, 2001;Öngür et al, 2009;Regenold et al, 2009, Adams et al, 2022 and an analysis of several published studies on genomic, transcriptomic, and proteomic factors associated with SCZ revealed 295 genes that mediate mitochondrial structure or function (Hjelm et al, 2015;Lam et al, 2019;Li et al, 2021;Schulmann et al, 2019;Vawter et al, 2021). Moreover, 22 genes encoding mitochondrial proteins have been mapped within the 108 risk loci (encompassing more than 300 genes) identified by the largest SCZ genome-wide association studies (GWAS) to date (Hjelm et al, 2015;Lam et al, 2019;Li et al, 2021;Ripke et al, 2013;Schulmann et al, 2019;Vawter et al, 2021) and further studies show a decrease of factors and enzymes involved in the production of energy (i.e., adenosine triphosphate-ATP-generation and storage) (Iwamoto et al, 2005;Karry et al, 2004;Klushnik et al, 1991;Middleton et al, 2002;Pennington et al, 2008;Washizuka et al, 2009). Alterations in mitochondrial activity have been consistently reported in SCZ patients: for example, reduced energy metabolism has been reported in patients with psychosis (Regenold et al, 2012) and phosphorous magnetic resonance studies (31P-MRS) reported lower levels of ATP and phosphocreatine in brain of patients with SCZ (Volz et al, 2000).…”

“…This has given rise to the hypothesis that SCZ may need to be studied in the context of developmental processes, and that interventions aimed at promoting normal brain development during late adolescence may prevent the pathological process (Gomes et al, 2019;Hadar et al, 2018;Millan et al, 2016;Owen et al, 2011;Tamura et al, 2016;Uhlhaas & Singer, 2011). Linkage analysis and gene expression studies suggest that a network of 160 genes contribute to the etiology of the disease (Hjelm et al, 2015;Lam et al, 2019;J. Li et al, 2021;Li et al, 2017;Pardiñas et al, 2018;Periyasamy et al, 2019;Ripke et al, 2013;Rodriguez-Murillo et al, 2012;Schulmann et al, 2019;Singh et al, 2022;J.…”

“…mitochondrial dysfunctions have been found in iPSC-derived neurons from individuals with 22q11DS with SCZ versus healthy control individuals(Li et al, 2021) and reduced ATP levels and reduced activity of complexes I and IV of the ETC have been found in patient-derived neurons. Overall, these results suggest that mitochondrial deficits may contribute to the development of SCZ in the context of 22q11DS but still no studies to date have indicated whether mitochondrial dysfunctions mediate the altered developmental mechanisms of the PFC as a result of the diminished number of 22q11 genes.…”

Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection

“…The potential beneficial effects of up regulating mitochondrial function have been suggested by the rapamycin inhibition of mTORC1 which decreased viral replication ( 23 ). Viral pathology might also be mitigated by neutralizing miR-2393 ( 34 ) and activation of mitochondrial biogenesis with bezafibrate ( 56 ).…”